Outcomes and Complications in Surgical and Urological Procedures

Outcomes and complications in surgical and urological procedures

Karl-Johan Lundström

Institutionen för kirurgisk och perioperativa vetenskaper Umeå 2017

Responsible publisher under swedish law: the Dean of the Medical Faculty This work is protected by the Swedish Copyright Legislation (Act 1960:729) ISBN: 978-91-7601-717-3 ISSN: 0346-6612 1HZ6HULHV1R1899 Omslagsbild: Anna Erlandsson Elektronisk version tillgänglig på http://umu.diva-portal.org/ Tryck/Printed by: UmU-tryckservice, Umeå universitet Umeå, Sverige 2017

If it ain´t broke, why fix it?

- Ronnie Coleman

Table of Contents i Abstract ii List of papers iiv Använda förkortningar v Enkel sammanfattning på svenska vi Bakgrund vi Mål vi Metod vi Resultat vii Slutsatser vii Introduction Overveiw 1 Groin hernia 4 Hydrocele 7 Prostate biopsy 10 Complications 11 Methodological considerations 14 Registries used in this thesis 15 Materials and methods Aims of this thesis 16 Patients, materials and methods Paper I 17 PaperII 18 Paper III 21 Paper IV 22 Paper V 27 Statistics 28 Results Paper I 29 Paper II 31 Paper III 33 Paper IV 34 Paper V 38 Discussion General 40 Paper I and II 45 Paper III amd IV 47 Paper V 49 Strenghts and weaknesses 51 Conclusions 52 Future perspectives 53 Acknowledgements 54 References 56

Abstract

Background: Minor procedures in surgery and urology such as groin hernia and hydrocele repair, as well as prostate biopsies are very frequent in routine cinical practice. Complications and poor outcomes that affect many patients with a significant cumulative effect is of major importance from a population perspective. Nevertheless, there is poos scientific evidence behind som of these procedures.

Aim: To explore complications and outcomes of surgical and diagnostic procedures and possible risk factors or predictors of adverse effects.

Methods: By using both national quality and administrative registers, and by complementing registers with patient reported outcome measures, examine outcomes such as complications, persistent pain and recurrences. In the case of hydro and spermatoceles, to report incidence numbers. Furthermore, by using a randomized trial, to explore a minimally invasive procedure such as sclerotheraphy compared to conventional surgery with respect to cure and adverse events. Lastly, to examine infection rates after prostate biopsy by extensive cross matching of high coverage rate quality control and other registers.

Results: Compared to open anterior mesh repair, the endoscopic technique was advantageous in that there is fewer patients reported outcome of persistent pain. The drawback was an increased risk of postoperative complications and reoperation for recurrence. Open pre-peritoneal mesh repair have the same risk of complications and recurrences, but with no apparent benefit regarding pain.

Incidence numbers for hydro and spematocele were 100/100000 men, seeking specialized health care. Aspiration (± sclerotherapy) had a significantly lower rate of complication rate compared to conventional surgery. Orchiectomy (removal of the entire testicle) was performed in more than 2 per cent of cases.

In the interim analysis of the randomized trial, comparing sclerotherapy to Lord´s procedure for hydroceles, the cure rate, defined, as the absence of symptoms from the ipsilateral side was similar between treatments. Definite conclusions cannot be made due to the risk of type 2 errors, and the study will thus continue.

ii In the case of prostate biopsy, rates of infections increased every year during the time frame of the study, with an approximate risk of two per cent in 2012 for hospital readmission within 30 days. No other risk factors for readmission were found, but comorbidity had a non-linear relationship to admissions. Mortality rates after prostate biopsy were similar in patients with an infection compared to those without.

Conclusions: The open anterior mesh procedure remains the preferred method for groin hernia repair in routine surgical practice.

Hydro and spermatocele surgery is associated with a high complication rate, and the indication for repair should be scrutinized. Sclerotheraphy for hydroceles seem to be a good choice for primary treatment.

The rate of infections after prostate biopsy is increasing and methods to reduce unnecessary biopsy procedures, as well as improved prophylaxis should be investigated.

iii List of papers

I. Risk Factors for Complications in Groin Hernia Surgery; A National Register Study

Karl-Johan Lundström, Gabriel Sandblom, Sam Smedberg, Pär Nordin

Ann Surg. 2012; 255:784–788

II. Chronic pain and recurrence after groin hernia repair: a register based patient reported outcome measure study

Karl-Johan Lundström, Henrik Holmberg, Agneta Montgomery, Pär Nordin

Manuscript, submitted, to British Journal of Surgery

III. Hydrocele and spermatocele; Incidence, treatment and complications

Karl-Johan Lundström, Lars Söderstrom, Henning Jernow, Pär Stattin, Pär Nordin

Manuscript, submitted to Urology

IV. Lord´s operation versus sclerotheraphy for testicular hydrocele, a randomised controlled study

Karl-Johan Lundström, Pär Nordin; Ongoing

V. Nationwide Population Based Study of Infections after Transrectal Ultrasound Guided Prostate Biopsy

Karl-Johan Lundström, Linda Drevin, Stefan Carlsson, Hans Garmo, Stacy Loeb, Pär Stattin, Anna Bill-Axelson J. Urol. Vol. 192, 1116-1122, October 2014

iv Använda förkortningar

PSA Prostate Specific Antigen

HIC High income country

BPH Benign Prostate Hyperplasia

SHR Swedish Hernia Register

NPR National inPatient Register

NPCR National Prostate Cancer Register

PCBaSe Prostate Cancer dataBase of Sweden

PIN Personal Identification Number

OAM Open Anterior Mesh repair

TEP Total Extra Peritoneal repair

TAPP Trans Abdominal PrePeritoneal repair

CAP Combined Anterior Posterior repair

OPPM Open PrePeritonel Mesh repair

ICD International Classification of Diseases

NOMESCO Nordic Medico-Statistical Committee

KVÅ Klassifikation av vårdåtgärder

IPQ Inguinal Pain Questionnaire

ASA American Society of Anesthesiology

UTI Urinary Tract Infection

OR Odds Ratio

RR Relative Risk

v Enkel sammanfattning på svenska

Bakgrund

Kirurgiska ingrepp för ljumskbråck, vattenbråck eller prostatabiopsier, har en risk att orsaka komplikationer eller besvär för patienten. Utöver dessa problem, kan olika metoder för att behandla samma diagnos ha olika effektivitet vad gäller bot. Eftersom dessa ingrepp görs ofta, kan även små risker för varje enskild individ leda till stora absoluta tal och stort lidande. Medicinsk vetenskap generellt, har som uppgift att ta fram underlag att förbättra behandlingar och minska risk för komplikationer. En del diagnoser är mindre undersökta än andra, viket leder till att patienter med dessa diagnoser inte kan få rätt information innan behandling för att fatta ett välgrundat beslut om vilken behandlingsform som skulle passa just dem.

Mål

Att undersöka komplikationer och utfall av kirurgiska ingrepp för ljumsk- och vattenbråck.

Metod

Med hjälp av nationella kvalitetsregister och administrativa register samt med enkätutskick som mäter patientens uppfattning efter kirurgi; mäta utfall som komplikationer, kronisk smärta och återfallsfrekvens. Vad gäller vattenbråck och spermiecystor, rapportera hur vanligt tillståndet är. Dessutom, med hjälp av en randomiserad (slumpmässig uppdelning till två olika behandlingsmetoder) studie avseende vattenbråck, jämföra två metoder avseende bot och komplikationer

vi Resultat

När man jämför den vanligaste operationen för ljumskbråck (främre nätförstärkt öppen operation) med titthålsoperation, var den senare bättre avseende förekomsten av kronisk smärta ett år från operationsdatumet. Baksidan med denna metod var en ökad risk för komplikationer samt att risken för återfallsoperation var fördubblad, från en procent till drygt två procent efter i genomsnitt 2,5 år. Öppen bakre nätförstärkt operation hade samma risk för komplikation och återfallsoperation men ingen minskad risk för smärta i jämförelse men titthålsoperation.

Förekomsten av vattenbråck och spermiecystor var cirka 100/100000 individer, som sökt sjukhusvård för detta problem. Tömning med nål med eller utan vävnadslim hade väsentligt lägre risk för komplikationer, jämfört med operation. I nästan två procent av fallen som behandlats för vattenbråck, användes en operation där hela testikeln tas bort.

Mellananalysen av den randomiserade studien, visar att det inte fanns någon större skillnad mellan tömning och vävnadslimsbehandling och en speciell operationsmetod som kallas Lord´s operation. Detta gäller patientupplevda besvär av vattenbråcket. Då antalet patienter i denna studie inte är tillräckligt stort, kan inga statistiskt säkra slutsatser dras i nuläget.

För prostatabiopsier ökade inläggningsfrekvensen för varje år under undersökningstiden, men ingen ökad dödlighet kunde kopplas till provtagningen.

Slutsatser

Det förefaller som att den främre nätförstärkta operationen för ljumskbråck fortfarande är den mest lämpliga metoden i allmän kirurgisk praxis.

Vattenbråck- och spermiebråcksbehandling är behäftad med stora komplikationsrisker, och anledningen till behandling bör se över. Tömning och vävnadslimsbehandling verkar vara ett bra alternativ till kirurgi. Infektioner efter prostatabiopsier ökar, och bättre profylax måste tas fram.

vii

viii

Introduction

Overview:

Groin hernia and testicular hydroceles share many common features.

The pathogenesis of both is mainly dependent on the migration of the testicles from the retroperitoneal space down to the scrotum (except direct and femoral hernias, discussed later). This is a processus vaginalis dependent process in which the processus leads the testicles thru the inguinal canal and in to the scrotum. This process pulls with if the peritoneum, and this layer surrounds the testicles but is obliterated cranially (fig. 1)1.

Figure 1. Processus vaginalis leading the testicle to the intrascrotal position

In children, this condition is normally due to a nonobliteration of this space, and thus, intra-peritoneal fluid collects in the lowest standing parts, which in standing position, is the scrotum. This fluid seeps back in the lying position and is thus named a communicating hydrocele. In the same manner, if the intra-abdominal contents are found in the scrotum or inguinal canal, following the same path, it is called an indirect or lateral inguinal hernia (fig 2). These conditions are treated the same way, with surgical exploration and ligation of the persistent peritoneal sac at the internal inguinal orifice1.

In adults, the mechanism of hydroceles is different. Communicating hydroceles are rare in adults, and hydroceles are most often non- communicating2 implying that only part of the processus vaginalis is open, and of unknown reasons, filled with fluid (Fig 2).

Figure 2. Principal mechanisms of communicating and non- communicating hydrocele and indirect inguinal hernia. (Reprinted with permission from Palmer1)

Although, the exact mechanism is unknown, it may possibly be an by an imbalance of secretion and absorption of fluid, possibly due to inflammatory, traumatic or, in rare cases, malignant changes2.

In sub-Saharan countries infection with Wucherichia Bancroftii is associated with hydrocele formation caused by ectasia of lymphatic vessels draining the processus vaginalis, thereby impairing the lymphatic drainage and thus, leading to fluid accumulation3.

Groin hernias can be medial (direct), lateral (indirect), or less commonly- femoral.

In the medial hernia, the protrusion lies medial to the epigastric vessels and is caused by weakness of the oblique internal/transversalis muscle. In the lateral hernia the protrusion is via the internal ring of the inguinal canal, a point of weakness in the abdominal wall in males4.

In inguinal hernia in adults, the pathogenesis is a weakness of the abdominal wall, especially the transversalis fascia, causing a protrusion of the peritoneum to extend in the inguinal canal. Sometimes, a lateral hernia sac

can extend all the way to the scrotum, following the processus vaginalis. A medial hernia follows the same path4.

Groin hernias also include the femoral hernia. This does not involve the inguinal canal but is a protrusion of the peritoneum in the femoral canal, just above the ligament of Cooper and medial to the femoral vessels5. The different types of hernias are displayed in figure 3.

Figure 3. Schematic description of different types of groin hernia.

As for women, hydroceles exist, in the Canal of Nuck (female counterpart of processus vaginalis), but is rare6. Groin hernias are also uncommon in females, since there has been no migration of testicles and thereby inherent weakness of the abdominal wall, existing in men7. The anatomical structure corresponding to the inguinal canal in women is the round ligament. Women are prone to get incarcerated hernias, leading to acute surgery and a substantial mortality risk8. A femoral hernia is often the cause of this. Femoral hernias is considerably more common in women9.

Prostate cancer is the most common cancer in Sweden, with incidence of 150/100000 individuals/ year10. The early discovery of prostate cancer, as a result of prostate-specific antigen (PSA) screening is one of the reasons for this high incidence figure. Treatment of localized prostate cancer can be either radiotherapy, surgery or active surveillance as well as watchful waiting11. For patients with metastatic disease, androgen deprivation therapy is commonly advised12

Groin hernia:

Epidemiology:

Groin hernia is a common disease, and hernia repair is the most common general surgical procedure in the world. The lifetime risk of a hernia repair is approximately 30% in men and 3% in women7, 13. The incidence of hernia repair in low-income regions is 17/100.000/year14

Indications for treatment:

Hernia repair is performed electively on patients with subjective symptoms or as an acute procedure in the case of incarceration. There seems to be little evidence that elective repair diminishes acute complications since a hernia that undergoes strangulation or incarceration rarely shows symptoms before the acute presentation15. It is therefore practice that asymptomatic hernias are managed by watchful waiting rather than repairing the hernia prophylactically16. However, most patients sooner or later develop symptoms and undergo surgery17

Treatment of groin hernia:

From the patient’s perspective, the question is which procedure is the preferred one? To be able to answer that question, we must have a clear understanding of the goals of hernia repair: 1. Cure (no recurrence) 2. No postoperative pain 3. Safety (i.e. absence of complications)

Two principally different aspects of repair need to be discussed.

The first of these is- should we use sutured or mesh repair?

Sutured repairs are based on the principle that the patient´s own tissues are sutured together to regain strength in the affected areas of the abdominal

wall- a so-called tension repair. Examples of repairs are Shouldice18, Bassini19 and McVay20.

In mesh repair, reinforcement of the abdominal wall with a mesh enables tension-free repair. Mesh repair is the method of choice today since recurrence and chronic pain rates are lower21. The most popular open mesh repair is the Lichtenstein repair, where a mesh is placed on the anterior side of the posterior wall of the inguinal canal22. Various form of mesh have been tried23, as well as density24, pore size25 and way of fixation26. Until now, only the use of lightweight mesh have shown superiority when considering chronic pain27.

The second aspect is; should the mesh be placed anteriorly or posteriorly (endoscopic or open)

The open anterior mesh repair is based on the principle that the posterior inguinal wall is reinforced anteriorly by placement of the mesh on the anterior side of the posterior inguinal wall. This is generally made by a Lichtenstein procedure. The advantage of Lichtenstein repair is a short learning curve28 and a low risk of serious adverse events29. The main concern of this procedure is that chronic inguinal pain and numbness is more common, compared to posterior endoscopic techniques30.

The posterior mesh repair is when the mesh covers the posterior aspect of the posterior inguinal wall. The mesh naturally covers the femoral canal, as well as medial and lateral hernia defects (fig. 4). However, an increased recurrence and adverse events rates have been reported31 and these techniques are technically demanding and require a high case load32.

Figure 4. Anatomy from the endoscopic (posterior) view

Because of the large number of individuals with groin hernia and the high incidence of emergency repairs, it is probably not feasible to restrict primary groin hernia repairs to specialised centres33. Studies on groin hernia repair must therefore take into account the effectiveness (i.e. the results under “normal” conditions) rather than efficacy34

Hydrocele

Epidemiology:

Testicular hydroceles are defined as an increased fluid volume surrounding the testicles2. There is no consensus as to when the amount of fluid should be considered pathologically increased, more important is that the patient complains of a uni- or bilateral lump or enlargement in the scrotum2.

The differential diagnosis is a spermatocele, which is a fluid containing cyst, originating from the epididymis.

There has been a lack of epidemiological studies on hydrocoele or on the burden of symptomatic disease in high-income countries (HIC), but one study, inviting healthy adults for ultrasonographic investigation, found evidence of a small or moderate fluid collection in 14 per cent35.

In the low-income countries in sub Sahara and eastern Asia, it has been estimated that 25.000.000 men suffers from hydrocele36, caused by lymphatic filaria. The sequelae of a hydrocele is major in these countries have a major impact on the working and social abilities of their inhabitants37

A symptomatic hydrocele has been defined as a hydrocele causing functional problems2.

Indication for treatment:

There is no uniform guideline regarding the indication of treatment. This is reflected in reports from clinical trials where indications for treatment are not clearly defined38. After ruling out a tumour of the testicle or a scrotal hernia, there are no problems with having a hydrocele, except for possibly impaired spermatogenesis in a minority of cases39. Hence, treatment should only be considered in patients with symptoms caused by the scrotal swelling.

Treatment of hydrocele:

The treatment principle of adult hydroceles is based on either space limitation, reduction in fluid production an/or increase in absorption of fluid. This can be achieved by either sclerotheraphy or surgery.

In sclerotheraphy, the hydrocele is emptied and an irritating substance is then injected in the space between the testicle and the parietal tunica vaginalis. The substances used vary and can be polidocanol40, tetracyline41,

alcohol42 or phenol43. These substances will cause an inflammatory response, causing the parietal tunica vaginalis to fuse with the visceral tunica vaginalis and thus leave no room for fluid accumulation (space limiting). Also, the production of fluid might be affected (decreased fluid production).

Surgical procedures are based on the reduction of fluid production by resection or plication of the parietal tunica vaginalis. It is also probable that an increase in fluid absorption by the dartos layer in the scrotum also occurs. Indirect proof of this is that there are some data on success with eversion techniques (Andrew procedure)44 and that some authors have found the “Window procedure” , where only a small window between the tunica vaginalis and Dartos muscle is created, to be sufficient45.

Little research to comparing alternative treatments for hydroceles is made. And as a result there are no definitive conclusions cannot be made on treatment effectiveness. Choice of treatment is thus based on patient/physician preference, economic considerations and access to surgical resource. Since aspiration/sclerotheraphy is less expensive and demands less personal resources this is often the method chosen.

The agent of choice in sclerotheraphy is not decided, and a discrepancy exists between studies. In general, sclerotheraphy must be repeated many times to achieve cure, and in general, the cure rate of each treatment is 50%40.

To date, studies have mostly focused on cure rates, and less on patient discomfort. In a benign disease, such as hydrocele, where treatment is often based on subjective symptoms, it could be argued that a less effective treatment with a few side effects is better than a highly effective treatment where side effects are major. A Danish study, came to this conclusion and furthermore showed polidocanol sclerotherapy to be better than tetracycline46.

On the other hand, in poor countries, cure seems more important, since short-term discomfort is secondary to cost47. When comparing the results of studies, cultural and economic backgrounds must therefore be taken into consideration. Results from one region may not apply to another

Direct comparison of results of surgery and sclerotherapy is equally difficult since there are three surgical methods (plication, eversion and excision) and even more sclerotherapy agents.

As a rule of the thumb, surgery is superior to sclerotherapy when comparing cure rates38 and complication rates are higher when comparing eversion and excisional techniques to sclerotherapy42, 44, 48. Some studies suggests that plicational techniques are similar to sclerotherapy with respect to complications and possibly with a higher cure rate49, 50.

Prostate biopsy

Epidemiology:

It is estimated that 1 million of prostate biopsies performed in Europe annually51.

Transrectal ultrasound guided biopsy is the gold standard in the investigation of suspected prostate cancer11. However, despite prophylactic antibiotics, serious adverse events including febrile urinary tract infection and urosepsis have been reported in one to four per cent of cases52-56. Previous studies have reported that diabetes; benign prostatic hyperplasia (BPH) and a history of urinary tract infection increased the risk of infections after prostate biopsy54, 57.

Indication:

The indication to perform prostate biopsy is raised prostate-specific antigen levels in the blood and/or a palpable tumour on digital rectal examination.

Complications of procedures

With all surgical procedures, the same complications may be expected, namely bleeding (or other visceral organ damage), infections and others (unspecified or procedure specific complications).

Also, complications affect the surgeon as well, often with lower quality of life and felling ”burnt out”58.

Still, it is important to know the natural history of the disease, since not treating the condition sometimes have a penalty.

In the case of groin hernia surgery, the quality of life improves substantially after symptomatic hernia repair59, 60. However, expectant management does not lead to a substantially increased risk for incarceration16.

As for hydroceles it is generally accepted that a hydrocele, without underlying infection, trauma or malignancy, is a truly benign disease, and that conservative treatment of asymptomatic patients does not carry a major risk.

For an undiagnosed prostate cancer, the risk of non-detection is related to cancer severity and remaining life expectancy (comorbidity and age), as showed by a competing risk analysis made61.

The main complications after these surgical procedures include 1. Pain 2. Bleeding 3. Infection 4. Other complications (i.e. ischemic orchitis, fertility, seroma formation, general surgical complications such as venous thrombosis, cardiovascular adverse events, urinary retention and erectile dysfunction)

Pain:

In groin hernia surgery, the minimally invasive approaches have an advantage regarding short term pain and sick leave30. For long-term pain, minimally invasive procedures seem beneficial for hernias31. The long-term pain has been reported to consist of mainly neuropathic62. This is probably caused by nerve damage during surgery, and posterior techniques seem advantageous in this respect. The definition of chronic pain for groin hernia repair have been suggested to be used after at least six months from repair,

since most surgical techniques uses a synthetic mesh, which causes an inflammatory reaction and probably longer healing time63.

For hydroceles, the short term pain rates after aspiration/sclerotherapy with both phenol and polidocanol are lower, compared to eversion surgery64.

In prostate biopsy, the use of local anaesthesia reduces pain during the biopsy but not when inserting of the probe65.

Bleeding:

In groin hernia repair, bleeding can be divided in minor or major. In open anterior herniorraphy, major bleeding is rare30. When considering major bleeding, the posterior techniques are more prone to get major vessel damage, probably due to the fact that the surgical field is close to these vessels30.

In hydroceles, the frequency of minor bleeding/hematoma is high after surgery; up to 10% of patients will suffer from a clinical hematoma66. This may be due to the resilient nature of the scrotum, not compressing a minor bleed, but rather allowing it to expand into a hematoma. Since there are no larger vessels nearby, life-threatening haemorrhage has, to our knowledge, not been reported. In sclerotherapy, bleeding is not normally an issue, due to the small trauma caused by aspiration40

For prostate biopsy, haematuria (10-40%), rectal bleeding (1-40%) and hemato-spermia can occur (practically all patients). These complications are mostly minor and rarely requires inpatient hospital treatment67.

Infection:

In groin hernia, infection rates are low, but rates favour minimally invasive procedures30. No antibiotic prophylaxis is considered necessary, even though a prosthetic implant is used68.

The surgical site infection rate in hydrocele treatment is probably higher in the surgery group, speculatively due to the skin wound, in comparative studies44, 48. When including epididymitis, one Swedish study found a 16% infection rate in one arm of sclerotherapy40. The genesis, bacterial or chemical, could not be further assessed.

In prostate biopsy infection rates are considered to range from 1-4%, depending on definitions of infections used54, 55. Also, data acquisition matter, for example wheater questionnaires or discharge codes are used.

Other complications:

In hernia surgery, other complications will sometimes represent visceral injury (intestines/bladder). In this respect, the open anterior mesh repairs seem advantageous possibly caused by the anatomical proximity to adjacent organs31. Other medical complications (venous embolism, cardiovascular events or infectious complications other than wound infections) does not seem to differ between surgery types but rather with patient characteristics29. Also, decreased sperm motility has been suggested, when using lightweight meshes69. Nevertheless, definite data on fertility is lacking.

In hydrocele treatment, one of the problems that need scrutiny is the risk of fertility or having to undergo an orchiectomy on the treated side, due to complications or complaints after treatment. For fertility, some advocate that the risk of impaired semen quality is significant in sclerotherapy70. In studies from surgery, there is a high risk of epididymal or vas deferens injury71, 72 (surrogate for impaired fertility). As for the risk of orchiectomy, in a Swedish study, revealed that this risk is 2% for a specific sclerosing agent73.

For prostate biopsy, other complications include urinary retention and lower urinary tract symptoms67. Erectile dysfunction seem mostly dependent if weather prostate cancer was found, so the impact of biopsies are probably low74.

Methodological considerations:

This thesis uses different study designs75.

Randomized controlled trial

The study design with the highest level of evidence is the randomized controlled trial (Level 1b). Here, neither patients nor the physician can choose treatment, which is randomly assigned to either modality. However, in this setting, inclusion and exclusion criteria is set to optimize patients for either treatment. Since not all patients will tolerate one of the treatments studied, for example, laparoscopic hernia surgery under general anaesthesia is not suitable for old and frail patients and these patients must be excluded.

The major benefit of randomisation is that all confounding variables should occur equally in each group and differences in outcome are presumed to be due to the treatment and not to other factors such as selection bias.

The drawback is that, due to selection of patients, results are not always generalizable to the patients actually treated, nor are, as in the case of surgery, the surgeons performing the procedures.

Observational studies (from whole population cohorts)

This is reflective of all patients and outcomes are the “real” outcome obtained from a procedure in a cohort of patients, if conducted on a large unselected generalizable cohort. In this methodology, you only observe, and not intervene; therefore, differences in outcomes can be due to other factors than the studied.

Registries used in the thesis

In Sweden, the personal identification number (PIN) is assigned at birth and used in virtually all contacts with authorities and health care76. This allows for tracking the patient in Sweden, irrespective if the patient moves to another city or county. The patient is untraceable if emigrating, or have a protected identity. Also, this can be used to cross link data from different registries to obtain results on factors normally not collected in quality registries such as education class77 or insurance claims for complications78.

Validations of the registries are of major importance, i.e., are the variables that are collected, true when comparing with the reality? If data is not validated, no secure conclusion can be drawn from them79.

Furthermore, the coverage of the register is an important factor. I.e. if patients in a register is selected or consist of only a small proportion of a population80, general conclusions are hard to draw.

Swedish Hernia register:

The Swedish hernia register (SHR) was founded 1991 and today cover almost all hernia repairs in Sweden. The variables included in the register are, among else, age, acute operation, operation time (>50min), type of anaesthesia, bilateral surgery, annual surgeon volume, or a repair of o recurrent hernia, hernia anatomy and postoperative complications. Annual validation of the register is performed at randomly chosen departments81.

Inpatient register:

The Swedish inpatient register is a nationwide register, covering all hospital- based health care, including ambulatory and outpatient visits, excluding the primary care. The coverage is nearly 100%. Validation studies suggest that surgical procedures, in particular, have a high sensitivity79.

Prescribed drug register:

The Prescribed Drug Register includes data on all prescriptions dispensed in Sweden. The register was established on July 1, 2005 and records individual level information about the dispensed drug, amount and dose, as well as the date of prescription and date dispensed at the individual level. The register covers all drugs prescribed and dispensed with the exception of drugs administered during inpatient hospital care and over-the-counter drugs. Less than 0.3% of dispensations lack patient identity data82.

The Cause of Death Register:

The Cause of Death Register collects date and underlying cause of death coded according to ICD10 with almost complete capture rate83, 84.

National prostate cancer registry (NPCR):

Since 1998, National Prostate Cancer Register (NPCR) of Sweden captures more than 96% of all newly diagnosed prostate cancers in the country, to which reporting is mandatory and regulated by law85. NPCR includes data on age at diagnosis and tumour and treatment characteristics with high validity. Additional data on comorbidity and drug use was obtained through the Prostate Cancer data Base Sweden (PCBaSe) that is linked to other nationwide health care registers and demographic databases using the Swedish 10- digit PIN86.

Materials and methods

GENERAL AIM OF THE THESIS:

The aim was to investigate the incidence and risk factors of postoperative complications in groin hernia and hydrocele repair as well as prostate biopsies. Also, to compare different methods of repair in respect to cure.

SPECIFIC AIMS

Papers I and II

Evaluate the short-term complications and chronic pain for different methods of repair in groin hernia surgery, in general surgical practice.

Papers III and IV

To investigate the incidence of scrotal cystic lesions in men and to analyse the risk of complications for commonly performed repairs. Also to compare open conventional surgery to sclerotherapy in hydrocele patients.

Paper V

To examine the risk factors for and time trends of infection after prostate biopsies.

METHODS

Paper I:

This was a register based observational cohort study. All herniorraphies in Swedish Hernia Register (SHR) from 1998-2009 were included. This represents a modern, whole population cohort, with almost complete national coverage. Complications within 30 days after surgery are reported by the surgeon, and are defined in table 1. Exclusion was made of patients with the first surgery registered in the SHR was a reoperation for recurrence or pain, and if patients had missing data on some of the variables analysed.

The primary endpoint was the proportion of complications according to method of repair.

The secondary endpoints were to assess other risk factors for complications and the risk of reoperation for recurrence for various complications

Table 1. Definitions, in SHR, of respective postoperative complication (within 30 days of surgery)

Complication Definition

Hematoma Bleeding causing significant tissue distension, bruising excluded

Urinary retention Need for catheterization

Infection Local signs of inflammation, purulent secretion and/or positive wound culture

Severe pain Postoperative pain, greater than the expected

Other complication Ischaemic orchitis, seroma, venous thromboembolism, infections other than wound etc.

Need for reoperation, other than recurrence

Paper II:

This was a register-based patient reported outcome measures study using a questionnaire to investigate the impact of surgical technique on the risk for chronic pain one year after surgery and the risk for recurrence during the study period.

By using the PIN and the register of the whole population, all patients with a groin hernia repair between the 1of September 2012 and 1 of April 2015 were identified and postal address obtained. A short questionnaire was sent to all patients, where the key question was “Grade the pain in the operated groin when it was the worst the latest week”. The answers were in a seven-grade scale whereas pain was defined as “pain, which could not be ignored and affected concentration on activities and leisure activities”, (i.e. 4 or more on the seven grade scale). 1. No pain 2. Pain present but easily ignored 3. Pain present, cannot be ignored, but does not interfere No Pain Pain No with everyday activities 4. PainPi present, cannot be b igno ired, d and di interferes f with ih concentration on chores and everyday activities 5. Pain present, interferes with most activities

6. Pain present necessitating bed rest Pain 7. Pain present, prompt medical advice sought.

The surgical methods were Open anterior mesh repair (OAM) Total extra peritoneal repair (TEP) Trans abdominal preperitonela repair Combined anterior/posterior repairs (CAP) Open preperitoneal mesh repairs

Sutured repairs were excluded due to a low number performed.

A sensitivity analysis, where the definition of pain was altered to 5 or more on that scale, corresponding to “pain preventing most activities”, was made to examine if the results in terms of odds ratios remained the same.

In a “lost to follow up analysis”, a random sample of patients who didn´t answer the questionnaire or the reminder, where interviewed on the telephone to obtain the answer of the key question.

A reliability test- retest of results was conducted on 680 consecutive patients as regards the key question.

Paper III:

A register based study on the incidence of cystic lesions and the complications treatment.

Using the Swedish inpatient register, the years 2005-2014, were examined.

First, the total incidence/year of International Classification of diseases (ICD) code N43.0-3 (Hydrocele) and N43.4 (Spermatocele) per 100.000 men was calculated. The total number of men at risk was defined as men alive the 31 of December without hydro or spermatocele diagnosis each year. Each man with these diagnoses was censored after each first registered code.

Treatment incidence was calculated the same way where NOMESCO (Swedish-KVÅ) codes: TKF60 (aspiration, with or without sclerotherapy), and surgical codes KFD20 (hydrocelectomy), KFC60 (epididymectomy), KFD16 (resection of epididymis) or KFC96 (other resection of scrotal content) was used.

The age specific incidence was calculated by dividing patients into 6 age groups (18-24, 25-44, 45-64, 65-74, 75-84, 85+).

For the risk of complications, individual patient data was obtained for all patients with an ICD diagnosis of hydro or spermatocele and a corresponding procedure code. Complication codes for postoperative epididymitis, hematoma, infection, wound dehiscence and other complications were examined 30 days from the date of treatment and onwards.

Inclusion criteria: Any diagnosis of hydro or spermatocele during the time period of the study.

Paper IV:

A multicentre randomized controlled study, started 2014-04-11. Patients, with at least minimal symptoms, fulfilling inclusion and no exclusion criteria had their hydroceles aspirated by sterile aspiration by a 16 Gauge (G) butterfly needle before randomization. This to make sure that the cysts could be completely emptied (otherwise sclerotheraphy would be likely to fail). If the fluid was opaque, the diagnosis of hydrocele is unlikely and spermatocele diagnosis was stated. Thus these patients were excluded. If randomized to sclerotheraphy, patients were treated at the same time with Polidocanol (30mg/ml), 4 ml injected in the hydrocele sac. If randomized to surgery, the butterfly needle was extracted without sclerotherapy and planned for elective surgery in local anaesthesia.

The end point was a patient reported outcome measure (PROM) of no inconvenience at follow-up, 3 and 6 months from randomization (not from treatment date). At 3 months, patients were planned to a follow-up visit at the outpatient clinic. If a symptomatic recurrence was found, patients were to be retreated the same way as original randomization. To minimize loss to follow-up, a questionnaire was sent as well. At 6 months only a questionnaire was sent, if no other treatment had been done after the first treatment. Complications within 30 days after the procedure were assessed by questionnaire.

Patients: Patients attending the urology outpatient clinic with a suspected or confirmed testicular hydrocele were eligible for participation

Inclusion criteria: Testicular, trans-illuminable hydrocele with symptoms that is at least ignorable not affecting daily activities (at least two points of a seven grade scale). Age >40 years and informed consent to participate.

Exclusion criteria: American Association of Anaesthesiology (ASA) grade>3, prior treatment on the same side, current ipsilateral groin hernia/testicular tumour/epididymitis, on-going urinary tract infection, ascites or dialysis. Patients with turbid fluid and incomplete aspiration were also excluded.

Definitions:

Inconvenience: A symptom answer of 2 or more (modified from the Inguinal pain Questionnaire87) from the question “Estimate the worst inconvenience you felt during this past week from the hydrocele”. The possible answers displayed under the “Methods” section for paper 2, with the difference that “pain” was changed to “inconvenience”

Complications:

If the patients answered; “Yes”, to having a complication within 30 days after the procedure that forced them to seek medical advice, an additional set of questions was answered:

“What kind of complication did you suffer? The alternatives were: ● Pain, greater than expected ● Bleeding: discolouration on the treated side only ● Bleeding: pronounced swelling and tensionof the scrotal skin ● Infection, on the treated side ● Epididymitis ● Other complication

If patients answered “Bleeding, only discoloration on the treated side” it was not considered as a complication, to allow patients to grade the bleed, and therefore to be able to differentiate from a minor “normal” hematoma, compared to a bleed considered significant for a health professional.

Procedures:

Sclerotherphy: After sterile washing, the hydrocele was covered with a sterile drape. Using sterile gloves, the hydrocele was punctured and the fluid was aspirated. After completely emptied, 4 ml of Polidocanol 30mg/ml was injected and rubbed in for 1 minute.

Surgery:

Lord´s procedure was performed under sterile conditions in the operation theatre. It was performed under local anaesthesia using a 50/50 mixture of Carbocain 10mg/ml and Ropivacain 7.5mg/ml, up to 60ml in total. The mixture was injected at the spermatic cord palpated at the pubic tubercle. A small amount of local anaesthesia was placed subcutaneously at the site of the transverse scrotal incision. The incision was made to the tunica vaginalis, which was dissected 0.5-1 cm around the skin incision (Fig 5).

Figure 5. Skin incision and dissection to the tunica vaginalis

Then the sac was opened and the fluid was emptied (Fig 6).

Figure 6. The opening of the tunica vaginalis and emptying the hydrocele by suction. Hydrocele sac is grasped by forceps.

The testicle was delivered through the incision, inspected and then the plication stitches was placed in a radial manner, starting at the epididymis, around the testicle, tied or placed in the scrotum and tied (fig 7).

Figure 7. Sutures placed radially. Before tying of the knots, the testicle has placed back into the scrotum.

The scrotum was sutured in 2 layers (uninterrupted dartos and intra- cutaneous resorb able suture 4.0 (Biosyn™)

Primary end point: Proportion of asymptomatic participants, defined as <2 points of the symptom score, 90 to 180 days from repair, with or without recurrence, after one treatment.

Secondary end point: Proportion of participants with self-reported complications within 30 days from procedure.

Paper V:

From PCBaSe, 56251 men with prostate cancer were eligible, diagnosed by transrectal ultrasound guided prostate biopsy between 2006 and 2011. We excluded 4930 due to missing biopsy date and the remaining 51321 formed the study population.

The date of prostate biopsy was the date of ICD code for transrectal ultrasound guided prostate biopsy (TKE00) in the NPR or the date of prostate cancer diagnosis from PCBaSe was used.

Antibiotics prescribed from 1 to 30 days after biopsy (from the prescribed drug register), thus excluding prescriptions the date of biopsy. Also hospitalizations related to infection related discharge diagnoses in the NPR were examined.

The type of antibiotics prescribed was divided into those for urinary tract infections, versus those prescribed for skin and other infections to serve as a comparison.

Different medications as well as previous history of urinary tract infections (UTI) based on dispensed prescriptions from 6 months to 3 days prior to biopsy, was analysed as a potential risk factor, as well as previous hospital admissions for UTI.

The 3 days before biopsy were excluded from analysis since any antibiotics during that period were considered as likely prophylactic use.

The Charleson comorbidity index (CCI) was calculated using ICD codes for discharge diagnoses in the In-Patient Register from ten years before the date of prostate biopsy and excluding prostate cancer diagnosis61.

A nested crossover analysis was done in order to estimate the background risk of urinary infection. Each person served as his own control and we investigated the risk of infection during a 30-day period six months prior to the biopsy date.

All-cause mortality within 90 days after biopsy was analysed based on national death records, which has high accuracy for cause of death and we analysed if the direct or contributing cause of death was a urinary tract infection83.

Statistics

Paper I:

The odds ratio for complications was calculated for type of surgery and adjusted for dichotomous variables such as sex, age (median), acute or elective, uni- or bilateral, operation time (median), recurrent or primary hernia as well as for hernia anatomy (medial, lateral, combined, femoral and other), anaesthesia (local, regional or general) and surgeon annual volume (1-5, 6-25,26-50 51-). A univariate Cox regression model was made to analyse the risk of reoperation for recurrence according to complications

Paper II:

Logistic regression analysis was made on the odds of chronic pain and reoperation for recurrence for different surgical methods, adjusted for covariates such as age (median), gender, recurrent hernia and annual surgeon volume. Cohen´s κ-statistics was used for reliability analysis.

Paper III:

Comparative analysis with Chi 2 test for proportions. Student t test for 2 independent samples for normally distributed variables.

Paper IV:

Students t test for continuous variables, Fisher exact test for proportions and Mann Whitney U test for ordinal variables.

Paper V:

Multivariable logistic regression was used to estimate odds ratios and 95% confidence intervals for risk of outpatient and inpatient infectious complications, as defined above. The odds ratios were adjusted for age, comorbidity, biopsy year, prior infection, antiplatelet medication, benign prostatic hyperplasia medication, diabetes and numbers of previous biopsy sessions. The comparison of mortality rates was done using Fisher's Exact Test.

Results

Paper I:

Complications were, in general more common than for all other procedures than OAM (table 2). Notably, most of the differences in complication rates between preperitoneal techniques and open mesh was a higher rate of other complications OR 2.59 (95 % CI 2.25-2.98) for laparoscopic repairs, and OR 1.94 (1.57-2.39) for OPPM. These are not specified in the register other than in table 1. Postoperative infections were significantly lower in laparoscopic surgery, OR 0.45 (0.35-0.59) while urinary retention was more common, OR 2.50 (1.96-3.18)

Table 2. Odds ratio (OR)* of any postoperative complication, in relation to method of surgery, open mesh as reference.

Method of surgery Any Complication OR (95 % CI)

OAM (n=87516) 1 (Ref.)

OS (n=16592) 1.01 (0.95-1.08)

CAP (n=17409) 1.12 (1.05 -1.19)

OPPM (n=2405) 1.31 (1.15 -1.49)

TEP/TAPP (n=11878) 1.35 (1.24 -1.47)

CI=confidence interval; OAM=Open anterior mesh repair; OS=Open sutured; CAP=Combined anterior and posterior techniques (plug, Prolene Hernia System, onstep); OPPM=Open preperitoneal mesh techniques; TEP = Endoscopic total extraperitoneal repair; TAPP=Laparoscopic transabdominal preperitoneal repair *Multivariate analysis according to logistic regression. In each analysis adjustments are made for gender, age group method acute anatomy bilateral anaesthesia operation time recurrent hernia, and surgeon´s annual volume

Other significant variables affecting the risk for any complication were younger age, acute surgery, long operation time (>50min), use of other form than local anaesthesia, bilateral surgery, a low annual surgeon´s annual volume and a repair of o recurrent hernia. Anatomy of the hernia also affected complication rates, especially if a femoral or combined hernia was encountered

The risk for reoperation due to recurrence was higher if a patient experienced severe pain or “other” complication (table 3).

Table 3. The relative risk (RR) (not adjusted for other variables) for a reoperation due to recurrence. No complication as reference. Complications could be more than one in number.

Complication (n) RR for recurrence 95% CI

No complication (138519) 1.00 (reference)

Haematoma (5248) 1.23 1.05-1.45

Infection (2017) 1.22 0.93-1.61

Urinary retention (900) 1.49 0.94-2.37

Severe pain (1143) 1.84 1.39-2.45

Other (3106) 1.69 1.41-2.01

Paper II:

Between September 2012 and April 2015, of the 32602 patients receiving the questionnaire, 24617 answered (75%). After exclusion of acute procedures, missing data on method of repair and sutured repairs, 22971 patients were eligible for analysis.

In the “lost to follow up” analysis, there was a statistically significant difference in terms of pain, where patients not responding to the questionnaire had less pain than the responders (3% vs. 15%).

Cohen´s kappa was 0.58 when analysing patients’ answers to the same questionnaire 1 month apart, corresponding to moderate reliability.

In general, more highly experienced surgeons performed posterior mesh repairs when compared to OAM. Proportionally less recurrent hernias and female hernias were repaired using OAM.

The odds ratio for long-term pain was lower in patients operated by TEP, OR 0.84 (95% CI 0.74 to 0.96) compared to OAM. No other method of repair differed from OAM in this respect.

The risk of having a reoperation due to recurrence during the study period was twice as high for TEP and open preperitoneal mesh repair, OR 2.14 (95%CI 152 to 2.98) and OR 2.34 (95% 1.42 to 3.71 respectively) compared to OAM (Table 4).

Table 4. Multivariable analysis: odds ratio for pain (IPQ Grade ≥4) and reoperation for recurrence$. Adjusted for age (two groups above/below median), gender, primary or recurrent hernia, annual surgeon’s volume (two groups with dividing point 26 procedures /year = median number of annual repairs annually)

Pain Reoperation for recurrence

Odds 95% CI Odds 95% CI ratio ratio

OAM n=18034 Ref. n.a Ref. n.a

TEP n=2688 0.84 0.74 to 0.96 2.14 1.52 to 2.98

TAPP n=380 1.05 0.79 to 1.38 0.64 0.16 to 1.74

CAP n=1022 1.01 0.84 to 1.20 0.55 0.26 to 1.13

OPPM n=793 1.01 0.82 to 1.24 2.34 1.42 to 3.71

OAM = Open anterior mesh repair; TEP = Endoscopic total extraperitoneal repair; TAPP = Laparoscopic transabdominal preperitoneal repair; CAP = Combined anterior and posterior techniques (plug, Prolene Hernia System, onstep); OPPM = Open preperitoneal mesh techniques

Paper III:

The incidence of cystic lesions in the scrotum in Sweden between 2005-2014 was 98/100000 men/year

The peak incidence was in the group 65 to 84 years of age

During the 10-year study period, more than 33.000 patients were diagnosed with either hydrocele or spermatocele. Of these, 13000 patients were eventually treated, corresponding to 40 per cent. Two per cent were treated with extirpation of the testicle (orchiectomy) as the primary treatment.

The risk for complication was higher after surgery, RR 3.79 (95% CI 2.27 to 4.40) than after aspiration/sclerotherapy (Table 5).

Table 5. Distribution and relative risk for postoperative complications within 30-days

Complication Aspiration Surgery Relative Risk

(Ref.) n=3920(%) n=9174 (%) (95% CI)

Epididymitis 84 (2.1) 152 (1.7) 0.77 (0.59-1.01)

Hematoma 42 (1.1) 807 (8.8) 8.21 (6.03-11.17)

Infection 49 (1.3) 488 (5.3) 4.26 (3.18-5.69)

Wound 0 (0.0) 48 (0.5) N.a rupture

Other 6 (0.1) 112 (1.2) 8.01 (3.53-18.19)

Total 181 (4.6) 1607 (17.5) 3.79 (3.27-4.40)

When the rate of antibiotic prescription during a 30-day period six months prior to treatment was compared to that within 30 days after treatment for each treatment, a higher risk for post intervention antibiotics was seen in the group treated by surgery.

Paper IV:

A total of 138 patients were screened for participation in the study. Of these, 83 did not meet the inclusion criteria or had exclusion criteria Excluded patients had a mean inconvenience score of 3.01 and a mean age of 62 years (data not shown).

A total of 55 patients were included, 30 patients randomized to sclerotherpy, 25 patients to surgery. Four patients were lost to follow up (Fig. 8).

Figure 8. Inclusion flowchart

The inconvenience score distribution is shown in fig 9.

Figure 9. Distribution of hydrocele inconvenience scores from participants

There was an imbalance between treatment groups in that patients in the surgery group had larger hydroceles and sclerotherapy patients had a higher ASA score (Table 6).

Table 6. Baseline characteristics

Surgery Sclerotherapy p-value (n=22) (n=29)

Age, mean 67 (70) 66.4 (66) 0.45 (median)

Mean volume 402 (253) 222(180) 0.025 (median)

Inconvenience 3.4 (3) 3.2 (3) 0.465 mean (median)

ASA mean 1.6 (2) 2.0 (2) 0.047 (median)

Side (right) 13 (59) 16 (55) 1.0

The mean time to follow up was 168 days, for the 33 patients who came to the outpatient appointment. Patients who answered the questionnaire were included in the final analysis even if no evaluation was made at the outpatient clinic.

There was no significant difference in cure rates when defining cure as being completely asymptomatic (Table 7). Nor was there any difference in self- reported complication rates (p>0.05)

Table 7. Interim results of the hydrocele treatment study on patients randomised to either Lord´s procedure or sclerotherapy.

Surgery Sclerotherapy p-value n=21 n=29

Symptomatic§ n=14 (%) 7(29) 8 (28) 0.74 No Symptoms n=37(%) 15 (71) 21 (72)

RecurrenceΦ (%) 3(14) 9 (31%) 0.09 No recurrence (%) 19 (86) 20 (69%)

§ Symptom score<2 (corresponding to completely asymptomatic)Φ Clinical or suspected recurrence on the treated side at follow up by the patient questionnaire,

Paper V

A total of 51,321 men, who underwent prostate biopsy between January 2006 and December 2011, were eligible. Of these men, 3210 men (6%) had a prescription for urinary tract antibiotics dispensed within one month after biopsy and 587 (1%) men were hospitalized for an infectious complication.

The strongest risk factor for an antibiotic prescription was a prior urinary tract infection during the six months prior to prostate biopsy (OR 1.59, 95% CI, 1.45−1.73), followed by high Charleson comorbidity score (CCI 2), (OR 1.25, 95% CI, 1.11−1.41). An increased risk was also observed for men with diabetes (OR 1.32, 95% CI, 1.17−1.49). Over the time period 2006-2011, there was a decrease in the risk of infections managed with outpatient antibiotics over time (OR 0.79, 95% CI, 0.70−0.90 for 2006 vs. 2011).

Conversely, the number of serious infections requiring hospitalization increased over the same period (OR 2.14, 95% CI 1.58-2.94) and was more likely in men with a high comorbidity score (CCI 2)(OR 1.54, 95% CI=1.16−2.01).

The 90-day mortality rate was not significantly increased in men with an outpatient infection (OR 1.19, 95% CI, 0.83−1.67) or with hospital admission for an infection after biopsy (OR 1.54, 95% CI, 0.70-2.97). The absolute 90- day mortality rates were low (table 8).

Table 8. Mortality within 90 days of prostate biopsy

Dispensed antibiotic for Admissions for urinary urinary tract infection tract infection

Death Yes No Yes No within 90 days

Yes n=38 (1.2) n=478 (1.0) n=9 (1.5) n=507 (1.0)

No n=3172 n=47633 n=578 (98.5) n=50227 (98.8) (99.0) (99.0) p-value 0.31 0.21

Finally, the nested crossover analysis showed that the background incidence of outpatient-managed infection in the cohort during a 30-day period six months prior to biopsy was 2%.

Discussion

General discussion

The treatment of patients with surgery is always a balance between the risk of doing harm and the chance of improvement. For this reason, the method of repair must be the one with the lowest risk and greatest benefit. This is not only a question of the method itself, but also the skill of the surgeon in performing that repair. One technique may be safe and effective in one surgeon’s hands, but less successful in another’s. Furthermore, patient factors such as age, gender, comorbidity, and body composition affect risk.

Minimally invasive vs. open surgery:

So-called “minimally invasive” techniques are becoming increasingly popular. Nevertheless, the name “minimally invasive” does not automatically mean that it is so. This is a matter of subjective opinion rather than a clearly defined entity.

For example, in groin hernia surgery there is evidence that laparoscopic (TAPP) repair has a higher severe complication rate, even though these are rare31. The abdominal cavity is entered using this method and is performed in the close proximity of visceral organs and vessels. Such a repair cannot be considered minimally invasive, even if the scars seen afterwards are small. On the other hand, in most cases, return to normal activity is more rapid and disability is less after laparoscopic repair30.

The minimally invasive procedures usually employed in the treatment of hydroceles i.e. aspiration/sclerotherapy may also be associated with severe complications. In a retrospective study from Stattin et al, two of 106 patients underwent acute orchiectomy because of an intense inflammatory response to the sclerosant sodium tetradecyl sulphate73. This is an example of a major complication after a minor procedure, and such disasters must be avoided. At the same time the burden of aspiration/sclerotherapy on healthcare resources is significantly lower than surgery, as seen in Figure 4.

Figure 4. Differences in treatment a hydrocele with surgery or aspiration/ sclerotheraphy.

Expertise:

Surgical skill in performing the method under consideration is another factor that must be taken into account. In a meta-analysis by the European Hernia Society, it was concluded that in one study, a single surgeon was responsible for the majority of recurrences in the TEP technique88, 89. When excluding this surgeon there was no difference in outcome between open anterior mesh techniques.

When comparing results from randomized trials, the experience of the surgeon seems to be a significant factor for success. In the Neumayer study, where surgeons had an experience of at least 25 open and 25 laparoscopic repairs, the complication rate was much higher in the laparoscopy group, with a 1.1 per cent life-threatening complications compared to 0.1 per cent in the open surgery group90. Contrary to these results, a Swedish study, in which the experience of the surgeons involved was not defined, reported practically no complications91.

Patient factors:

Patients with preoperative pain who undergo groin hernia repair, preoperative pain seem to have an increased risk of chronic pain postoperatively92. Age can also influence the reporting of postoperative pain after surgery, in that younger patients seem to experience higher levels of pain postoperatively. Weather this is caused by physiological differences or that younger patients are more physically active and therefore experience more pain is unclear63. Gender also, seems to play an important role as women are more prone to experience pain postoperatively93 and have an increased risk of femoral hernias9.

It is thus important that surgical treatment should be tailored to the patient, bearing these specific factors in mind. This enables the surgeon to offer his/her patient the method with the best results and that is least likely to cause problems afterwards.

Study design:

Differences in results between the studies in this thesis and other studies must be analysed in the context of study design.

For example, in randomised trials it is not unusual for the majority of patients to be excluded94, and these may have vastly different outcomes than those included95.

In most studies, surgeons participating in studies are highly skilled in one particular procedure unless expert based randomization is used96. One Swedish study comparing OAM and TEP using the same end-points and roughly the same inclusion criteria as ours, reported very different results. In that study, only 2- 3% of patients experienced pain using the same definition as in Study II of this thesis, where 15% experienced pain. This is difficult to explain, but one possible reason is that all procedures in the other study were performed by surgeons with a special interest in hernia surgery91.

An observational design, on the other hand, may be flawed by low coverage, i.e. patients registered in a register do not reflect the ”normal” patient population. This is important since many registers have low coverage. The commonly used Surveillance, Epidemiology, and End Results (SEER) register, for example, has a coverage of only 28%80. Other registries can be voluntary, as the Herniamed registry97 which makes selection bias probable when performing studies based on data from these registers.

Register-based randomised studies may well be the new gold standard. However, registration of the whole population is a prerequisite, as well as the possibility to follow up patient outcome over long periods of time98.

Instead of the register-based randomised design, we propose the use of register-based patient-reported outcome measure (PROM) studies. The PIN may be used to obtain the addresses of patients, and data from registers can be cross-matched and combined to create a unique database for both quality improvement and research. The National Health Service in the United Kingdom, covering several interventions including hernia surgery, is currently using a PROM study in a nationwide project. The coverage between 2009 and 2012 for hernia surgery was 46%, of which 75% actually answered the questionnaires. This will be used for quality assessment of hospitals, helping patients to choose where to be operated99.

Randomised vs. observational (registry) trials-or both?

As this thesis includes different study designs the on-going discussion on which study design who entails the true results of research must be addressed100.

Since this thesis includes several study designs, the on-going debate on which study design delivers the best research results must be addressed101.

Randomised trials are considered to be the design of choice when comparing different interventions, since they diminish selection bias. In surgical trials, however, there are other aspects to be considered. These include Surgical expertise- is the skills of the surgeons participating in the study comparable to surgeons actually performing the procedure in routine clinical practice? Inclusion and exclusion criteria- do the patients in the study reflect the “normal” patient population? Are the outcomes of the study valid- i.e. is comparison meaningful? Are the indications for surgery valid? Is there double blinding (i.e. neither patient nor the surgeon evaluating the outcome is aware of which procedure is being performed)?

The results of surgical studies can differ accordingly. For example, the two major studies on groin hernia surgery named above seem to be very similar in form s but they came to completely different conclusions90, 102

One-way do decrease to difficulties in surgical trials are an expert based randomization. That is, a patient is randomly, or non randomly103, assigned to an expert in a specific procedure rather than to a procedure performed by a surgeon with unknown experience or skill.

Do results from randomized trials generally differ from those of observational trials? Meta analysis comparison shows that the results generally are the same104. Observational studies and randomized studies should therefore be used in a complementary manner, since they are both flawed by methodological problems. Hence, neither of these study designs can guarantee valid results, but valid results can be obtained by both designs if performed correctly, and the validity increases if these are used together.

Paper I and II; Hernia repair

The current thesis focuses on the rate of adverse events after hernia surgery compared to the rate of cure of hernia. A general remark regarding the present results is that open anterior mesh repair remains the method of choice in hernia repair, since the benefits of minimally invasive or open posterior mesh repairs are minor in comparison, whereas recurrence and complication rates are higher.

Complications:

The risk for complication within 30 days after hernia repair was generally higher after laparoscopic repair, compared to open anterior mesh repair. Complications after laparoscopic procedures consisted mainly of urinary retention, even when adjusting for form of anaesthesia, and of “other complications” not specified in the SHR. However, these include potentially dangerous complications such as deep venous thromboembolism, myocardial infarction or serious non-surgical site infection such as pneumonia29. We cannot say whether or not “other complications” were clinically meaningful in this study and this question needs further investigation. On the other hand, preperitoneal techniques were less prone to cause severe postoperative pain and infection. When comparing our results with two large studies comparing these techniques, there are conflicting results. In the study by Eklund et al. there was no difference of short-term complications between groups105. There was less pain in the laparoscopic group, and return to normal activities was faster, and again, there were more serious complications even if rates were low. In the Neumayer study, that had a study design similar to that of Eklund et al, the complication rates as well as recurrence rates were higher after laparoscopic techniques 90.

Patient related risk factors were significant predictors of complications in paper 1. Theese are seldom modifiable- such as gender, age and hernia anatomy. The procedure specific details seem more important, because they can be altered. Such factors, such as form of anaesthesia106, 107 or surgeon´s annual volume108, 109 affect complication rates.

Chronic pain:

When discussing chronic pain, TEP was superior to open anterior mesh. TEP for elective primary inguinal hernia repair is considered, by guidelines, the best procedure reducing this risk110, as reported in the present study. This positive effect of TEP was less pronounced in the present study than in most

randomised studies102, 111. A reduction in the odds of pain with TEP of 16%, would correspond to a maximum of 2.5% absolute decrease in pain rates, even though the odds ratio cannot directly can be translated to relative risk112.

When comparing the Lichtenstein and TEP techniques using data from the German register Herniamed™, a significant difference in the rate pain was seen in favour of TEP (relative risk 0.54)113, and no difference in recurrence rates. This can, in part, be explained by the fact that Herniamed™ is a voluntary register, mainly used by surgeons with a special interest in hernia surgery97. The SHR, however, covers practically all hernia repairs performed in Sweden, regardless of surgeon’s special interest or not.

Recurrences:

The present results concur with those of a meta-analysis from 2012 showing that reoperation rates for recurrence are higher with TEP than with OAM31 . Furthermore, Kald et al. reported that not all recurrences are re-operated and that true recurrence rates are probably higher than reoperation rates114. Reoperation rates also seem to continuously rise with prolonged follow-up88. In the present study both endoscopic and open preperitoneal mesh repair were associated with a higher reoperation rate for recurrence.

An interesting finding in paper I was that a postoperative complication predicts reoperation for recurrence. A possible, but speculative, interpretation is that complications are a surrogate marker for surgical skill, which is correlated to recurrences. In hernia surgery, the “skill” parameter has not been examined. In a study on bariatric surgery, the skill, as rated by a group of surgeons watching a movie recorded from surgery, was strongly correlated to the 30 days complication rates and reoperation rate115

Paper III and IV; Hydrocele and spermatocele repair

The results of the randomised trial presented in this thesis, though premature, lead us to conclude that sclerotherapy is the method of choice for primary treatment of hydrocele, with few exceptions. This conclusion is based on the seemingly small benefit of surgery but disadvantage in terms of inconvenience, higher complication rates and greater demand on healthcare resources.

Incidence:

To the best of my knowledge, paper III is the first study examining the incidence of hydro and spermatoceles. We can conclude that this is a complaint of quite significant proportions. The incidence, compared to other diseases affecting only men, is substantial.

Study III showed that most hydroc0eles and spermatocoeles are left untreated, corresponding to 60% over a 10-year follow–up period. These results are basically in line with the proportion of men excluded in the randomised trial. This highlights the fact that neither treatment is mandatory under a clinical or observational trial.

Hydrocele is an old man’s disease. Most of these men are not bothered by fertility concerns. However, men who may wish to become a father might reevaluate the indication for treatment. A trial from Osebge et al. showed poor semen quality after sclerotherapy, leading to the exclusion of younger patients from trials of sclerotherapy70. On the other hand, neither is surgery without risk regarding fertility, with rates from 5 to 17 per cent with significant epididymal injury72,. Further studies on this subject are necessary, probably differentiating between hydrocele and spematocele. Theoretically, any treatment of a spermatocele is likely to disturb the delicate tubular structure of the epididymis and hinder sperm migration.

Treatment:

In paper III the adverse event rate seen after surgical management of hydrocele was more than threefold that after sclerotheraphy. The severity of complications could not be assessed. The results from the current study are in line with other retrospective trials on surgery and complications66, 116. Most being single centre retrospective studies, with between 160-220 patients. Thus, this nationwide, whole population studies provide robust data, supporting former studies, also being able to compare aspiration vs. surgery.

The interim analysis of our randomised trial comparing sclerotherapy and surgery was made to see if data were already strong enough to be able to draw any definite conclusions. Until now, however, results indicate that there is no major difference regarding cure (defined as an asymptomatic patient).

Paper IV is the first study to clearly define the treatment indication in terms of inconvenience score. Prior studies have defined treatment indication as “symptomatic” hydrocele44, 48. However, almost 65% of patients included in this study had mild symptoms, thus not affecting daily activities. It could be argued that the threshold for treatment should be set at “symptoms not easily ignored”, rather than on “symptoms easily ignored”, in view of the inconvenience of the procedure itself as well as the risk for complications.

In the original study design, “symptoms not easily ignored” was the threshold for inclusion, but this was later downgraded to “symptoms easily ignored” since patients, insisted on treatment, even with low inconvenience scores (NCT02082613).

In other studies on hydrocele the definition of cure is not always clearly stated, but is often a combination of patient satisfaction and absence of hydrocele at follow-up where surgery is chosen by the patients44, 48. The current study focused on patient inconvenience rather than cure of the hydrocele, implying that a patient can be considered cured if he doesn’t have a complaint, even if residual fluid accumulation is present. Once again, our preliminary results indicate that there is no difference in cure rates between surgery and sclerotherapy.

As expected, the cure rates, defined as recurrent hydrocele showed a trend to be greater in the surgery group. Also, other studies show far better cure rates for surgery when no recurrence of hydrocele fluid is the definition of cure 42, 44, 117.

Paper V; prostate biopsy

Six per cent of men who underwent prostate biopsy developed an infection treated with antibiotics in an outpatient setting and one per cent of patients were admitted for an infection within 30 days after biopsy. The strongest risk factors for infections treated in the outpatient setting were previous urinary tract infection, diabetes and other comorbid conditions. The only significant risk factors for hospital admission for infection were high comorbidity and later year of biopsy. One observation was a decrease in filled prescriptions and a significant increase in infections leading to hospitalization. No statistically significant increase in the risk for 90-day mortality for those with an infection was seen.

An overall risk for infection rate of 6% is higher than has been previously reported. For example, Loeb et al. 54 reported an infection rate of 4% using data from the European Randomized Study of Screening for Prostate Cancer (ERSPC). However, that study was questionnaire-based and did not use dispensed antibiotic prescriptions as an objective assessment. That study also differed from paper V, in that high-risk patients (diabetics, steroid users) systematically received prophylaxis for five days, whereas the frequency of prophylaxis is unknown in the current study. The rate of infections requiring hospitalization in our population was similar to other studies with rates of about 1% 54, but lower than in a study in Canada where 3% of men were admitted to the hospital for an infection after biopsy in 200555.

In a previous study, exclusion of men with an indwelling urinary catheter, patients with prior UTI or where a positive dipstick test was positive, reduced the rate of infections that led to hospitalization to less than 0.5% and the need for antibiotics to 1%52. Since this study was conducted in Sweden (under the same conditions as the current study) it highlights the fact that awareness of patient related risk factors and actions taken accordingly will reduce the complication rate to a minimum.

An increased risk for infection in men with diabetes and other comorbidities was seen. The latter association has previously been shown with infections leading to hospital admissions but not for infections managed in the outpatient setting54, 56, 57. These findings highlight the importance of maintaining strict indications for biopsy in frail men especially those with a low risk of advanced prostate cancer56.

The absolute 90-day mortality rate in the our study was higher than in the ERSPC trial, 1% versus 0.2%118, but similar to a study in Canada including all

men who underwent prostate biopsy in a defined geographical area119. This reflects the fact that our study and the Canadian study were observational studies on unselected population-based cohorts. The absolute numbers of deaths due to infections was low, in total 34/51321, corresponding to 0.07% of all patients undergoing prostate biopsy. This is in accordance with the study by Nam et al who found the overall 30-day mortality rate to be 0.09%. Thus, even with unexpectedly high overall mortality after biopsy it seems that this is unrelated to the biopsy procedure itself and rather caused by other factors in this male population.

Strengths and weaknesses:

The greatest strength of this thesis is the high capture rate of the registers used resulting in a highly representative population-based cohort that included virtually all patients diagnosed with groin hernia, hydrocele/ spermatocoele or prostate cancer.

The large study population allows multivariate analysis with adjustments for confounding factors. The SHR, NPR and NPCR constitute unselected and non-biased databases that reflect routine everyday surgical/urological practice, as performed by surgeons and urologists with varying backgrounds and experience of surgery.

The randomised trial has the strength of random allocation to surgery and sclerotherapy, bringing selection bias to a minimum.

The greatest limitations of the studies in this thesis were the lack of systematic individual information on the preoperative symptoms of patients operated for hernia, and the absence of specific information on prophylactic antibiotic treatment in patients undergoing prostate biopsy. Another limitation was that the registers only included patients treated or diagnosed with groin hernia and hydro- or spermatocele at a specialised healthcare centre (hospital), not those at a primary healthcare facility. Furthermore, the study only included men in whom prostate cancer was confirmed and not those with a negative biopsy result. Finally, although we adjusted for many likely confounders, there may still be residual confounding factors affecting these register studies.

In the interim analysis of the randomised study on hydrocele management, randomisation was insufficient, leading to a greater mean hydrocele volume in the group allocated to surgery. This was probably due to an insufficient number of patients being randomised. Furthermore, the large number of patients that were excluded limits the generalizability of the results. The study will now be expanded to compensate for these weaknesses.

Conclusions:

General conclusions

Groin, scrotal and prostate procedures, minimally invasive or not, may lead to adverse events. It is not always the procedure with the smallest skin incision that has the most favourable outcome. Study results must be interpreted in the light of the study’s design, patients included, cultural aspects and skills of the surgeon.

Papers I and II

Laparoscopic procedures for groin hernia repair are associated with less long-term pain, but the risks for reoperation due to recurrence, and short- term complications, mainly urinary retention and undefined “other” complications, are higher than with open anterior techniques. Conventional open anterior mesh repair remains the recommended technique for hernia repair.

Papers III and IV

In the management of hydrocele or spermatocoele, complication rates seem to be higher with conventional surgery without there being any special benefit in terms of increased rate of cure. We conclude that sclerotherapy may well be the method of choice for hydrocele treatment.

Paper V

The infection rate after prostate biopsy appears to be increasing, especially infections leading to hospital admission. This warrants scrutiny of current indications for biopsy and better prophylaxis guidelines.

Future perspectives:

The conclusion of the present thesis is that in general surgical practice; open anterior mesh surgery is still the method chosen by most surgeons for groin hernia repair. We need to define the specific indications for other procedures such as posterior repair, and for specific patient groups such as women, young men, and recurrent hernia, all of which are known risk factors for postherniorrhaphy pain93, 107, 120-122.

We also need to determine whether or not local anaesthesia combined with open repair can decrease the rate of long-term pain while maintaining a low rate of reoperation for recurrence.

As regards hydrocele management today, we cannot say that surgery is inferior to sclerotherapy. We have yet to determine which of the sclerosing agents has the best outcome in terms of cure and lack of complications. Furthermore, the question of effect on fertility or semen quality after surgery and sclerotherapy must be answered. Only when we have these answers will we be able to say with conviction that sclerotherapy is the method of choice in the treatment of hydrocele in modern Western healthcare.

Regarding prostate biopsy, we must investigate new antibiotic regimens for prophylaxis, and we must even test non-antibiotic prophylactic measures if we are to put a stop to the increasing rate of infection after prostate biopsy.

Acknowledgements

Pär Nordin, my tutor. I chose supervisor rather than subject. It has been great fun, discussing, arguing (not only science), traveling, drinking beer, gossiping. Hope to continue doing so in the future. Who said science is boring?

Pär Stattin, co-tutor, head of the national prostate cancer register and innovative Prostate cancer database of Sweden. Always curious on any new ideas on research I might propose. Fast reply´s, often with turning mail. Also, supporting new, sometimes weird, ideas, with the major goal to improve prostate cancer care in Sweden.

Anna Bill Axelson, co-tutor. First author of the most cited paper regarding prostate cancer. Last author and responsible for my second published paper. Immense patience with my writing of that paper, which took time enough to travel the world around a couple of times by bicycle. Hope to join the SPCG 17 any time now.

My Co Authors Gabriel Sandblom- scientifically correct, polite and always interested in discussing hernias.

Sam Smedberg- wisdom and experience. A clinical guru regarding hernia surgery. Many sound and clinically relevant points in writing a paper.

Henrik Holmberg- Statistics is hard for me, especially the handling of large datasets in computers. I am better interpreting results than generating them, and with your help, the statistics has been easy.

Agneta Montgomery- The head of the Swedish surgery society. Important contributions regarding especially paper II. Easy to discuss scientific problems and will not compromise with study quality.

Lars Söderström- biostatistician, R&D department, Region Jämtland/Härjedalen. Endless patience in solving problems regarding paper III. Deep knowledge of medical statistics and a genuine interest in the questions asked.

Henning Jernow- one of the first students I have co-tutored. To think outside the box is great.

My Colleagues at the Urology Unit, Östersunds Hospital- Thanks for understanding the need for me to abandon you during the writing of this thesis.

My former and present bosses- Thanks for allowing me to do this, even if queues are long. Payback is near.

Annika Enarsson- Logistics in research. Always working hard to track patients and questionnaire, or invoices or anything. And thanks for Plopp…

Christofer Lagerros- without your computer skills, PROMS would not have been possible to achieve

Johan Styrke- the next professor to be in Urology in the north of Sweden. Hope to continue doing research with you. Maybe after this we can start talking business.

Jon Fridriksson- The doctor with most included patients in study IV. Even if working at a University Hospital. That’s is a great achievement. And I am sorry for the bad advice regarding the moose.

Petter Kollberg and Magnus Wagenius- For clinical mentorship regarding the more demanding urological surgery.

Thomas Drevhammar, Joakim Johansson, Göran Larsson and Susanne Johansson.

The Family Lisa- The best wife. And the fastest. And the most durable. Without you, this had not been possible, (p<0.001). Extremely understanding the last three months.

Stella- For the meaning of it all and trying to interpret the figures in the text, finding inconsistencies changed before publication. And also, for showing understanding and not disturbing me during the writing.

Theo- For the meaning of it all, and asking me a lot of time if “brosk” is a dangerous condition, and how you would know if you got one. The two most important questions regarding hernia ad hydrocele put by a seven year old boy.

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