Linköping University Medical Dissertation

No.1251

Fast track abdominal hysterectomy

On the mode of anesthesia, postoperative recovery and health economics

by

Ninnie Borendal Wodlin

Obstetrics and Gynecology, Division of Women and Child Health

Department of Clinical and Experimental Medicine

Faculty of Health Sciences

Linköping University, 581 85 Linköping, Sweden

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Fast track abdominal hysterectomy

On the mode of anesthesia, postoperative recovery and health economics

©Ninnie Borendal Wodlin 2011 ISSN 0345-0082

ISBN 978-91-7393-107-6

Graphic design: Tomas Hägg

Printed by LiU-Tryck, Linköping, Sweden 2011.

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List of publications

This thesis is based on the following original articles;

I. Borendal Wodlin N, Nilsson L, Kjølhede P. The impact of mode of anaesthesia on

postoperative recovery from fast-track abdominal hysterectomy: a randomised clinical

trial. BJOG. 2011;118(3):299-308.

II. Borendal Wodlin N, Nilsson L, Årestedt K, Kjølhede P. Mode of anesthesia and

postoperative symptoms following abdominal hysterectomy in a fast-track setting. Acta

Obstet Gynecol Scand. 2011;90(4):369-79.

III. Borendal Wodlin N, Nilsson L, Kjølhede P. Health-related quality of life and

postoperative recovery in fast-track hysterectomy. Acta Obstet Gynecol Scand.

2011;90(4):362-8.

IV. Borendal Wodlin N, Nilsson L, Carlsson P, Kjølhede P. Cost-effectiveness of general

anesthesia versus spinal anesthesia in fast track abdominal benign hysterectomy. Am J

Obstet Gynecol (2011).doi:10.1016/j.ajog.2011.05.043

Reprints were made with kind permissions from the publishers.

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Contents

LIST OF PUBLICATIONS ......................................................................................................................................... 3

CONTENTS .............................................................................................................................................................. 4

ABBREVIATIONS .................................................................................................................................................... 6

INTRODUCTION ...................................................................................................................................................... 9

BACKGROUND ..................................................................................................................................................... 10

FAST TRACK PRINCIPLES.................................................................................................................................... 10

ANESTHESIA ....................................................................................................................................................... 13

ABDOMINAL HYSTERECTOMY............................................................................................................................ 14

HEALTH-RELATED QOL (HRQOL) .................................................................................................................. 16

HEALTH ECONOMICS .......................................................................................................................................... 16

THEORY AND HYPOTHESES ............................................................................................................................... 17

AIMS OF THE THESIS .......................................................................................................................................... 18

MATERIAL AND METHODS ................................................................................................................................ 19

STUDY DESIGN ................................................................................................................................................ 19

PARTICIPANTS ................................................................................................................................................ 19

RANDOMIZATION ........................................................................................................................................... 20

NON-PARTICIPANTS ...................................................................................................................................... 20

INCLUSION OF PARTICIPANTS ....................................................................................................................... 22

SPEED OF RECRUITMENT OF PARTICIPANTS ........................................................................................... 22

COLLECTION OF DATA ................................................................................................................................... 22

THE FAST TRACK PROGRAM .......................................................................................................................... 24

ANESTHESIA ................................................................................................................................................... 26

GENERAL ANESTHESIA .............................................................................................................................. 26

SPINAL ANESTHESIA .................................................................................................................................. 27

SURGERY ......................................................................................................................................................... 28

STANDARDIZED DISCHARGE CRITERIA ......................................................................................................... 29

DIARY .............................................................................................................................................................. 29

SICK LEAVE ..................................................................................................................................................... 29

MEASUREMENTS OF POSTOPERATIVE SYMPTOMS .......................................................................................... 29

THE SWEDISH POSTOPERATIVE SYMPTOMS QUESTIONNAIRE ................................................................. 29

MEASUREMENTS OF HRQOL ............................................................................................................................ 30

SF-36 ............................................................................................................................................................. 30

EQ-5D ............................................................................................................................................................ 31

HEALTH ECONOMICS .......................................................................................................................................... 31

STATISTICS .......................................................................................................................................................... 33

HANDLING OF MISSING DATA ....................................................................................................................... 33

ETHICS ................................................................................................................................................................. 34

RESULTS AND COMMENTS ................................................................................................................................. 35

OBJECTIVE EFFECT VARIABLES (MEASURED BY THE HEALTH CARE SYSTEM) .......................................... 36

DURATION OF HOSPITAL STAY ................................................................................................................. 36

CONSUMPTION OF ANALGESICS ................................................................................................................ 37

COMPLICATIONS ........................................................................................................................................ 39

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ACCOMPLISHMENT OF ANESTHESIA......................................................................................................... 41

SUBJECTIVE EFFECT VARIABLES (MEASURED BY THE WOMAN) ................................................................ 41

POSTOPERATIVE SYMPTOMS .................................................................................................................... 41

PAIN AND DISCOMFORT ........................................................................................................................ 42

PONV .................................................................................................................................................... 44

PRURITUS ............................................................................................................................................... 45

FATIGUE AND SLEEP DISTURBANCE..................................................................................................... 46

HRQOL ........................................................................................................................................................... 47

SICK LEAVE ..................................................................................................................................................... 50

COST EFFECTIVENESS .................................................................................................................................... 50

NON-PARTICIPATING GROUP .................................................................................................................... 52

GENERAL DISCUSSION ........................................................................................................................................ 53

METHODOLOGY .............................................................................................................................................. 53

RANDOMIZATION ........................................................................................................................................... 53

STUDY DESIGN ................................................................................................................................................ 53

PATIENT SAFETY ............................................................................................................................................ 54

QUESTIONNAIRES .......................................................................................................................................... 54

SPSQ .......................................................................................................................................................... 54

EQ-5D AND QALY MEASUREMENTS ...................................................................................................... 54

SF-36 ......................................................................................................................................................... 55

FINAL CONSIDERATIONS................................................................................................................................ 55

CONCLUSIONS ..................................................................................................................................................... 56

CLINICAL IMPLICATIONS .................................................................................................................................... 57

FUTURE PERSPECTIVE........................................................................................................................................ 57

SUMMARY IN SWEDISH - SAMMANFATTNING PÅ SVENSKA ............................................................................ 59

ACKNOWLEDGEMENTS ...................................................................................................................................... 62

REFERENCES ....................................................................................................................................................... 64

APPENDIX............................................................................................................................................................ 72

PAPER I

PAPER II

PAPER III

PAPER IV

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Abbreviations

AE Adverse events

ANCOVA Analysis of covariance

ANOVA Analysis of variance

ASA American Society of Anesthesiologists

BMI Body mass index

EQ-5D EuroQoL-5D questionnaire

ERAS Enhanced recovery after surgery

GA General anesthesia

HT Hormone therapy

HRQoL Health related quality of life

MCS Mental component summary

MOS Medical Outcomes Study

NSAID Nonsteroidal anti-inflammatory drugs

NICE National Institute for Health and Clinical Excellence

PACU Post-anesthesia care unit

PCS Physical component summary

POCD Postoperative cognitive dysfunction

PONV Postoperative nausea and vomiting

QALY Quality adjusted life years

QoL Quality of life

RCT Randomized controlled trial

RDD Recommended daily dosage

SA Spinal anesthesia with intrathecal morphine

SAE Serious adverse events

SD Standard deviation

SEK Swedish kronor

SFAI The Swedish Society of Anaesthesiology and Intensive Care Medicine

SF-36 Short-Form-36 Health Survey

SPSQ Swedish Postoperative Symptoms Questionnaire

TTO Time trade off

VAS Visual analog scale

WHO World Health Organization

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Every really new idea looks crazy at first. (Alfred North Whitehead 1861-1947)

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Introduction

Hysterectomy is the most common major gynecological operation in the Western World [Gorlero 2008]. Approximately 5000 benign hysterectomies are performed in Sweden every year mainly due to myomas and bleeding disturbances [Socialstyrelsen 2010]. Consequently it is a surgical procedure that affects many women.

The route of hysterectomy can be abdominal, vaginal, laparoscopic or laparoscopic-assisted, and the route selected in the individual case is often dependent on the surgeon‟s preference [Persson 2009a]. The abdominal route is still the most common and the only surgical approach available when dealing with an enlarged uterus [Nieboer 2009]. Irrespective of mode of hysterectomy the procedure is still a challenge concerning perioperative health care, perceived postoperative symptoms including Quality of Life (QoL) aspects and health economics.

Fast track surgery is a multimodal strategy to reduce hormonal surgical stress response and achieve an enhanced postoperative recovery without an increased readmission rate [Kehlet 2008b; Carter 2010]. The strategy of fast track is today considered to be evidence based in colorectal surgery but has still been scarcely studied in association with gynecological surgery [Kehlet 2008a; Kroon 2010]. One exceedingly important part of fast track is the application of anesthetic and analgesic techniques shown to contribute to the enhancement of perioperative care [Kehlet 2008a]. Postoperative organ dysfunction and morbidity may be related to changes induced by the hormonal stress response caused by surgery. Regional anesthesia diminishes this stress response and therefore constitutes a significant part of a fast track concept [Wilmore 2001]. Spinal anesthesia is one kind of regional anesthesia that provides benefits in the form of an extended effect on analgesia and reduced postoperative morbidity [Kehlet 1998; Rodgers 2000; Kehlet 2002]. Spinal anesthesia is commonly used for cesarean section and adding intrathecal opioids to the anesthesia has been shown to further prolong the peri- and postoperative analgesia [Dahl 1999]. General anesthesia is still the most commonly used anesthetic technique in relation to abdominal hysterectomy. Recent findings indicate benefits favoring spinal anesthesia compared with customary general anesthesia even in association with abdominal hysterectomy although this has not been studied for a fast track model [Massicotte 2009]. It is most likely that employing strategies of fast track including spinal anesthesia could provide substantial benefits for women requiring surgical removal of the uterus.

The multimodal strategy in fast track is composed of many different components and is consequently complex. Based on the published studies of fast track surgery it is difficult to determine the impact of each specific component of the strategy on the outcome measures i.e. the enhanced postoperative recovery.

Spinal anesthesia with or without other strategies of fast track has been applied in association with abdominal hysterectomy in several hospitals in Sweden during the last decade in the hope of enhancing postoperative pain management and recovery, even though not evidence based. Therefore it seemed important to investigate the possible specific advantages of spinal anesthesia as a part of a fast track model compared with standard general anesthesia in

10

abdominal hysterectomy. Enhancing postoperative recovery could imply less perceived postoperative symptoms, improvements in QoL with faster recovery of working ability and possibly improvement in cost-effectiveness. Thus there are expected benefits both for the patient and the health care system. To be able to make a contribution to the understanding of these issues we conducted the multicenter study “General anesthesia versus spinal anesthesia with intrathecal morphine in fast track abdominal hysterectomy” - the GASPI study and this clinical trial constitutes the basis for my thesis.

Background

The principles of fast track were introduced in colorectal surgery in the early 1990s by Henrik Kehlet in Denmark. The purpose was to reduce perioperative stress response and enhance postoperative recovery following elective surgery. Today the concept “fast track” is used synonymously with “enhanced recovery after surgery” (ERAS) [Varadhan 2010]. Multiple factors contribute to postoperative morbidity, duration of hospital stay and postoperative recovery; these factors include pain, postoperative nausea and vomiting (PONV), paralytic ileus and fatigue. A multimodal approach to prevent and minimize these factors is therefore essential. Fast track principles include providing the patient with preoperative education concerning pre- peri- and postoperative care, safe and short-acting anesthetics including regional anesthesia with minimal use of opioids, minimal invasive surgery, optimizing management of pain and nausea, enteral nutrition and early mobilization and perioperative intravenous fluid regulation [Wilmore 2001; Kehlet 2003; Holte 2006; Wind 2006; White 2007; Kehlet 2008a]. The involvement of the entire surgical and anesthesiological team as well as nursing staff is mandatory in order to obtain the potential advantages of fast track on postoperative recovery [Kehlet 2006].

Fast track principles

Ideally elective surgery should not influence the patient negatively, that is, the patient should be able to walk to the operating-table and following surgery be able to return home immediately. However, the reality is different. Surgery and anesthesia have negative impacts on physiology and also cause discomfort. Fast track is a concept that systematically uses multimodal strategies to reduce the negative influences of surgery and anesthesia.

Careful preoperative information and education are essential to obtain a confident and well-informed patient before surgery. This practice has been shown to reduce the need for pain relief postoperatively [Miro 1999; Wilmore 2001; Shehmar 2010].

Optimizing anesthesia with a multimodal opioid-sparing strategy including use of local anesthesia, regional anesthesia, and postoperative analgesia based on orally administered non-opioids improves recovery, patient satisfaction and accelerate normalization of quality of life [White 2007; Kehlet 2008b]. Multimodal analgesia involves use of more than one modality of pain control to obtain additive or even synergistic beneficial effects while reducing opioids administered orally or intravenously, that is by combining peripheral and central acting analgesics and analgesics with different mechanism of action. Intrathecally applied opioids in connection with regional anesthesia have been shown to have several advantages in

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preventing the surgical stress response and prolongation of the analgesia postoperatively [Dahl 1999; Karaman 2006].

Minimally invasive surgery is associated with a decrease in inflammatory responses but the potential effects of this on postoperative recovery remain incompletely understood and investigated [Wilmore 2001]. Other surgical aspects of care may influence postoperative recovery. The perioperative application of orogastric tubes, urinary catheters and drains should be based on current evidence [Kehlet 2002; Kehlet 2003]. Use of tubes, catheters and drains are associated with pulmonary and gastrointestinal morbidity and urinary tract infections [Saint 2000; Petrowsky 2004; Nelson 2007].

PONV is, together with pain, the most prevalent postoperative symptom with an incidence between 20- 30% in relation to anesthesia and surgery [Alkaissi 2004b]. The incidence of PONV remains high despite pharmacological antiemetic therapies. Several risk factors for PONV have been elucidated and include female gender, nonsmoker status, history of PONV or motion sickness and intraoperative and postoperative use of opioids. It has been proposed that a prophylactic strategy should be considered for patients with at least two of these risk factors [White 1999; Apfel 2003; White 2007]. Since antiemetic prophylaxis with pharmaceuticals often carries adverse effects, non-pharmacological techniques, such as acupressure wrist bands on acupuncture meridian point P6, can be useful in replacing standard antiemetic drugs [White 2002; Alkaissi 2004a; Lee 2009]. Other strategies to reduce the risk of PONV include use of propofol, adequate hydration and minimizing volatile anesthetics, nitrous oxide and perioperative opioid use [Kehlet 2005]. Visceral pain is also a major cause of PONV [Chia 2002] and adequate pain control reduces the incidence and severity of PONV [Alkaissi 2004b].

Several studies support the belief that early enteral nutrition is to be preferred instead of parenteral nutrition because this is advantageous with respect to improved surgical outcomes [Kehlet 2003; Soop 2004; Gabor 2005]. An active postoperative rehabilitation strategy consisting of early start of feeding and mobilization has been shown to cause a decreased duration of postoperative intestinal paralysis and prevent wasting and fatigue [Holte 2000; Pasero 2006]. Early mobilization postoperatively seems to be crucial to ensure an enhanced recovery but this is only possible when disturbing postoperative symptoms, such as pain and PONV, are sufficiently treated. Using preoperative per oral administration of glucose-containing fluids may prevent postoperative insulin resistance, attenuate the catabolic responses to surgery and reduce PONV [Hausel 2005; Noblett 2006].

Perioperative intravenous fluid regulation for patients undergoing abdominal surgery remains controversial and there is disagreement about the optimal amount of fluid to be administered. Fluid excess may compromise cardiac and pulmonary function, prolong recovery of bowel function and impair tissue oxygenation, which might interfere with wound healing. On the contrary, hypovolemia may likewise cause organ dysfunction. A meta-analysis of studies of standard, restrictive and supplemental fluid administration in surgery establishes advantages with restrictive rather than standard fluid management [Rahbari 2009].

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The fast track methodology is in this manner based on a combination of evidence-based unimodal principles of care to enhance postoperative recovery (Figure 1).

Figure 1. Fast track principles.

The comprehensive effect of fast track is to reduce surgical stress response. Surgical trauma is a physical and psychological stressing condition that triggers a systemic response regulated by a complex network of endocrine, neural and immunological mechanisms [Desborough 2000]. The stress response leads to an increased sympathetic nervous activity with elevated secretion

Staff preparation and training

Enthusiastic surgeon and anesthesiologist

Entire surgical team involvement

Procedure specific, protocol-based care plans

Preoperative

Patient education and optimization of organ function

Preoperative carbohydrate loading

Prophylaxis for nausea and vomiting

Intraoperative

Stress reduction – effective pain relief, regional anesthesia, minimal invasive surgery,

Prophylactic antibiotics Less use of drains Intravenous fluid

regulation

Postoperative

Effective opioid-sparing pain relief

Early mobilization and nutrition

Early catheter removal

Outcomes

Reduced stress response and postoperative morbidity

Enhanced recovery

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of glucocorticoids and catecholamines as well as an early hyper inflammatory status that is essential for tissue repair and host defense, but it also provokes alterations of both cellular and humoral immunity resulting in a transient immunosuppression [Wilmore 2002; Moselli 2011]. The overall metabolic effect of the hormonal changes is increased catabolism which mobilizes substrates to provide energy sources, and a mechanism to retain salt and water and maintain fluid volume and cardiovascular homeostasis. It is likely that the stress response developed as a survival mechanism but in current surgical practice it seems unnecessary [Desborough 2000]. Postoperative organ dysfunction and morbidity are almost always related to changes induced by this physiological endocrine-metabolic response to anesthesia and surgery [Wilmore 2001]. Attenuation of these undesirable effects with stress reduction techniques will improve postoperative outcome and optimize recovery [Wilmore 2002].

Anesthesia

General anesthesia is considered as the standard anesthetic technique in association with abdominal hysterectomy [Massicotte 2009]. Data from hospitals participating in the Swedish National Register for Gynecological Surgery in 2010 (Mats Löfgren, personal communication) concerning registered mode of anesthesia in relation to abdominal hysterectomy are shown in Table 1.

Table 1. Data from the Swedish National Register for Gynecological Surgery 2010 concerning mode of anesthesia in abdominal hysterectomy on benign indications.

Mode of anesthesia Abdominal hysterectomy

n=2026

Spinal anesthesia 41 (2.0%)

Epidural anesthesia 8 (0.4%)

General anesthesia 788 (38.9%)

General anesthesia + spinal anesthesia 367 (18.1%)

General anesthesia + epidural anesthesia 79 (3.9%)

Mode of anesthesia not registered 743 (36.7%)

General anesthesia provides effective intraoperative analgesia, muscle relaxation and unawareness but contributes unfortunately to unfavorable postoperative symptoms such as PONV, fatigue and drowsiness. The introduction of short-acting volatile and intravenous anesthetics permits earlier recovery and has the potential to shorten the stay in post-anesthesia care unit (PACU) [Kehlet 2003; White 2007]. General anesthesia carries the risk of inducing physiological changes often due to hypotension. This may lead to morbidity, such as myocardial infarction, cardiac arrhythmia, pneumonia, pulmonary and kidney failure and even mortality [Buhre 2003; Aitkenhead 2005; Ferreyra 2009]. The main causes of anesthesia-related mortality are problems with airway management and cardio-circulatory events, with a risk of approximately 1 per 10.000 anesthetics [Aitkenhead 2005; Braz 2009].

In obstetrics spinal anesthesia has become the gold standard for cesarean section but is not commonly used for abdominal hysterectomy [Massicotte 2009]. Adding opioids intrathecally to the spinal local anesthetic further prolongs intraoperative and postoperative analgesia with

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a concurrent depression of endocrine-metabolic stress response that could be due to a nearly total afferent neural blockade [Dahl 1999; Kehlet 2002; Karaman 2006]. General anesthesia for major abdominal surgery is therefore often combined with a concomitant injection of an opioid drug into the subarachnoid space to result in effective and prolonged postoperative analgesia [Lavand'homme 2006]. Possible side effects that are associated with spinal anesthesia including intrathecal opioids comprise intraoperative hypotension, PONV, pruritus, urinary retention, respiratory depression and post-dural puncture headache. The main concern related to regional anesthesia is the risk of permanent neurologic damage. In a review article dealing with neuropathy following regional anesthesia the risk was found to range from 0 to 4 per 10.000 applied spinal anesthetics [Curatolo 2010].

Postoperative cognitive dysfunction (POCD) affects a wide variety of cognitive functions, such as attention, memory executive function and speed of information processing [Rasmussen 2006]. POCD affects surgical patients in all age groups on a short-term basis, but resolves faster in a younger population [Monk 2008]. The etiology remains elusive but POCD has been connected with effects of general anesthesia, use of opioids and disturbed sleep architecture postoperatively. A multimodal approach within fast track principles of pain management with reduced opioids combined with a reduction in inflammatory responses with minimal invasive surgery and pharmacological anti-inflammatory intervention and improvement of postoperative sleep may therefore have a potential for improving postoperative cognitive function [Krenk 2010]. These findings may therefore speak in favor of a more frequent use of spinal anesthesia to avoid undesired cognitive effects of general anesthesia. Disrupted sleep following surgery could also create an increase in perceived fatigue and abate the ability to regain health postoperatively [Gögenur 2009].

Abdominal hysterectomy

The most common indication (85-90%) for surgical removal of the uterus is myomas with or without bleeding disturbances. Uterine myomas are the most common solid pelvic tumor in women, occurring in 20-40% of the women in the reproductive years. They are benign lesions originating from smooth muscles of the uterus, may be solitary or multiple and vary in size. The majority of women with myomas is asymptomatic and need no treatment or follow-up. If symptomatic, the symptoms usually consist of excessive menstrual bleeding and/or irregular bleeding, but could also imply mechanical discomfort and a feeling of pelvic pressure due to the size of the enlarged uterus and sometimes even pain [Duhan 2010].

Many women with symptomatic myomas have been treated conservatively with pharmaceuticals or minimal-invasive surgery as a first hand alternative to hysterectomy. Pharmaceutical treatments include use of nonsteroidal anti-inflammatory drugs (NSAID), tranexamic acid, levonorgestrel releasing intrauterine device and/or per oral or injection of progestogens. Minimal-invasive surgery comprises endometrial ablation, hysteroscopic myomectomy, embolization of the uterine artery or enucleation of myoma [NICE 2007]. Hysterectomy is therefore often the only remaining option, especially for women with a substantially enlarged uterus due to myomas not responding to other treatments. The hysterectomy contributes to significant improvements concerning preoperative symptoms and

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postoperative QoL irrespective of mode of surgical approach [Kjerulff 2000a; Kjerullf 2000b; Kuppermann 2010; Spies 2010; Persson 2009b].

Abdominal hysterectomy involves removal of the uterus through an incision in the lower abdomen (Figure 2). Total hysterectomy involves removing the entire uterus including the cervix. Subtotal hysterectomy comprises removing the body of the uterus while the lower part of the cervix is preserved. Vaginal hysterectomy is accomplished by surgery via the vagina and laparoscopic and laparoscopic-assisted hysterectomy via “keyhole surgery” through small incisions in the abdomen and removal of the uterus through the vagina. All surgical approaches include different risks and benefits that are also influenced by the surgeon‟s experience; therefore the final decision of which approach to use should be in the hands of a well-informed woman in discussion with her surgeon [Nieboer 2009]. Fast track principles have so far not been used in studies comparing different surgical approaches to hysterectomy. The abdominal approach is still the most common and is always possible, even when dealing with an oversized uterus. In the US approximately 60% of the benign hysterectomies were conducted abdominally in 2005 [Merrill 2008]. In Sweden today nearly 70 % of the hysterectomies are performed abdominally [Socialstyrelsen 2009].

.

Figure 2. Abdominal hysterectomy.

The issue of perceived postoperative symptoms after hysterectomy is often not discussed. Textbooks in gynecological surgery seldom present data on postoperative symptoms and how long they remain [Käser 1985; Te Linde 1992]. Pain and PONV are in general the only evaluated symptoms following abdominal hysterectomy, leaving out other possibly important and disturbing postoperative symptoms [Eberhart 2000; Kain 2000; Massicotte 2009]. The

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duration of the symptoms and how recovery proceeds has also been only scantly studied. Randomized studies concerning abdominal hysterectomy do not contain detailed information about how women experience postoperative symptoms and mainly describe pain experienced solely during the hospital stay [Massicotte 2009; Nieboer 2009].

All citizens in Sweden are covered by a national health insurance program funded by income-tax revenue and this program meets the costs of salary reimbursement during sick leave. The employer is responsible for the reimbursement during the initial two weeks of sick leave but then the Social Insurance Office carries the responsibility for repayment. Duration of postoperative sick leave is supposed to reflect the length of time needed to recover full working capacity. Sick leave is, however, only a rough measure of postoperative recovery and is often influenced not only by medical factors but also by factors not directly related to patient recovery such as governmental and insurance regulations, local traditions, economy and patient and doctor expectations [Socialstyrelsen 2010; Persson 2008; Persson 2010].

Health-related QoL (HRQoL)

QoL has been defined by the World Health Organization (WHO) as “individuals„ perception of their position in life in the context of the culture and value systems in which they live, and in relation to their goals, expectations, standards and concerns” [WHO 1998].

Hence QoL is a broad term that covers several aspects of life. One element of QoL is HRQoL that concerns the parts of life directly affected by changes in health. HRQoL evaluates the patient´s satisfaction with a specific level of function [Rejeski 1996]. Two distinct types of data can be collected when measuring HRQoL: health profiles and utility measures. Health profiles provide descriptive information concerning health. Utility measures reflect preferences of a health state [Berzon 1996]. Gynecological disorders, such as uterine myomas and heavy bleeding, may severely affect women´s QoL and hence are important effects to be evaluated in the context of hysterectomy [Rannestad 2000].

Health economics

Economic evaluations are needed in addition to clinical outcomes and QoL in order to make decisions regarding introduction and acceptance of new treatments and to consider the consumption of health resources [Bijen 2009]. Health economic evaluations may consist of different methods for analyses of costs in health care programs. Cost analysis compares only the costs for alternative treatments or health care programs. This analysis includes both direct costs (resources in the health care sector) and indirect costs (productivity losses in work time). Analysis of cost-effectiveness comprises comparison both of the costs and the effects or consequences of the program or treatment. In cost-utility the evaluation focuses on the quality of health as the effect outcome. The health improvement is measured in quality-adjusted life-years (QALY) gained and compared with the costs [Räsänen 2006]. The result could be expressed as cost per QALY gained [Drummond 2005]. To obtain a more comprehensive understanding of effects and costs in relation to hysterectomy it seems essential even to include and evaluate an analysis of cost-effectiveness.

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Theory and Hypotheses

The advantages of fast track principles in connection with abdominal surgery seem to embrace even the field of gynecology. The comprehensive effect is an enhanced postoperative recovery following reduction of the endocrine-metabolic stress response. Adding regional anesthesia including an intrathecally applied opioid to the fast track principles could further reduce the surgically induced stress reaction and carry additional benefits in avoidance of undesired cognitive effects of general anesthesia. The benefits should be measurable by using objective measures, i.e. measures obtained from health care, as well as by using subjective measures, i.e. measures perceived by the health care receiver.

Based on this theory the following hypotheses were proposed and constitute the basis for the thesis.

Spinal anesthesia with intrathecal morphine (SA) promotes an enhanced postoperative recovery and will therefore give rise to a shorter duration of hospital stay compared with general anesthesia (GA) in association with fast track abdominal hysterectomy.

The use of SA in fast track abdominal hysterectomy provides better pain management postoperatively compared with GA.

Performing abdominal hysterectomy under SA is associated with less perceived postoperative symptoms than hysterectomy done under GA.

Women who have fast track abdominal hysterectomy under SA will improve perceived HRQoL postoperatively more rapidly than women who have the operation carried out under GA.

In fast track abdominal hysterectomy, health economic evaluations will be in favor of SA compared with GA.

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Aims of the thesis

In order to test these hypotheses the following aims were elaborated and investigated in the thesis.

- to determine whether the duration of hospital stay after benign abdominal

hysterectomy in a fast-track model differs between women receiving SA and women receiving GA during the surgery.

- to study whether presence and intensity of postoperative symptoms differ between women undergoing benign fast track abdominal hysterectomy in SA and in GA.

- to investigate if SA provides a better and more prolonged pain relief in abdominal hysterectomy than GA

- to analyze if the speed of postoperative recovery, with emphasis on duration of sick leave and HRQoL, differs regarding use of SA and GA in fast track hysterectomy.

- to investigate the cost-effectiveness of using SA instead of GA in fast track abdominal hysterectomy.

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Material and Methods

Study design

The research on which this thesis is based was carried out in the multicenter trial “General anesthesia versus spinal anesthesia with intrathecal morphine in fast track abdominal hysterectomy. A randomized prospective open study” comparing the efficacy of GA and SA in fast track benign abdominal hysterectomy (the GASPI study).

The departments of Obstetrics and Gynecology at five hospitals of different sizes in the southeast health region of Sweden participated: the University Hospital in Linköping, Vrinnevi Hospital, in Norrköping, Ryhov County Hospital in Jönköping, Värnamo Hospital in Värnamo, and Höglands Hospital in Eksjö.

Participants

Women who were admitted to the units for elective abdominal hysterectomy between March 2007 and June 2009 were asked to participate in the study. Inclusion and exclusion criteria are shown in Figure 3.

Inclusion criteria

age between 18 and 60 years.

scheduled for abdominal total or subtotal hysterectomy.

benign indications (cervical dysplasia included).

expected that at least one ovary would be preserved at conclusion of surgery.

spoke Swedish fluently and understood it equally well.

accepted participation in the study and signed informed consent.

Exclusion criteria

contraindication against spinal or general anesthesia.

ASA ≥ class 3.

allergy towards morphine or any of the study medications.

gynecological malignancy present or in history.

previous bilateral oophorectomy.

operation expected to encompass more than hysterectomy, salpingectomy and appendectomy.

postmenopausal without hormone therapy (HT).

o if the woman was on treatment with HT, this should be maintained 6 months postoperatively.

physically disabled to a degree which could be expected to affect mobilization postoperatively. severe psychiatric disease or mental disabled.

Figure 3. Inclusion and exclusion criteria in the GASPI study.

Careful emphasis was put on the information concerning all parts of the study before the woman made her decision about participation. The mode of skin incision (low transverse or low midline) and type of abdominal hysterectomy (total or subtotal) were decided on by the surgeon in cooperation with the woman prior to randomization. After having given oral and written informed consent the included study patient was randomized to receive either GA or SA.

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Randomization

A computer generated the randomization into blocks of 10 with equal numbers of the two modes of anesthesia. The allocated mode of anesthesia was written on a label that was sealed in opaque consecutively numbered envelopes. At each center the envelopes were opened in consecutive number order of patient inclusion in the study. The participating centers were assigned slightly different numbers of blocks corresponding to the expected number of eligible patients at the hospital. If a center could not keep up with the pace of inclusion required by the study the remaining planned randomizations for that unit were distributed to the other participating centers.

Non-participants

All women admitted to the participating hospitals for benign hysterectomy were registered during the study period. Reasons for not being able to participate were recorded. During March 2008 until June 2009 women admitted for benign hysterectomy who could not or would not participate in the study were asked to fill in the base line questionnaires. The flowchart of eligible women in the study is shown in Figure 4. Eighty-four women who did not want to or could not participate in the study for various reasons completed the questionnaires preoperatively and constituted a group of non-participating women.

Figure 4. Flowchart of eligible women.

The flowchart of the randomized women in the study is shown in Figure 5.

Eligible women n= 464

Not willing to

participate

n= 83

Not informed about

study

n=17

Not fulfilling entrance

criteria for study

n= 95

Planned vaginal or

laparoscopic

hysterectomy

n= 89

Non-participating

group

n= 84

Randomized women

n= 180

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Figure 5. Flowchart of randomized women.

Allocated to General anesthesia

n = 89 Allocated to Spinal anesthesia

n = 91

Protocol violation/lack

of compliance

Withdrew consent prior

to surgery

n = 1 n = 2

n = 3 n = 6

Received allocated intervention n = 82

Received allocated intervention

n = 86

Analyzed

n = 80 Analyzed

n = 82

Excluded due to

malignancy

n = 1 n = 1

Hysterectomy could not be done due to surgical

technical reasons

n = 1

Withdrew consent after

surgery

n = 3

Randomized n = 180

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Inclusion of participants

The number of included women in the participating centers is presented in Figure 6.

0

10

20

30

40

50

60

70

Cou

nt

Link

öpin

g

Nor

rköp

ing

Jönk

öpin

g

Värn

amo

Eksj

ö

Figure 6. Number of included women in each center.

Speed of recruitment of participants

The inclusion time in the study was slightly more than two years. All centers kept the pace of inclusion except for one center that just included one patient. The time for cumulative recruitment in the study is shown in Figure 7.

020406080

100120140160180

Cou

nt

Mar

ch 0

7 - A

ugus

t 07

Sept

embe

r 07

- Feb

ruar

y 08

Mar

ch 0

8 - A

ugus

t 08

Sept

embe

r 09

- Feb

ruar

y 09

Mar

ch 0

9 - J

une

09

Figure 7. Cumulative recruitment.

Collection of data

Base line data were obtained approximately two weeks prior to surgery. The pre-, per- and postoperative data were registered continuously in the case report form. Data concerning complications, sick leave and additional medication if any were collected at the follow-up visit with the research nurses according to the study protocol. Specific registration of time of occurrence was done for the variables shown in Table 2.

23

Table 2. Registration of set times of occurrence.

Occurrence Set of time

Arrival in the ward YY-MM-DD; HH:MM Start of anesthesia YY-MM-DD; HH:MM Start of surgery HH:MM End of surgery HH:MM

End of anesthesia* HH:MM Arrival in PACU YY-MM-DD; HH:MM Arrival in gynecological ward YY-MM-DD; HH:MM Removal of transurethral catheter** YY-MM-DD; HH:MM

First pass of gas** YY-MM-DD; HH:MM First pass of bowel movement** YY-MM-DD; HH:MM Discharge from the gynecological ward YY-MM-DD; HH:MM End of sick leave YY-MM-DD

YY = year; MM = month; DD = day; HH = hour of day; MM = minutes * For GA time of extubation; for SA time when leaving the operating room. ** Registered in the gynecological ward or in the diary, depending on when it occurred.

A summarized flow sheet for assessments in relation to time during the study period is shown in Table 3.

Table 3. Summarized flow sheet for assessments.

Timing Assessment

Base line Demographic data

Questionnaires concerning QoL

During hospital stay Perioperative data

Questionnaires concerning QoL and perceived postoperative symptoms

At discharge Questionnaires concerning QoL and perceived postoperative symptoms

Start of diary concerning daily consumption of analgesics and informal

care

Once a week Telephone contact with research nurse (for support and as a reminder)

Continues the diary concerning use of analgesics and informal care

Questionnaires concerning QoL and perceived postoperative symptoms

Extension of sick leave, if necessary

5 – week follow-up visit

at the research nurse

Diary collected

Registration of complications occurring since discharge

Registration of duration of sick leave

Questionnaires concerning QoL and perceived postoperative symptoms

6 - month telephone contact with research nurse

Registration of additional sick leave and complications occurring

between the 5 – week visit and the 6 – month contact.

Questionnaires concerning QoL

24

Adverse events (AE) and serious adverse events (SAE) were registered separately. AE is any undesired event in health or side effect that occurs in a patient during the study period, not necessarily connected with the treatment. SAE is a serious adverse event recorded during the study resulting in either death, is life-threatening, demanding for readmission to in-hospital care or prolongs the duration of on-going hospital stay or causing remaining/considerable disablement.

The fast track program

All participating women in the study received similar and standardized information about care and advice for the perioperative period according to all parts of the fast track program irrespective of the randomized mode of anesthesia. The program specified that there would be no use of sedatives preoperatively, analgesics based on non-opioids, pre-emptive antiemetic therapy using acupressure wristbands, intravenous fluid regulation, early start of enteral nutrition and mobilization postoperatively and standardized criteria of discharge. A table summarizing the fast track program is presented in Table 4.

25

Table 4. Fast track protocol with standardized regimes.

Preoperatively Information Information was given and repeated concerning pre-, per- and postoperative

care, management of pain and PONV, early postoperative mobilization, enteral nutrition and discharge criteria.

Premedication Two grams paracetamol orally were given one hour before surgery. Clear fluids orally until two hours before surgery. Acupressure wrist bands applied and maintained through hospital stay.

Peroperatively

Parenteral fluids A restricted regimen mainly based on crystalloids was used in both groups and aimed at 25 ml/kg and day. Fenylephrine was given if systolic blood pressure decreased > 30% from the baseline.

Local anesthesia 100 mg bupivacaine (2.5 mg/ml) were injected subcutaneously and pre-fascially in abdominal wound at conclusion of surgery.

Prevention Antibiotic and antithrombotic prophylaxes were administered according to the routine of the department.

Bladder catheter Transurethral catheter was inserted before start of surgery. Catheter was left until next morning.

Postoperatively Post anesthetic

care unit (PACU)

Pain management was initiated orally with paracetamol and diclofenac.

Additional pain management with morphine was offered if VAS (visual analog scale) score > 3. The woman was permitted to drink. Mobilization was actively encouraged. Rescue antiemetic treatment when needed was given with droperidol and/or 5-

HT3 receptor antagonist. The woman was discharged to the gynecological ward when vital signs were stable.

Gynecological

ward.

Monitoring of hemodynamic and respiratory stability, sedation, pain, nausea and

pruritus was conducted once every hour during first 12 hours postoperatively, then once every third hour for another 12 hours. Pain management orally was continued with 1,330 mg paracetamol and 50 mg diclofenac three times daily. Additional pain relief was offered if VAS score >3.

Opioids avoided if possible. Rescue antiemetic treatment as in PACU. The woman was encouraged to drink and eat as soon as possible. Mobilization was actively encouraged.

Standardized criteria of discharge: woman was mobilized, tolerated normal diet, had sufficient pain control with oral analgesia (VAS ≤ 4), had no signs of mechanical bowel obstruction and had preferable spontaneous voiding with residual urine ≤ 150 ml; otherwise a transurethral catheter was left at discharge.

After discharge from hospital

Pain management orally continued with 1,330 mg paracetamol and 50 mg diclofenac three times daily. If NSAID were contraindicated tramadol 50 mg four times daily were given. A package of 6 tablets of oxycodone (10 mg twice daily) was given to the woman if necessary. Duration of treatment with analgesics

decided by the woman.

26

Anesthesia

General anesthesia

GA (Figure 8) was induced with propofol 1-2 mg/kg and fentanyl 1-2µg/kg intravenously. Tracheal intubation was facilitated by rocuronium 0.6 mg/kg intravenously. The anesthesia was maintained with a continuous intravenous infusion of propofol 6-10 mg/kg/hour and oxygen in air. Rocuronium and fentanyl were repeated if necessary according to the attending anesthetist. 5 mg of morphine was given intravenously twenty minutes before ending the surgery. An orogastric tube was used during surgery and removed before ending the anesthesia. A continuous infusion of fenylephrine (40µg/ml) was accessible and used if the systolic blood pressure decreased by more than 30% from start of anesthesia.

Preoperative

administration of

oxygen

Intravenous

administration of drugs

Intubation

27

Figure 8. General anesthesia (with permission of the patient).

Spinal anesthesia

SA (Figure 9) was administered with a 25-gauge needle in the L3/L4 or L2/L3 intervertebral spaces. Hyperbaric bupivacaine 20 mg (5mg/ml) and morphine 0.2 mg (0.4mg/ml) was applied intrathecally. Fifteen minutes after administration of the anesthesia the level of neural blockade was determined with a cold test and registered. Sedation was obtained throughout the surgery with a continuous intravenous infusion of propofol 2-5mg/kg/hour. In case of insufficient effect of SA the woman received GA according to the study protocol. A continuous infusion of fenylephrine (40µg/ml) was accessible and used if the systolic blood pressure decreased by more than 30% from start of anesthesia. Any aberration in coagulation, local or severe general infection or progressive neurological disease were considered to be contraindications for SA and thus for participation in the trial.

Ready for surgery

Local disinfection

28

Figure 9. Application of spinal anesthesia (with permission of the patient).

Surgery

Mode of skin incision and type of hysterectomy performed were as decided on preoperatively. The hysterectomy was to be carried out as the “routine procedure” of the department but the surgical technique was otherwise left to the surgeon‟s discretion. It was advised to avoid peritonealisation in the pelvic surgical field and anchoring of the round ligaments to the vaginal cuff or cervical stump. Plication of the sacrouterine and cardinal ligaments was permissible. Drains were not to be used routinely.

Intrathecal

administration of drugs

Administration of local

anesthesia

Spinal puncture

29

Standardized discharge criteria

Standardized criteria of discharge comprised the following mandatory components:

If the transurethral catheter was not removed due to urinary retention or for other reasons at discharge it was removed in the outpatient clinic a couple of days later. The residual urine volume was subsequently controlled by means of a portable bladder ultrasound scan.

Diary

At discharge the woman was requested to complete a diary once a day for 35 days postoperatively. She was instructed to register consumption of analgesics and recovery of bowel function. Time to first pass of gas and first bowel movement was recorded in case these had not already occurred during hospital stay. The woman also registered kind and extent of postoperative support in household (informal care) if any, performed by a relative, friend or neighbor. The time spent with informal care was registered by the patient in hours per week and subsequently added up for all weeks.

Sick leave

At discharge from the hospital the woman was granted sick leave for 14 days. The sick leave was prolonged, on the basis of the woman‟s request, by at most seven days at a time until she was able to return to work or felt sufficiently recovered. Duration of sick leave was defined as the time from the day of surgery until the day of return to work to the same extent as the woman had preoperatively.

Measurements of postoperative symptoms

The Swedish Postoperative Symptoms Questionnaire

Perceived postoperative symptoms were measured by use of the Swedish Postoperative Symptoms Questionnaire (SPSQ) (shown in Appendix). To our knowledge there was no validated form to measure perceived postoperative symptoms following benign hysterectomy.

30

We chose to use the SPSQ since it was developed for gynecological surgery patients in general in order to address and assess postoperative symptoms based on the patient´s own assessment of recovery. The SPSQ also has the advantage of measurements in three various aspects; at the moment, at the peak during the day and on the average over the day [Alkaissi 2004a]. SPSQ has previously been partly validated through pre-testing of the questionnaire concerning content validity. Reliability has been investigated with a test-retest and correlation coefficients between 0.77 and 0.95 were reported. Appropriateness of the questions was asked for and said to give a correct picture of the experience of symptoms by 98% of the patients [Alkaissi 2004b].

The woman completed the questionnaire on a daily basis and at the same time every day starting in the evening after surgery (day 0) and continuing the first seven days postoperatively. Thereafter the SPSQ was to be completed once weekly until the 5-week follow-up visit.

The questions in the SPSQ were both open- and closed-ended. The closed-ended questions had options on a Likert-type scale. The open-ended questions required written responses from the woman. The woman was initially asked if she at the moment experienced a number of symptoms commonly reported postoperatively (pain in the area of surgery, nausea, retching, headache, abdominal pain, fatigue, drowsiness, blurred vision and pruritus) and how she rated the intensity of these. The answers were rated on a 4-point scale from “none” (0) to “yes, a lot” (3). In order to estimate an overall postoperative discomfort from these symptoms except pruritus a sum score was calculated with the minimum sum score of 0 and the maximum sum score of 24. The higher the sum score, the more discomfort the woman perceived. The woman was further asked to report the intensity of pain in the surgical area at peak and on average during the day. The answers were rated on a 7-point scale from “none” (0) to “very severe” (6). Eleven other troublesome postoperative symptoms, except pain in the surgical area, were also registered and the woman reported intensity in the same way as concerning pain. The troublesome symptoms were categorized as PONV, headache, abdominal pain, drowsiness, fatigue, blurred vision, pruritus, gastro-intestinal symptoms, urinary tract symptoms, musculoskeletal system symptoms and wound-related symptoms. In the SPSQ the woman also recorded any experience of vomiting with the answers: “no vomiting”, “once” or “several times” daily. The quality of sleep at night was asked for and could be answered as: “well”, “neither well nor bad”, or “badly”.

Measurements of HRQoL

To assess HRQoL the Short Form-36 Health Survey (SF-36) and the EuroQol EQ-5D (EQ-5D) questionnaire were used.

SF-36

The SF-36 form was used preoperatively, at five weeks and six months postoperatively. The SF-36 was chosen since it is a generic, descriptive, multipurpose, short-form health survey consisting of 36 questions yielding an eight-scale health profile of scores as well as physical and mental health summary measures [Ware 1994; Ware JE Jr. 2000]. The SF-36

31

questionnaire is widely used for assessments of HRQoL, even following hysterectomy [Gimbel 2003, Thakar 2004]. The form has been translated and validated under Swedish circumstances [Ware 1992; Ware 1993; Sullivan 1995; Sullivan 2002]. SF-36 provides a practical alternative to longer measures and the eight scales and two summary scales rarely miss a noteworthy difference in physical or mental health status in group comparisons [Katz 1992; Ware 1993; Ware 1994]. Eight health components are included in the health survey – physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional and mental health. Sum scores are calculated for each component and also the summary component for physical and mental health respectively. The summary components cover 35 of the 36 items in the questionnaire; 21 in the physical component summary (PCS) and 14 in the mental component summary (MCS). All scores are on a scale from 0 to 100. A higher score represents a better HRQoL.

EQ-5D

The EQ-5D questionnaire was used preoperatively, daily during the first week after surgery, then once weekly until the 5-week visit and finally at the 6-month postoperative follow-up. We chose to use the EQ-5D since it is a validated, generic, established instrument and applicable to a wide range of health conditions and interventions measuring HRQoL and has previously also been used in association with studies concerning hysterectomy [The EuroQoL Group 1990; Garry 2004; Gorlero 2008]. It was developed by the EuroQoL Group, a consortium of investigators in Western Europe and the original format was simultaneously developed in Dutch, English, Finnish, Norwegian and Swedish. The questionnaire includes five attributes – mobility, self-care, usual activity, pain/discomfort and anxiety/depression [The EuroQoL Group 1990; Kind 1996]. Each attribute has three levels: “no problem”, “some problems” and “major problems”. A unique EQ-5D health state as a utility measure is defined by combining one level from each of the five attributes thus defining 35 =243 possible health states. A value of each of these has been estimated on a utility scale based on interviews using the Time Trade Off (TTO) technique on a random sample of 3395 members of the adult population of the United Kingdom [Dolan 1995]. The utility measures are on a scale from -0.594 to 1. Zero indicates the state of death and 1 the state of full health.

Health economics

Direct costs related to hospital stay and indirect costs (i.e. cost for productivity loss due to sick leave) were calculated in Swedish kronor (SEK) for the study groups respectively using costs from the year 2010. Standard unit cost for time spent in the operating theatre was estimated based on cost accounting records from the University Hospital, Linköping, for year 2010. The use of a standard unit cost was justified on the basis of no significant differences between the study groups concerning time of anesthesia, time of surgery and costs for devices and material. Relevant costs that differed are presented separately including time for the anesthesiologist to induce anesthesia and costs for anesthetic drugs. Costs for time in PACU and duration of hospital stay in the gynecological ward were derived from cost accounting records from University Hospital, Linköping 2010. Costs for productivity loss due to sick

32

leave were estimated by the human capital approach, based on the average annual income for women aged 20-64 years in Sweden 2008 [Socialstyrelsen 2010].

To estimate the number of QALYs gained we used the average differences in health state index scores between the study groups assessed through the EQ-5D questionnaire. For the first week the differences in measured QoL (a weight 0-1) between the study groups were calculated for each day. For the second to the fourth week the average differences per week were calculated based on mean health state index scores on day 7, 14, 21 and 28, respectively. The day differences were summed together and divided by number of days with a gain in QoL (1.86/29=0,064)). We assume no effect after day 29. The gain in QoL during 29 days/365 days = 0.08 of a whole year is expressed in average gain representing Quality adjusted life year (QALY) per patient.

33

Statistics

Sample size in the trial was estimated based on the primary objective – duration of hospital stay. In order to obtain a 90% power given an α = 0.05 the sample size was estimated to be 180 women including a drop out of 10% provided that the mean stay in hospital after benign abdominal hysterectomy in GA before commencing the study was 3.7 ± 2.0 days and based on the assumption that the duration of stay in hospital after hysterectomy would be reduced by one day after SA compared with GA. Data are presented as mean and (one standard deviation (SD)), median and (range) or number and per cent as appropriate. All analyses were done according to intention-to-treat principles. Full application of intention to treat is possible only when complete outcome data are available for all randomized subjects [Hollis 1999]. Due to research ethical considerations it is not possible to collect information from subjects who are withdrawing their consent. Intention-to-treat principles were followed in the analyses for those subjects with complete data. In addition, per protocol analyses were performed and reported appropriately in the text. In univariate analyses Student´s t-tests (two-sided), Mann Whitney U-tests, Yates corrected χ2tests and Fishers´ exact tests were used, when appropriate, to compare descriptive and clinical data between the two groups. Analysis of covariance (ANCOVA) was used to test differences in continuous outcome measures between the two groups and logistic regression analysis to analyze nominal effect measures. Analyses of data measured repeatedly were done by means on repeated-measures analysis of variance. Level of significance was set at 5%.

To validate the sum score in the SPSQ, factor analyses (principal component factoring with orthogonal/varimax rotation) were performed to reveal the dimensionality of the scale. In the first step, the Kaiser criteria (communality >1.0) were used to identify the numbers of factors. In the second step, a predetermined factor solution with one factor was tested. Factor loadings ≥0.4 were regarded as significant. The internal consistency reliability was estimated by means of Cronbach‟s alpha. All validation analyses were performed on data in the SPSQ derived at the third occasion of measurement i.e. in the evening on the second day after the surgery. The software StatView for Windows, SAS Institute Inc. Copyright© 1992 - 1998, Version 5.0.1 was used for the statistical analyses except for the factor analyses which were performed with STATA 11.0 for Windows (StataCorp LP).

Handling of Missing data

In using repeated-measures analysis of variance data for every moment is required and missing answers has to be considered and dealt with. If an answer was missing in the SPSQ, the cell was substituted by the mean value of the score for the group on that occasion. Missing data in the SPSQ made up 1.4% and a complete form was missing in 0.7%. In the SF-36 a missing cell was substituted by the truncated mean value of the other items in the specific subscale for the individual. If all cells in a subscale were missing they were substituted by the truncated mean value of each cell in the group. In case of a complete missing questionnaire, each cell was substituted by the truncated mean value of the cell for the group on that occasion. Missing cells for the SF-36 on all three occasions were 0.44% and a complete missing questionnaire occurred in 2.26%. Missing data in the EQ-5D made up 1.68%. In these

34

cases the health state index score was substituted for by the mean value of the group. The frequency of missing data was equally distributed between study groups and considered to be of low rate which strengthens the results.

Ethics

The study was approved by the Regional Ethical Board at Linköping University and the Swedish Medical Products Agency. An additional ethical approval was obtained to be able to analyze a non-participating group of women. The study was planned, designed, conducted and monitored in accordance with Good Clinical Practice and the Declaration of Helsinki. Careful ethical considerations were taken into account when preparing and planning for the study. Both GA and SA are well established anesthetic procedures in association with surgery and carry known but rare risks for complications. Resources and competence concerning proceedings for possible prevention and dealing with arising complications were accessible. AE and SAE were registered and dealt with when necessary in order to assure the safety of the participants. Thorough information was given to the possible participants both orally and in writing before individual informed consent was obtained. All women were guaranteed and treated with confidentiality thus defending the integrity of the individual woman.

35

Results and comments

The randomization process worked well since there were no significant differences in baseline demographic and clinical data between the study groups as seen in Table 5.

Table 5. Perioperative demographic and descriptive data.

Characteristics GA

(n=80) SA

(n=82)

Age (years) 45 (33 – 58) 46 (35 – 58)

Body mass index (kg/m2) 25.3 (19.0 – 41.5) 25.4 (18.9 – 38.0)

BMI ≤ 25 39 (48.8%) 35 (42.7%)

BMI > 25 and < 30 24 (30.0%) 31 (37.8%)

BMI ≥ 30 17 (21.2%) 16 (19.5%)

Physical work load (no. of women) n=74 n=78

Sedentary 19 (25.7%) 34 (43.6%)

Medium 25 (33.8%) 21 (26.9%)

Heavy 30 (40.5%) 23 (29.5%)

Parity 2.0 (0 – 5) 2.0 (0 – 8)

Smokers 16 (20.0%) 13 (15.9%)

Previous laparotomy 29 (36.3%) 29 (35.4%)

Previous anesthesia General anesthesia 21 (72%) 21 (70%)

Spinal/epidural anesthesia 8 (28%) 9 (30%)

Concomitant diseases Psychiatric 8 (10.0%) 6 (7.3%)

Musculoskeletal 11 (13.8%) 6 (7.3%)

Cardiovascular 8 (10.0%) 9 (11.0%)

Chronic pulmonary 3 (3.8%) 7 (8.5%)

Concomitant medication Analgesics 21 (26.3%) 11 (13.4%)

Antidepressants 8 (10.0%) 5 (6.1%)

Indication of hysterectomy Bleeding disturbances 46 (57.5%) 46 (56.1%)

Mechanical symptoms 27 (33.7%) 29 (35.4%)

Cx dysplasia/end. hyperplasia 4 (5.0%) 5 (6.1%)

Endometriosis/dysmenorrhea 3 (3.8%) 2 (2.4%)

ASA Class I 59 (73.7%) 55 (67.1%)

Class II 21 (26.3%) 27 (32.9%)

Mode of hysterectomy Total abdominal 55 (68.8%) 51 (62.2%)

Subtotal abdominal 25 (31.2%) 31 (37.8%)

Mode of skin incision Midline 6 (7.5%) 7 (8.5%)

Low transverse 74 (92.5%) 75 (91.5%)

Figures denote median and (range) or number and (%). Cx = cervical; end. = endometrial

36

Objective effect variables (measured by the health care system)

Duration of hospital stay

The duration of hospital stay was measured as the time in hours from start of anesthesia to the time of discharge from hospital. The cumulative distribution of duration of hospital stays (in hours) is presented in Figure 10.

GA SA

0

,1

,2

,3

,4,5

,6

,7

,8

,9

1

0 20 40 60 80 100 120 140 0

,1

,2

,3

,4,5

,6

,7

,8

,9

1

0 20 40 60 80 100 120 140

Figure 10. Cumulative distribution of hospital stays in relation to mode of anesthesia.

Number of women randomized and completing the study and median duration of hospital stay for each center is shown in Table 6.

Table 6. Number of women randomized and completing and duration of hospital stay in each center.

Center

Number (%) of women randomized

in the trial

Number (%) of women completing

the trial

Duration of hospital stay (hours)

Median and (range)

Linköping 66 (36.7%) 64 (39.5%) 44 (22-125)

Norrköping 60 (33.3%) 53 (32.7%) 51 (26-74)

Jönköping 30 (16.7%) 23 (14.2%) 51 (34-80)

Värnamo 23 (12.8%) 21 (13.0%) 43 (25-98)

Eksjö 1 (0.5%) 1 (0.6%) 53 (--)

No significant difference was found between the study groups concerning hospital stay. The GA group had a median hospital stay of 50 hours (range 24-100 h) compared with 46 hours (range 22-125 h) for the SA group. In the analysis of duration of hospital stay, adjustments were made for mode of hysterectomy, skin incision, BMI, smoking habits and occurrence of change of mode of anesthesia, since these are possible confounding factors even though we are dealing with a randomized study. Compared with the results in published randomized studies concerning abdominal hysterectomy our study reports a considerably shorter duration of hospital stay than do any of these studies [Thakar 2002; Learman 2003; Nieboer 2009; Persson 2010]. However, in most of these studies the duration of hospital stay was not clearly defined. It was frequently described as hospital stay only or postoperative hospital stay

hours

Cumulative relative frequency

37

without any specific information about how, exactly, it had been calculated. In some of the studies more detailed information was given [Ottosen 2000; Learman 2003; Persson 2010], but not in a manner relating to point of time. In order to compare duration of hospital stay, stay must be precisely defined. The preoperative time in hospital may vary widely depending on local traditions and medical, social and geographic conditions. It is therefore not practical to use time of admission to hospital as the starting point in the measurement of hospital stay in elective surgery for benign conditions. In this study we chose the time from start of anesthesia and consider this to be a useful starting point for calculation of hospital stay in surgery since it eliminates the time spent during all actions preoperatively that are not controlled or standardized. However we did not find any significant difference between study groups in time spent in the hospital prior to surgery, with the median 2.7 hours in the SA group and 2.8 hours in the GA group. It also seems appropriate to compare hospital stay after hysterectomy in hours since the trends are turning towards a shorter hospital stay and possibly eventually even to a day care procedure. Standardized criteria of discharge well known by staff and patient are required in order to be able to assess duration of hospital stay due to medical reasons above all. All women and staff members in this trial were well informed about the fast track concept and that discharge was possible and expected when the discharge criteria were met. This has probably influenced and shortened the duration of hospital stay in our study compared to time in hospital following traditional postoperative care and may be the main cause for the discrepancy between length of hospital stay in other randomized studies of benign abdominal hysterectomy and our trial in a fast track setting.

Feasible time of discharge from hospital still influences the registered duration of hospital stay even considering fast track programs. Usually most of patients are limited to discharge in the morning or middle of the day due to routines of the ward, hence restricting the distribution of registered time of discharge. In our study the registered time of discharge from the gynecological ward varied between 10 am and 8 pm, with discharge being most frequent around noon. This might have concealed a difference in duration of hospital stay between the study groups.

None of the previously published randomized studies concerning abdominal hysterectomy have clearly stated that they used a fast track concept, but the duration of hospital stay in these studies was considerable longer than in our study (2.5-10 days) which speaks against use of a fast track model [Thakar 2002; Learman 2003; Nieboer 2009; Persson 2010]. It seems that the provision of thorough preoperative information concerning expected perioperative care and discharge criteria is more important than, for example, mode of anesthesia, mode of hysterectomy or kind of incision in influencing the duration of hospital stay.

Consumption of analgesics

The day-by-day consumption of analgesics postoperatively during hospital stay is illustrated in Table 7. The consumption of opioids on day 0 and day 1 was significantly lower in the SA group. Speed of recovery of bowel function was associated with the consumption of opioids. Time to first bowel movement was median 50 hours (range 11-153 hours) in the SA group, which was significantly shorter than the 57 hours (range 22-124) in the GA group. However, this did not affect the need for rescue treatment of nausea or the duration of hospital stay.

38

Table 7. Postoperative analgesics during hospital stay.

GA SA

Analysis of covariance*

p -value

Day 0 (= day of surgery) n = 80 n = 82

Equivalent morphine dose (mg) 18.5 (5.0 – 49.5) 0.4 (0.0 – 35.8) <0.0001

Non-opioid analgesics (RDD) 2.1 (1.1 – 2.8) 1.8 (1.2 – 2.8) 0.8074

Day 1 n = 80 n = 82

Equivalent morphine dose (mg) 0.0 (0.0 – 42.7) 0.0 (0.0 – 40.8) 0.0462

Non-opioid analgesics (RDD) 2.0 (0.0 – 2.7) 1.2 (0.0 – 2.7) 0.0400

Day 2 n= 56 n=47

Equivalent morphine dose (mg) 0.0 (0.0 – 15.0) 0.0 (0.0 – 26.7) 0.6913

Non-opioid analgesics (RDD) 0.0 (0.0 – 2.0) 0.0 (0.0 – 2.3) 0.6407

Day 3 n= 12 n= 9

Equivalent morphine dose (mg) 0.0 (0.0 – 6.7) 0.0 (0.0 -16.6) 0.2918

Non-opioid analgesics (RDD) 0.5 (0.0 – 2.0) 0.7 (0.0 -2.2) 0.8834

Figures denote median and (range). RDD = sum of recommended daily dosage. *Adjusted for mode of hysterectomy, skin incision, BMI, smoking habits and change of mode of anesthesia.

Table 8 shows the summary consumption of analgesics during hospital stay and postoperatively after discharge. Information concerning equivalent morphine is shown only for day 0-4 and for day 0-8 for the non-opioids since the doses after these days were very low in both groups.

Table 8. Summary of consumption of analgesics.

GA SA Main effect

between groups Main effect over time

Equivalent i.v. morphine dose (mg)

Day 0 18.5 (5.0 - 49.5) 0.4 (0.0 – 35.8)

p < 0.0001 p < 0.0001

Day 1 0.4 (0.0 - 42.7) 0.0 (0.0 – 40.8)

Day 2 0.0 (0.0 – 15.0) 0.0 (0.0 – 27.6)

Day 3 0.0 (0.0 – 13.3) 0.0 (0.0 – 16.6)

Day 4 0.0 (0.0 – 12.5) 0.0 (0.0 – 15.2)

Non-opioids (RDD)

Day 0 2.1 (1.1 – 2.8) 1.8 (1.2 – 2.8)

p = 0.2590 p < 0.0001

Day 1 2.0 (0.0 – 2.7) 2.0 (0.0 – 2.7)

Day 2 1.7 (0.0 - 2.7) 1.7 (0.0 – 3.3)

Day 3 2.0 (0.0 – 2.7) 1.8 (0.0 – 2.7)

Day 4 2.0 (0.0 – 2.7) 1.4 (0.0 – 2.4)

Day 5 1.5 (0.0 – 2.0) 1.3 (0.0 – 2.0)

Day 6 1.3 (0.0 – 2.2) 1.0 (0.0 – 2.0)

Day 7 1.0 (0.0 – 2.0) 1.0 (0.0 – 2.0)

Day 8 1.0 (0.0 – 2.0) 0.9 (0.0 – 2.0)

Figures denote median and (range). RDD = sum of recommended daily dosage.

39

The lower consumption of opioids on day 0 and day 1 in the SA group could indicate that SA supplied a superior and prolonged analgesia since the SA group also reported significantly less pain during the corresponding time. This has also been reported in previous studies concerning SA [Karaman 2006; Massicotte 2009].

Complications

The complications that occurred during hospital stay and within five weeks after discharge from hospital are presented in Table 9.

The number of complications did not differ significantly between the SA and the GA group or between centers and the complication rates were comparable to those presented in previous studies concerning abdominal benign hysterectomy [Gimbel 2003; Learman 2003; Thakar 2004; Gorlero 2008; Brummer 2011]. Four women were readmitted to in-hospital care, three women in the GA group and one in the SA group.

SAEs were registered and reported to the Swedish Medical Products Agency in the annual report of SAE in clinical trials. A total of 17 events were reported and none was considered to be connected with the drugs used in anesthesia, i.e. the drugs under investigation. Nine of the events were considered to be surgically related and two events anesthesiologically related although not associated with the particular drugs of anesthesia. The remaining six events were neither related to surgery, anesthesia nor postoperative care. The events associated with surgery or anesthesia are known complications and have been reported in previous studies. Table 10 shows all the registered SAEs, when the event was first noticed in relation to time elapsed from the day of surgery, and mode of anesthesia.

To be able to prevent complications following hysterectomy several important sources of complications have to be dealt with. The most common complication is postoperative infectious morbidity. Risk factors for infectious morbidity are age, smoking habits, obesity, use of prophylactic antibiotics, duration of surgery, duration of use of transurethral catheter, mode of hysterectomy and length of hospital stay [Mäkinen 2001; Peipert 2004]. In our study the occurrence of postoperative infections comprised 75% of the registered complications. Patients that developed complications had a significantly higher body mass index (BMI) and a longer duration of hospital stay.

40

Table 9. Number and type of complications within five weeks after abdominal hysterectomy. Major complications GA SA

Heavy bleeding, exceeding ≥ 1000 ml 2 (2.5%) 2 (2.4%)

Blood transfusion (no. of women) 3 (3.8%) 0 (0%)

Bladder injury 1 (1.3%) 2 (2.4%)

Reoperation due to bladder injury 0 (0%) 1 (1.2%)

Reoperation due to retained surgical towels 1 (1.3%) 0 (0%)

Retroperitoneal and subcutaneous emphysema 1 (1.3%) 0 (0%)

Pulmonary embolism 0 (0%) 1 (1.2%)

Post-dural puncture headache 0 (0%) 1 (1.2%)

Prolonged neuropathy 0 (0%) 1 (1.2%)

Minor complications

Lower urinary tract infection 6 (7.5%) * 5 (6.1%)

Fatigue 1 (1.3%) 0 (0%)

Pain/neuralgia 5 (6.3%) 3 (3.7%)

Urticaria 1 (1.3%) 1 (1.2%)

Urinary catheter at discharge 2 (2.5%) 2 (2.4%)

Cholecystolithiasis 1 (1.3%) 0 (0%)

Abdominal wound complications 10 (12.5%) * 12 (14.6%)

Vaginal bleeding/vaginal hematoma/infection 3 (3,8%) * 2 (2.4%) *

Treatment for anemia 1 (1.3%) 1 (1.2%)

Constipation 1 (1.3%) 1 (1.2%)

Sore throat 0 (0%) 1 (1.2%)

Vaginal and oral candidiasis 0 (0%) 1 (1.2%)

Figures denote number and (%). * indicates a woman needing readmission to in-hospital care. Table 10. Registered SAEs.

SAE Event occurred or observed (no. of days from surgery) Mode of anesthesia

Surgical related

Subcutaneous/retroperitoneal emphysema 0 GA

Vascular injury of pelvic vessel 0 GA

Pulmonary thrombo-embolism 1 SA

Intraabdominal bleeding 1 GA

Infected pelvic hematoma 6 GA

Vaginal cuff infection 7 GA

Infected pelvic hematoma 7 SA

Abdominal wall wound infection 15 GA

Lower urinary tract infection 22 GA

Anesthesiological related

Neuralgic pain in right hip and femur 0 SA

Postdural puncture headache 2 SA

Not related to anesthesia or surgery

Leiomyosarcoma uteri 50 SA

Acute cholecystitis 60 GA

Traumatic fracture of vertebra Th12 84 GA

Amoebic dysentery 88 GA

Gastroenteritis with septic chock 99 SA

Subarachnoidal bleeding 101 SA

41

Accomplishment of anesthesia

In the GA group the anesthesia given according to the study protocol could not maintain sufficient depth of anesthesia in five women (6.3%) and N2O or sevoflurane was added. Two women in the GA group experienced severe pain in the immediate postoperative period in PACU despite additionally administered intravenous opioids and therefore also received a supplementary regional anesthesia. Eight women (9.8%) in the SA group had an insufficient anesthesia for surgery and in addition also received GA according to the study protocol.

There are diverging data concerning failures in spinal anesthesia and the rates reported differ significantly between 0% and 11.6% [Puolakka 2000; Kinsella 2008; Fettes 2009; Massicotte 2009; Sadashivajah 2010; Weed 2011]. Reaching a sufficient level of neural blockade according to the determined surgical procedure provides a challenge to the attending anesthesiologist. The spinal anesthetic was delivered through intervertebral space L2/3 in 8.6%; in L3/4 in 87.7%; and in L4/5 in 3.7%. The upper level of sensory blockade was median to the level of Th4 (range C3–Th10) which was quite sufficient for the intended surgery [Massicotte 2009]. None of the women in the SA group needed respiratory assistance due to high level of motor blockade. In previous studies of SA different doses of intrathecal morphine have been used [Dahl 1999; Rodanant 2003; Karaman 2006; Gehling 2009; Massicotte 2009]. There is a dose -effect/side effect response to intrathecal morphine. Doses of 0.1-0.3 mg seemed to be efficient without increasing the frequency of side effects, such as PONV, pruritus and respiratory depression [Dahl 1999; Gehling 2009]. We chose to use 0.2 mg morphine as a standard dose since it seemed to be efficient and safe with a relatively low and clinically acceptable frequency of side effects. This is in accordance with previous studies showing that a dose < 0.3 mg of intrathecal morphine carries the same risk of respiratory depression as systemic opioid analgesia [Gehling 2009].

Subjective effect variables (measured by the woman)

Postoperative symptoms

Perceived postoperative symptoms were measured by SPSQ. Symptoms originating from the immediate postoperative period are presented in Paper I. Paper II describes postoperative symptoms including intensity and prevalence appearing until the 5 week follow-up. All women gave comments about the appropriateness of the questions at the end of each questionnaire. The SPSQ was described as appropriate and giving a correct picture of their perceived symptoms by 95 % of the women. Factor analyses were performed to investigate and validate the creation of a sum score (Table 11). The analyses revealed that a sum score was useful and valid for demonstrating the comprehensive expression of the postoperative symptoms asked for.

42

Table 11. Factor analyses (principal component factoring with orthogonal/varimax rotation) of the sum score in the SPSQ, n=155.

Factor analysis no. 1 Factor analysis no. 2

Item no. Symptom

Factor I Loadings

Factor II Loadings

Factor III Loadings

One predetermined factor

Loadings

1 Pain in the area of surgery 0.112 0.043 0.873 0.575

2 Nausea 0.068 0.874 0.175 0.601

3 Retching 0.083 0.909 -0.030 0.516

4 Headache 0.544 0.372 0.013 0.556

5 Abdominal pain 0.108 0.074 0.903 0.605

6 Tiredness 0.620 0.171 0.357 0.689

7 Drowsiness 0.722 0.250 0.270 0.748

8 Difficulty with accommodation 0.815 -0.077 0.024 0.501

Communality, after rotation 1.90 1.83 1.80 2.92

Explained variance, cumulative 0.24 0.47 0.69 0.37

Cronbach’s alpha 0.65 0.75 0.78 0.73

Factor loadings ≥0.4 are defined as significant (marked with bold).

Pain and discomfort

Postoperative symptoms in the immediate postoperative period are to a large extent related to the undergone anesthesia and surgery. Pain is the most prominent postoperative symptom and minimizing postoperative pain has a very high priority among patients [Jenkins 2001; Carvalho 2005; Idvall 2008]. Previous studies suggest that postoperative pain often is undertreated as a result of inadequate education of care providers [Kalkman 2003]. Abdominal surgery tends to be the most painful among all surgery types and 70% of patients who undergo upper abdominal surgery suffer from severe pain [Rejeh 2010]. Postoperative pain affects the cardiovascular, respiratory and endocrine systems and continuing pain is associated with delayed healing, higher complication rates, anxiety, sleep disturbances, increased suffering and lowered quality of life [Myles 2000; Choi 2008; Rejeh 2010]. Acute postoperative pain also increases the likelihood of chronic postsurgical pain [Kim 2001: Katz 2009]. With this background it seems important to promptly notify and treat postoperative pain. Regional anesthesia including an intrathecal opioid provides prolonged analgesia in the postoperative period. This is also seen in our study where the SA group reported significantly less pain in the surgical area both at peak and on average (Figure 11) during the first two postoperative days in spite of lower requirement of opioids compared with the GA group.

43

0

1

2

3

4

5

6D

ay 0

Day

1

Day

2

Day

3

Day

4

Day

5

Day

6

Day

7

Day

14

Day

21

Day

28

Day

35

Sp-moGA

Figure 11. Average pain intensity. Boxes indicate mean and bars indicate one standard deviation.

Intrathecally applied opioids have been shown to prevent surgical stress response [Borgdorff 2004; Karaman 2006] which also might explain the difference in overall postoperative discomfort measured by SPSQ sum score, in favor of the SA group (Figure 12).

0

2

4

6

8

10

12

14

16

Day 0 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 14 Day 21 Day 28 Day 35

Sp-moGA

Figure 12. SPSQ sum score. Boxes indicate mean and bars indicate one standard deviation.

The proportion of women perceiving abdominal pain postoperatively without considerations of intensity of the pain was still high in spite of the expected advantages of the fast track

SPSQ sum score

Pain intensity on average

GA

SA

GA

SA

Intensity scale

Sum score

44

concept (Figure 13). However, abdominal pain was reported in a significantly lower proportion of women in the SA group day 0 and day 1 than in the GA group which might reflect the effect of a prolonged postoperative analgesia with SA.

Figure 13. Prevalence of abdominal pain.

The advantages of SA concerning pain and discomfort on day 0 and day 1 became more apparent when the number of women reporting “no pain” or “no discomfort” at all the first three postoperative days was presented in the GA and SA group respectively (Table 12).

Table 12. Number and (%) of women who report “no pain” or “no discomfort” on Day 0 - 2.

GA (n=80)

SA (n=82)

No pain Day 0 0 (0%) 23 (28.0%) Day 1 2 (2.5%) 11 (13.4%)

Day 2 5 (6.2%) 9 (11.0%) No discomfort

Day 0 4 (5.0%) 16 (19.6%) Day 1 5 (6.2%) 9 (11.0%)

Day 2 8 (10.0%) 8 (10.0%)

PONV

Acupressure wrist bands stimulating acupoint P6 were provided for pre-emptive antiemetic therapy. The proportions of women using the acupressure wrist bands and the use of rescue antiemetics did not differ between study groups. In Paper I the measured frequency of vomiting is that observed by the staff. In Paper II the perceived PONV and the explicit occurrence and frequency of vomiting is that noticed by the woman and reported in the SPSQ.

GA

SA

45

Figure 14. Prevalence of PONV.

The prevalence of perceived PONV in SPSQ did not differ between SA and GA as illustrated in Figure 14. On the other hand, self-reported vomiting occurred significantly more often and more frequently in the SA group but only during the day of surgery. The explanation of this could be that only the women who had GA received an orogastric tube and gastric emptying during surgery. It is a clinical observation that vomiting is not always preceded or accompanied by nausea. Vomiting could be triggered by the gastric paralysis after intraabdominal surgery. Intrathecally applied morphine could also contribute to an increase in vomiting [Gwirtz 1999; Gehling 2009].

Pruritus

The prevalence of pruritus reported in this study is in accordance with other studies [Gwirtz 1999]. Pruritus occurred in the immediate postoperative period but disappeared within 48 hours and was significantly more prevalent in the SA group compared with the GA group as shown in Figure 15.

Figure 15. Prevalence of pruritus.

Pruritus is a well-known side effect of intrathecal morphine [Dahl 1999; Gehling 2009]. The mechanism of pruritus is not well understood. It is likely due to migration of the intrathecal morphine in cerebrospinal fluid and subsequent interaction with the trigeminal nucleus located superficially in the medulla, an “itch centre” [Chaney 1995]. Opioid receptors are

GA

SA

GA

SA

46

present in the trigeminal nucleus and nerve roots and the most common location of induced pruritus is in the facial areas innervated by the trigeminal nerve [Snyder 1977; Ballantyne 1988]. Opioid-induced pruritus is often responsive to naloxone but antihistamines may also be an effective treatment for pruritus, possibly secondary to sedative effects [Chaney 1995]. The intensity of pruritus following intrathecal opioids varies widely from 0% to 100% and it is often elicited only after direct questioning [Chaney 1995]. In our study both the occurrence and the intensity of perceived pruritus was assessed by the SPSQ. The reported intensity of pruritus in the SA group on the day of surgery is presented in Figure 16.

Figure 16. Intensity of pruritus in the SA group day 0.

Fatigue and sleep disturbance

Postoperative fatigue is common following abdominal surgery. The type of surgery is a possible predictor of fatigue severity, with major abdominal, gynecological, cardiac and minor surgery associated with greater fatigue than orthopedic surgery [Rubin 2004]. Fatigue is reported as a prominent complaint after hysterectomy and often interferes with daily activities. Fatigue may occur as a result of biopsychosocial demands for energy that exceed the resources for coping [Kim 2001; Kim 2009]. It is often related to postoperative pain and fragmented sleep and may lead to negative psychologic health sequela and POCD [Kim 2001; Krenk 2010]. Fatigue was reported as a troublesome symptom by a substantial proportion of the women in our study. More than 40% in the GA group reported fatigue on the day of surgery and still 3 weeks postoperatively more than 20% in both study groups reported fatigue in spite of the multimodal approach of fast track postoperative care (Figure 17).

No. of women

47

Figure 17. Prevalence of fatigue.

Sleep disturbances postoperatively can be associated with fatigue and impaired postoperative recovery [Bisgaard 1999; Kim 2001; Krenk 2010]. Changes in sleep are influenced not only by the surgical intervention, postoperative recovery, hospital environment but also preoperative sleep disturbances [Schofield 1991; Kim 2001]. The self-reported quality of sleep did not differ between women in the SA and GA group at any occasion of measurement. The results of the first three nights postoperatively are presented in Table 13. After the first week fewer than 10% stated they slept badly, equally reported in the two groups. No measurements were done preoperatively concerning quality of sleep.

Table 13. Self-reported quality of sleep postoperatively.

Night no. 1 Night no. 2 Night no. 3

Quality of sleep GA SA GA SA GA SA

Well 18 (23%) 30 (36%) 32 (40%) 42 (52%) 40 (50%) 40 (49%)

Neither well nor badly 23 (30%) 26 (32%) 24 (33%) 24 (30%) 33 (41%) 26 (32%)

Badly 37 (47%) 26 (32%) 21 (27%) 15 (18%) 7 (9%) 16 (19%)

p-value* 0.0818 0.3002 0.1149

Figures denote number and (%). * Yates‟ χ2- tests (df = 2).

HRQoL

We chose to use both EQ-5D and SF-36 for complementary addition to reassure the results of HRQoL and for demonstration of both utility measures and health profiles.

Base line scores did not differ significantly between the study groups except for the mental health aspect in SF-36. The SA group had a faster recovery in HRQoL measured by EQ-5D (Figure 18). Measurements of HRQoL by means of SF-36 revealed that SA was associated

GA

SA

48

with better perceived HRQoL concerning bodily pain, vitality, social functioning, role emotional, mental health and MCS (Table 14).

0

,2

,4

,6

,8

1

1,2P

reop

Day

0

Day

1

Day

2

Day

3

Day

4

Day

5

Day

6

Day

7

Day

14

Day

21

Day

28

Day

35

6 m

onth

s

Sp-moGA

Figure 18. EQ-5D weighted health state index in relation to occasion of measurement.

Previous studies concerning HRQoL following abdominal benign hysterectomy in standard postoperative care have definitely shown long-term improvements [Rannestad 2001; Gimbel 2003; Garry 2004; Thakar 2004; Gorlero 2008]. Fast track strategies are known to improve clinical outcomes in general abdominal surgery but HRQoL has not previously been focused upon [Kehlet 2008a; Kehlet 2008b]. There are very few studies of benign abdominal hysterectomy in fast track programs and none of them focuses on HRQoL [Møller 2001; Hansen 2007; Jensen 2009; Kroon 2010]. The advantages of SA concerning postoperative perceived pain and discomfort seem to be consistent with a faster recovery of HRQoL concerning mental aspects of health as well. There was a distinct connection between occurrence of complications and lower perceived HRQoL. Splitting complications into categories of minor and major revealed a trend of minor complications that was influencing the mental aspects above all whereas major complications were especially influencing the physical aspects of quality of life. It seems important to try to minimize the occurrence of complications with a view to improving HRQoL postoperatively.

GA

SA

Index

49

Tabl

e 14

. SF-

36 su

bsca

les a

nd su

mm

ary

scor

es.

B

asel

ine

5-

wee

k 6-

mon

th

Rep

eate

d m

easu

res

AN

OV

A

SF

-36

subs

cale

s G

A

SA

G

A

SA

G

A

SA

Mai

n ef

fect

be

twee

n m

odes

of

anes

thes

ia

Mai

n ef

fect

ov

er t

ime

Inte

ract

ion

effe

ct

Phy

sica

l fun

ctio

ning

83

(21

) 87

(15

) 78

(21

) 80

(19

) 92

(14

) 96

(9)

p

= 0

.079

2 p

< 0

.000

1 p

= 0

.788

9

Rol

e ph

ysic

al

65 (

43)

70 (

40)

14 (

29)

19 (

36)

88 (

28)

90 (

29)

p =

0.2

890

p <

0.0

001

p =

0.8

864

Bod

ily p

ain

60

(28

) 67

(26

) 45

(20

) 54

(24

) 90

(20

) 91

(18

) p

= 0

.020

4 p

< 0

.000

1 p

= 0

.153

2

Gen

eral

hea

lth

76 (

19)

76 (

21)

81 (

18)

81 (

19)

85 (

17)

85 (

19)

p =

0.9

575

p <

0.0

001

p =

0.9

663

Vita

lity

55 (

24)

60 (

24)

49 (

23)

58 (

22)

75 (

21)

80 (

19)

p =

0.0

210

p <

0.0

001

p =

0.5

233

Soc

ial f

unct

ioni

ng

79 (

23)

83 (

23)

68 (

25)

77 (

22)

92 (

15)

96 (

10)

p =

0.0

248

p <

0.0

001

p =

0.3

395

Rol

e em

otio

nal

78 (

37)

86 (

31)

69 (

43)

76 (

41)

87 (

31)

96 (

17)

p =

0.0

297

p <

0.0

001

p =

0.9

332

Men

tal h

ealth

73

(18

) 78

(17

)

79 (

16)

81 (

20)

85 (

17)

90 (

12)

p =

0.0

495

p <

0.0

001

p =

0.5

284

Phy

sica

l com

pone

nt s

umm

ary

scor

e 46

(11

) 47

(9)

38

(7)

39

(9)

54

(6)

54

(7)

p

= 0

.326

3 p

< 0

.000

1 p

= 0

.614

6

Men

tal c

ompo

nent

sum

mar

y sc

ore

46 (

12)

48 (

11)

47 (

11)

50 (

13)

51 (

9)

54 (

6)

p =

0.0

229

p <

0.0

001

p =

0.9

412

Figu

res i

ndic

ate

mea

n (1

SD

).

50

Sick leave

Sick leave was required for 151 women, 73 in the GA group and 78 in the SA group. For those not requiring sick leave in the GA group, five women had a disability pension and two were already on a sick leave prior to surgery. In the SA group two women already had a disability pension and two had a present sick leave. There was a significant difference in duration of sick leave between the study groups but not between centers. In the SA group the median duration was 22.5 days (range 2-258 days) compared with 28 days (range 7-81 days) in the GA group. There was no difference between the groups concerning preoperative physical work load. Sick leave was prolonged in a standardized manner and the patients themselves decided when they were able to return to work. In the measurements of EQ-5D the time to regain HRQoL to the same extent as prior to surgery was 21 days, which is in accordance with the duration of sick leave in the SA group.

Complications prolonged the duration of sick leave in general. Women with a registered complication had a median sick leave duration of 31 days (range 6-258) compared with women without any complication with a sick leave of 22 days (range 2-60). Previous studies have also shown associations between postoperative complications and length of sick leave [Persson 2008; Persson 2010]. This further emphasizes the importance of doing what is possible to avoid complications in order to improve postoperative recovery.

Sick leave in the SA group was shorter than that usually reported following abdominal hysterectomy [Härkki-Sirén 2000; Learman 2003; Persson 2008; Persson 2010] and also shorter or equal to that reported for laparoscopic and vaginal hysterectomy [Ottosen 2000; Brummer 2009] but these studies were not made according to fast track principles, and the duration of sick leave was decided on with advice from the surgeon. Our results could be an effect of reduced perceived pain and discomfort postoperatively in the SA group causing faster recovery of HRQoL. Health care providers‟ advice regarding expected sick leave influences the actual duration of absence [Clayton 2007]. When leaving the decision to the patient concerning duration of sick leave, following certain evidence-based guidance from the staff, it may possibly more reflect the regain in HRQoL and postoperative recovery than traditions and expectations from health care providers. In Sweden the National Board of Health and Welfare has recently published national guidelines concerning the duration of sick leave after hysterectomy [Socialstyrelsen 2010]. Patients with sedentary or medium physical work load undergoing abdominal hysterectomy are recommended for sick leave duration of 3-4 weeks, with duration prolonged to 4-6 weeks in association with a heavy physical work load.

Cost effectiveness

Total costs were calculated for the study groups respectively, divided into direct and indirect costs as seen in Table 15. Direct costs are related to the treatment and indirect costs represent productivity losses and informal care. The amount of informal care needed during the five weeks did not differ significantly between the groups (median 15 hours (range 0-105 hours) for the GA and 11 hours (range 0-168 hours) for the SA); hence no calculation of the value of

51

this care has been made. Ten per cent of the women in each group did not need informal care postoperatively.

Table 15. Total costs per patient (SEK).

GA SA Difference in costs

(GA-SA)

Direct costs

Time in operating theatre 9804 9399 405

Induction of anesthesia by anesthesiologist 145 241 -96

Anesthetic drugs 305 155 150

Time in PACU 1895 1572 323

Cost of supplementary anesthesia 10 44 -34

Hospital care in gynecological ward 25068 23770 1298

Total hospital cost 37227 35181 2046

Indirect costs

Sick leave 27766 22836 4930

Total cost (direct + indirect) 64993 58017 6976

SA provided a less costly procedure of benign abdominal hysterectomy dependent on less total hospital costs but mainly due to a shorter duration of sick leave. The saving for each patient was approximately 7000 SEK. It is not meaningful to compare costs between different hysterectomy studies since the economic data is not sufficiently specified and seldom includes indirect costs [Bijen 2009].

As mentioned before the SA group had a faster recovery measured by HRQoL. Health state index scores measured with the EQ-5D questionnaire form the basis of calculation of QALYs gained. A difference in utility measures was noticed between the study groups for the first 21 postoperative days, favoring SA. Gain in QALYs was therefore only calculated for the first postoperative month. SA dominated GA owing to both higher effectiveness and lower costs and therefore we have not calculated the incremental cost-effectiveness ratio as cost per QALYs gained. It is not possible to compare these results with previous studies since no economic analyses have been presented following fast track abdominal surgery [Møller 2001; Ottosen 2002; Wind 2006; Hansen 2007; Kehlet 2008a; Kehlet 2008b; Gouvas 2009; Jensen 2009; Kroon 2010]. A superior method of hysterectomy as concerns cost-effectiveness has not yet been presented [Lumsden 2000; Garry 2004; Sculpher 2004; Bijen 2009] but fast track principles have not been included in these studies.

52

Substantial benefits could be achieved concerning cost-effectiveness considering all benign abdominal hysterectomies in Sweden being performed in SA.

Non-participating group

Of the 464 eligible women 180 were randomized in the study (39%). This is a significantly higher proportion than the 5.5-18% reported in other randomized studies of abdominal hysterectomy [Gimbel 2003; Learman 2003; Ellström 2010; Persson 2010]. The group of 84 non-participating women was compared with the 162 women in the study group regarding age and preoperative assessments of HRQoL as seen in Table 16. The analysis did not show any significant difference between the groups, hence improving the possibility of generalization of the results.

Table 16. Comparisons between women in the non-participating group and the study group.

Non-participating group Study group p – value*

Age (years) 46 (7) 46 (6) 0.4656

EQ-5D (index) 0.70 (0.29) 0.76 (0.21) 0.4569

SF-36 PCS (score) 46 (10) 47 (10) 0.6934

SF-36 MCS (score) 46 (12) 47 (11) 0.5748

53

General discussion

Methodology

This randomized controlled trial (RCT) compares the intervention (SA) with that of the conventional standard treatment (GA). An RCT is considered to be the most reliable form of scientific study and results from several RCTs may be combined in systematic reviews. The most important advantage of RCTs is the reduced risk of bias although there is always a risk of selection bias as to which individual decides to participate in a study. On the contrary, RCTs may have limited external validity i.e. the extent to which the results are applicable outside the setting of a randomized trial. This could influence the possibility of generalizing the results.

Randomization

In the early planning of this trial we considered a double blinded placebo controlled study comparing spinal anesthesia with and without intrathecal morphine in conjunction with general anesthesia. However, such design would not have given an answer to the objectives of our study since it did not represent the conventional clinical practice of using general anesthesia alone. There are potential risks for complications related to spinal puncture [Faccenda 2001]. For ethical reasons it seemed reasonable to avoid intrathecal placebo as well as “sham” spinal puncture and we abandoned that study design. In order to evaluate the impact of mode of anesthesia on outcomes in fast track hysterectomy we decided to compare the anesthetics solely, i.e. SA with GA and kept the fast track program and monitoring equivalent in the groups. Randomizing between fast track and traditional perioperative care could also have been an option for the trial and probably of great interest. However, the risk of bias would probably be substantial with two routines of care either being mixed up in the same ward or of different routines of care being followed in different centers.

Blinding and/or placebo control was not possible in this study for obvious reasons. The temporary paralysis of the lower extremities after SA would be observed immediately by the woman as well as by the staff. The lack of blinding may pose a risk of bias. In order to reduce other potential bias the women were informed and monitored similarly and the mode of incision and type of abdominal hysterectomy were decided on prior to randomization.

The analysis of the non-participating group compared with the study group revealed no significant differences concerning age and preoperative assessments of HRQoL. This would improve the possibility of generalization of the results.

Study design

The multicenter design of the study augmented the possibility of generalization. Results from a multicenter study including hospitals of different sizes have the advantage of reflecting common practice in general. There were no differences between the modes of hysterectomy in relation to time of surgery or occurring postoperative complications. Mode of anesthesia is seldom stated in the comparison of outcomes following different methods of hysterectomy [Nieboer 2009]. The importance of mode of anesthesia for the postoperative recovery is therefore not determined. Vaginal hysterectomy is often declared to carry benefits for the

54

patient [Ottosen 2000; Nieboer 2009]. Whether a conceivably applied SA has influenced the postoperative outcomes is unknown.

Abdominal hysterectomy is a routine procedure carried out in a rather standardized fashion. The surgical technique therefore comprised only a few limitations according to the study protocol and the operations were performed or supervised by consultants in obstetrics and gynecology in order to represent the daily practice of abdominal benign hysterectomy. Swedish gynecologists are well qualified to perform gynecological and obstetric surgery under SA although the vast majority of abdominal hysterectomies in Sweden are carried out under GA. We found no indications of “a learning curve” for hysterectomy under SA in the study based on using operation time and estimated bleeding volume as dependent variables. Surgical skill and experience are probably the most important factors for “a learning curve” in hysterectomy, even when conducted under SA.

Emphasis was put on providing careful information to all study participants concerning expected peri- and postoperative care as well as criteria for discharge to avoid information bias. All staff members were also provided with the same information prior to start of the study and regularly during the progress of the study. An information sheet, “The GASPI News”, was sent to the participating centers for information regarding pace of inclusion, monitoring, events of SAE and other mutual issues. A total of six editions were dispatched during the study period.

Patient safety

Prevalent guidelines concerning peroperative anesthesia and surgery were followed to ensure patient safety. Safety checks in accordance with WHO Surgical Safety Checklist were applied by the staff in the operating room [WHO 2011]. Postoperatively all women irrespective of mode of anesthesia were monitored according to current guidelines from the Swedish Society of Anaesthesiology and Intensive Care Medicine (SFAI) valid following usage of intrathecal opioids [SFAI 2011]. Hemodynamic and respiratory stability, degree of sedation, pain, nausea and pruritus were repeatedly measured and evaluated during 24 hours postoperatively.

Questionnaires

SPSQ

The questionnaire faces the patient frequently with questions concerning experience and intensity of several postoperative symptoms. This might have brought the attention even to symptoms otherwise not noticed and therefore created an overestimation of perceived symptoms. On the other hand, 95% of the women in our study reported the questions as “appropriate giving a true picture of their experiences”.

EQ-5D and QALY measurements

EQ-5D is easy to use, applicable to a wide range of interventions and develops an index which facilitates ranking of the state of health and further the calculation of QALY. The disadvantage consists of the simple design with only five dimensions of health with three response levels per dimension. This may pose a risk of failing to register important differences between different interventions. In addition most previous studies concerning

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hysterectomy do not report differences in utility during the first postoperative month [Garry 2004; Sculpher 2004; Gorlero 2008; Taipale 2009]. The frequent measurements of utility in our study made it possible to calculate QALYs for the first postoperative month when the regain in health would be most apparent.

SF-36

The SF-36 was constructed to satisfy minimum psychometric standards necessary for group comparisons. The eight health concepts were selected from 40 concepts included in the Medical Outcomes Study (MOS) [Stewart 1992]. Those who were chosen represent the most frequently measured concepts in widely used health surveys and those most affected by disease and treatment [Ware 1992; Ware 1994]. Some SF-36 scales have shown 10-20% less precision than the long-form MOS measures that SF-36 scales were constructed to reproduce [McHorney 1992]. This disadvantage should be weighed against the knowledge that some of these long-form measures place a 5-10 times greater burden on the respondent. SF-36 provides a practical alternative to longer measures and the eight scales and two summary scales rarely miss a noteworthy difference in physical or mental health status in group comparisons [Katz 1992; Ware 1993; Ware 1994].

Final considerations

Several aspects concerning clinical and HRQoL outcomes speak in favor of SA. SA carries substantial advantages even five weeks postoperatively. The comprehensive explanation of this finding is indistinct. Less perceived postoperative symptoms as a consequence of reduced perioperative hormonal stress response could lead to favorable psychological effects with a better preserved cognitive function. This issue has not been carefully studied but nevertheless awareness of this is very important to be able to further enhance postoperative recovery [Rasmussen 2006; Krenk 2010]. Regional anesthesia may decrease the incidence of short-term POCD but previous studies carry crucial limitations [Rasmussen 2003].

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Conclusions

The duration of hospitalization in connection with fast track abdominal hysterectomy

did not differ between women who received SA compared with GA.

The most common postoperative symptoms were pain, PONV, pruritus and fatigue.

Abdominal pain, drowsiness and fatigue occurred significantly less often among the

women in the SA group. Pruritus and vomiting was more common following SA.

Women in the SA group reported less perceived pain in the surgical area on day 0 until

day 2, both at peak and on average. They also required less opioids day 0 and day 1

compared with women in the GA group.

The SA group reported less overall postoperative discomfort compared with the GA

group.

HRQoL improved significantly faster in the SA group compared with the GA group.

Duration of sick leave was shorter following SA compared with GA.

Total costs were lower for the SA group and the gain in QALYs for the first

postoperative month exceeded that of the GA group. SA was considered cost-effective

in comparison with GA.

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Clinical implications

There is substantial evidence for the benefits of following fast track principles in general surgery. Including regional anesthesia seems to provide additional advantages for the postoperative recovery of the patient. There is no reason to believe that the advantages would not embrace gynecological surgery. However, it is apparent that many have been reluctant to accept and adopt the principles of fast track. There are several possible reasons for this including a lack of collaboration in the surgical team and lack of awareness and failure to accept evidence based data [Kehlet 2008a]. Widespread information and education are needed to enhance the rate of implementation of fast track in general. The importance of close cooperation between the surgical-, anesthesiological- and nursing staff to achieve further development of the surgical care cannot be overestimated. The results of the GASPI study have influenced the perioperative care of patients in the gynecological ward in Linköping. Fast track principles have been adopted generally and SA is recommended as the first choice to patients in connection with benign abdominal surgery. Providing thorough information repeatedly to all involved staff both at staff meetings and through written guidelines has been crucial to being able to introduce and implement fast track in this manner. The presence of informed staff providing patients with well-grounded information is essential for reaching the goal of enhanced postoperative recovery.

Future perspective

The results of this study emphasize the advantages of following fast track principles including SA but also bring out the remaining needs of improvement in postoperative care. There is an obvious need for further reducing postoperative symptoms such as pain and pruritus to enhance recovery. Addition of the α-2 adrenergic agonist clonidine intrathecally can be used in conjunction with intrathecal morphine to further enhance and prolong the effect of spinal analgesia. The addition of clonidine augments the analgesic effect of morphine and allows a reduction of the morphine dose to possibly minimize the potential side effects of intrathecal morphine [Lena 2003; van Tuijl 2006; Lavand´homme 2008; Andrieu 2009].

The transition of acute postsurgical pain to chronic pain is complex and poorly understood but seems to be related to declared preoperative pain and perceived acute postoperative pain to some extent [Brandsborg 2009; Katz 2009]. Reducing and preferably preventing pain in relation to surgery could lower the risk of developing chronic pain. SA provides a nearly complete block of afferent noxious activity and could have a protective role for development of chronic pain [Brandsborg 2007]. The incidence of chronic pain arising following gynecological surgery is unknown. Future studies have to elucidate the incidence of both preoperative pain and remaining postsurgical pain in relation to anesthesia and surgery to be able to evolve treatments to prevent chronic pain.

Occurrence of complications influences perceived HRQoL and duration of sick leave. The majority of complications is minor and of infectious origin. Encouraging overweight patients to lose weight and to terminate smoking could be worth attempting preoperatively [Cheadle

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2006; Gendall 2007; Thomsen 2010]. Proper use of prophylactic antibiotics and reducing the duration of use of transurethral catheter also diminish the risk of postoperative infections [Kocak 2005; Niël-Weise 2005]. Adopting fast track principles is compatible with fewer postoperative infections due to decreased need for hospitalization.

Preoperative psychological factors affect the perception of postoperative recovery [Persson 2008; Persson 2010]. Exploring psychological interventions including cognitive therapy to fortify behaviors to enhance postoperative recovery could be feasible [Shehmar 2010]. The most effective kind and extent of postoperative follow-up is unknown and therefore needs to be investigated to be able to offer a cost-effective postsurgical medical service.

There is currently no obvious evidence from high quality studies to support fast track principles in association with gynecological cancer surgery [Lv 2010]. Randomized clinical trials are needed to elucidate the possible advantages of fast track principles and the conceivable benefit of SA instead of the commonly used continuous epidural analgesia, requiring several days with transurethral catheter.

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Summary in Swedish - Sammanfattning på svenska

Bakgrund

Hysterektomi (borttagande av livmodern) är den vanligaste större gynekologiska operationen i västvärlden och i Sverige utförs cirka 5000 hysterektomier per år (ej inräknat canceroperationer) framför allt pga. blödningsrubbningar och besvärande muskelknutor. Det är således ett ingrepp som påverkar många kvinnor. Hysterektomi kan utföras via buksnitt, med ”titthålsteknik” eller via slidan. Buksnitt är fortfarande den vanligaste metoden i Europa och USA. De olika teknikerna har både för- och nackdelar och man har inte kunnat konstatera någon helt överlägsen metod. Valet av metod ska göras i samråd mellan gynekolog och den kvinna som ska bli opererad. Alla kirurgiska ingrepp ger mer eller mindre besvär vilket påverkar förmågan till återhämtning efter operationen. Trots utveckling av metoder för exempelvis bedövning, sövning och smärtlindring är det fortfarande många kvinnor som upplever besvärande symtom efter hysterektomi vilket kan påverka återhämtning, sjukskrivningstid och även hälsoekonomi.

Inom tarmkirurgi har man under flera decennier studerat effekten av s.k. Fast Track (”snabbt spår”) för att påskynda återhämtningen efter operation. Man har kunnat visa att Fast Track bidrar till snabbare återhämtning, minskad andel komplikationer och kortare vårdtid efter tarmkirurgi. Motsvarande studier har inte genomförts inom gynekologisk kirurgi. I metoden ingår noggrann information till kvinnan avseende operationens karaktär, smärtlindring och förväntat vårdförlopp. I Fast Track ingår också att inleda smärtlindring och förebyggande behandling mot illamående redan innan operationen samt om möjligt undvika morfinpreparat i tablettform eller via injektioner, för att minska risken för ogynnsamma biverkningar. Snabb återgång till normalt födointag och hjälp att komma upp efter operationen påverkar också återhämtningen positivt. Ryggbedövning ingår ofta i Fast Track för att ytterligare förbättra effekten och durationen av smärtlindringen. Ryggbedövning används mycket ofta i samband med kejsarsnitt men i samband med hysterektomi är det vanligast med traditionell sövning. På vissa kliniker i Sverige har man dock använt ryggbedövning även i samband med hysterektomi och då tyckt sig se många fördelar för kvinnan, såsom minskat smärtlindringsbehov och snabbare återhämtning. Fördelarna med ryggbedövning i jämförelse med sövning i samband med Fast Track inom gynekologisk kirurgi har dock inte tidigare beskrivits i några studier. Därav väcktes idén om att undersöka detta vetenskapligt för att närmare studera om ryggbedövning ger fördelar avseende symtom, livskvalitet, vårdtid, sjukskrivning och hälsoekonomi.

Studiens syfte var att fastställa om återhämtningen efter livmoderoperation via buksnitt skiljde sig åt mellan kvinnor som opererades i vanlig sövning (GA) och i ryggbedövning med tillägg av morfin (SPI) i samband med ett Fast Track program (GASPI studien). Bedövningsformen fastställdes genom lottning till GA eller SPI, så kvinnan, anestesiläkaren eller gynekologen kunde inte påverka detta.

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Metod

Fem kvinnokliniker i sydöstra sjukvårdsregionen (Eksjö, Jönköping, Linköping, Norrköping och Värnamo) deltog i studien som pågick mellan mars 2007 och december 2009. 180 kvinnor inkluderades i studien och 162 kvinnor fullföljde studien. 80 av kvinnorna erhöll GA och 82 fick SPI. Operationen omfattade antingen hela livmodern (total hysterektomi) eller endast livmoderkroppen med kvarlämnande av livmodertappen (subtotal hysterektomi). Som buksnitt användes antingen lågt tvärsnitt (bikinisnitt) eller längsgående snitt i medellinjen från naveln och nedåt. Samtliga kvinnor behandlades enligt principerna för Fast Track. Fasta och förutbestämda obligatoriska utskrivningskriterier gällde för att kvinnan skulle kunna åka hem från vårdavdelningen. I studien jämfördes vårdtid, symtom efter operationen, återhämtning av livskvalitet, längd på sjukskrivning och hälsoekonomiska data mellan de kvinnor som fick GA respektive SPI.

Resultat

Vårdtiden mättes som tiden från start av bedövning i samband med operationen till dess kvinnan lämnade vårdavdelningen. Vårdtiden var kort i jämförelse med tidigare studier avseende hysterektomi men skiljde sig inte åt mellan grupperna. Kvinnor i GA gruppen hade en median vårdtid på 50 timmar jämfört med 46 timmar för kvinnor i SPI-gruppen. Den korta vårdtiden i bägge grupper skulle kunna vara en effekt av noggrann information till kvinnan före operationen angående de kriterier som skulle vara uppfyllda för att hon skulle kunna åka hem och att om kriterierna var uppfyllda redan dagen efter operationen så fanns inga hinder för utskrivning.

Kvinnor som fått SPI rapporterade signifikant mindre smärta och behövde mindre mängd morfinpreparat de första dagarna efter operationen. Det minskade behovet av morfin gjorde också att tarmen kom igång fortare. Detta påverkade dock inte förekomst av illamående eller vårdtidens längd. Effekten av SPI på smärta och behov av morfinpreparat kan tyda på en kraftigare och förlängd smärtlindrande effekt jämfört med GA. Detta är också visat i tidigare studier. Generellt obehag mättes genom en sammanslagen skala baserad på kvinnans upplevda intensitet av åtta vanliga symtom efter operationen och där SPI-gruppen rapporterade mindre obehag första veckan. Trötthet är ett mycket vanligt symtom efter kirurgi och i denna studie rapporterades trötthet som ett besvärande symtom hos mer än 40 % i GA-gruppen på kvällen efter operationen, vilket var fler än i SPI-gruppen. Tre veckor efter operationen rapporterade mer än 20 % i bägge grupper att de fortfarande upplevde besvärande trötthet. Nackdelar med SPI var klåda noterat under de två första dagarna efter operationen samt en större risk för kräkning direkt efter operationen, vilket också är kända nackdelar med morfininnehållande ryggbedövning. Komplikationsfrekvensen efter hysterektomi var lika i bägge grupper och även likvärdig med tidigare studier avseende hysterektomi utförd via buksnitt. 75% av de registrerade komplikationerna utgjordes av infektioner i buksår eller slidtopp. Kvinnor som fått SPI skattade sin livskvalitet högre de första tre veckorna efter operationen mätt med livskvalitetsformuläret EQ-5D. Hälsorelaterad livskvalitet mätt med livskvalitetsformuläret SF-36 visade en bättre livskvalitet för SPI-gruppen fem veckor efter operationen avseende smärta, vitalitet, social funktion, känslomässiga problem och mental hälsa. Komplikationer påverkade livskvaliteten negativt i bägge grupper. Sjukskrivningstiden

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för kvinnor som fått SPI var kortare än för kvinnor som fått GA. SPI-gruppen var sjukskriven median 22.5 dagar jämfört med 28 dagar i GA-gruppen. Sjukskrivningstiden bestämdes av kvinnan själv för att den i större utsträckning skulle spegla kvinnans återhämtning och livskvalitet och i mindre grad traditioner eller förväntningar från sjukvårdspersonal. Uppkomst av komplikationer förlängde sjukskrivningstiden generellt. Hälsoekonomiska data visade att den totala kostnaden för hysterektomi utförd med SPI var 7000 kr lägre än för GA. Den största delen av besparingen ligger i den kortare sjukskrivningstiden (5000 kr per patient). Eftersom SPI resulterade i både lägre kostnader och bättre livskvalitet kan man konstatera att SPI är kostnadseffektiv jämfört med GA i samband med hysterektomi i ett Fast Track program.

Konklusion

Sammanfattningsvis så ger ryggbedövning innehållande morfin en rad fördelar jämfört med traditionell sövning för en kvinna som genomgår hysterektomi med buksnitt i Fast Track. Trots fördelarna upplever många kvinnor ändå kvarvarande besvärande symtom, framför allt av smärta, illamående och kräkning, klåda samt trötthet. Detta påverkar återhämtningen efter operationen negativt. Studier som syftar till att ytterligare optimera förhållanden före, under och efter operationen behöver göras för att möjliggöra en så snar återhämtning som möjligt. Detta är fördelaktigt både för kvinnans upplevelse och livskvalitet men även samhällsekonomiskt.

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Acknowledgements

I wish to thank all of you that in different ways have made great contributions to the work of this thesis, and especially to:

Associate Professor Preben Kjølhede, my excellent main supervisor and friend, for an extraordinary joyful journey eventually reaching the goal of dissertation. I have never regretted that I said yes when you invited me into the field of research

Lena Nilsson, MD, PhD, my co-supervisor and friend, for invaluable sensible advice and hard work throughout all the work of this thesis.

Research nurses Petra Langström, Pernilla Nilsson and Amy Leval for dedicated work with the GASPI study.

All members of the “GASPI study group” in the Departments of Obstetrics and Gynecology and Departments of Anesthesiology in Eksjö, Jönköping, Linköping, Norrköping and Värnamo for great accomplishment of the study.

Sofia Wodlin, one of three beloved children, for careful and skilled work with parts of the datasets.

Research nurse Lotta Lindh Åstrand, PhD, for advice and carrying the main responsibility for monitoring of the study.

Professor Lawrence Lundgren for rapid and successful linguistic advice.

All colleagues in the Department of Obstetrics and Gynecology in Linköping for support and for keeping up the good work when I have been absent from clinic.

Associate Professor and Head of the Department of Obstetrics and Gynecology in Linköping, Ann Josefsson, Gulnara Kassymova, MD and Evelyn Lundin, MD, creating a generous schedule for me to keep up the pace of this work.

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Research nurse Kristofer Årestedt, PhD, and Professor Per Carlsson, co-authors, for adding valuable advice and knowledge when writing Paper II and Paper IV.

Associate Professor Jan Brynhildsen, Professor Göran Berg, Associate Professor Ann Josefsson, Associate Professor Marie Blomberg, Professor Per Carlsson, Gabriella Falk, MD, PhD, Elizabeth Nedstrand, MD, PhD, Caroline Lilliecreutz, MD, PhD, Dean Turina, MD, Per Persson, MD, PhD, for constructive criticism and comments on parts of the thesis.

Professor Folke Sjöberg and Associate Professor Richard Lindgren, for valuable and useful comments, advice and support in connection with the midpoint review.

All the women that participated in the study. You will get the “Summary in Swedish” sent to you!

Connie Kjølhede, for splendid hospitality always serving tea at the right moment!

Peter Wodlin, my life companion and never-ending love, for keeping children, dog and house-keeping on the track during my absence due to research.

The study was supported by grants from the Medical Research Council of Southeast Sweden, ALF Grants, the County Council of Östergötland and Lions forskningsfond mot folksjukdomar.

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Appendix

The Swedish Postoperative Symptoms Questionnaire (SPSQ) – Day 0 and Day 1

OBEHAG/SMÄRTA/ILLAMÅENDE

Vi vill få reda på hur ont Du haft idag efter operationen, dvs hur stor operationssmärta Du känt. Vi vill också få reda på hur stora besvär Du känt till följd av illamående, huvudvärk och magvärk, m m. Besvara sidorna i detta formulär på operations-dagens kväll, helst någon gång mellan klockan 20 och 21. De flesta av frågorna kan Du besvara genom att sätta kryss i rutor.

Att besvaras på operationsdagen Datum:________________ Här kommer först några frågor om hur Du känner Dig just nu, när Du fyller i formuläret. (Sätt kryss för det svar Du tycker stämmer bäst.)

Ja, Ja, Ja, Nej lite något mycket

1) Om operationssmärta: Har Du fortfarande ont efter operationen? 2) Om andra besvär: Är Du illamående? Har Du kväljningar? Har Du huvudvärk? Har Du magvärk? Är Du trött? Är Du dåsig? Har Du dimsyn? Har Du klåda? Känner Du av andra besvär? Ja Nej Om Ja, i så fall vilka: …………………………………………………………………………………………. 3) Hur ont hade Du idag efter operationen när Du kände av operationssmärtan som mest?

(Sätt kryss i en ruta för det svar Du tycker stämmer bäst.) Ingen smärta Obetydlig smärta Mild smärta Måttlig smärta

Rätt svår smärta Svår smärta Mycket svår smärta

4) Hur stora besvär kände Du idag efter operationen när besvären var som störst? Tänk inte på smärtan efter operationen, utan på hur obehagliga besvären var när de var som värst. (Sätt kryss i en ruta för det svar Du tycker stämmer bäst.)

Inga besvär Obetydliga besvär Milda besvär Måttliga besvär

Rätt svåra besvär Svåra besvär Mycket svåra besvär

5) Vad har varit särskilt besvärande? (Sätt kryss i en eller flera rutor.) Inget Illamående/kräkning Huvudvärk Magvärk Dåsighet Trötthet Dimsyn Klåda Andra besvär Ja Nej Om "Ja" vilken/a : ___________________________________________________________

73

6) Beskriv hur ont Du har haft idag efter operationen. Tänk då inte på hur det var när det var som värst, utan försök ge en sammanfattande beskrivning av hur Du upplevt smärtan efter operationen idag. (Sätt kryss i en ruta)

Ingen smärta Obetydlig smärta Mild smärta Måttlig smärta

Rätt svår smärta Svår smärta Mycket svår smärta 7) Försök beskriva hur mycket besvär Du haft idag efter operationen. Tänk då inte på

smärtan, utan försök ge en sammanfattande beskrivning av de besvär Du haft. (Sätt kryss i en ruta)

Inga besvär Obetydliga besvär Milda besvär Måttliga besvär

Rätt svåra besvär Svåra besvär Mycket svåra besvär 8) Vilka besvär tycker Du har varit särskilt obehagliga när Du tänker sammanfattande på

hela dagen efter operationen? (Sätt kryss i en eller flera rutor.) Inget Illamående/kräkning Huvudvärk Magvärk Dåsighet Trötthet Dimsyn Klåda Andra besvär Ja Nej Om "Ja" vilken/a : ___________________________________________________________ 9) Har Du kräkts idag efter operationen?

Nej Ja, en gång Ja, flera gånger 10) Hur mycket är klockan när Du fyllt i dessa sidor? …………………….. Klockslag

74

OBEHAG/SMÄRTA/ILLAMÅENDE

Att besvaras dagen efter operation Datum: ____________

Vi vill få reda på hur ont Du haft idag den första dagen efter operationen, dvs hur stor operationssmärta Du känt. Vi vill också få reda på hur stora besvär Du känt till följd av illamående, huvudvärk och magvärk, m m. Besvara sidorna i detta formulär på dagen efter operation, helst någon gång mellan klockan 20 och 21. De flesta av frågorna kan Du besvara genom att sätta kryss i rutor.

1) Hur sov Du natten efter operationen? Bra Varken bra eller dåligt Dåligt

Här kommer några frågor om hur Du känner Dig just nu, när Du fyller i formuläret. (Sätt kryss för det svar Du tycker stämmer bäst.)

Ja, Ja, Ja, Nej lite något mycket

2) Om operationssmärta: Har Du fortfarande ont efter operationen? 3) Om andra besvär: Är Du illamående? Har Du kväljningar? Har Du huvudvärk? Har Du magvärk? Är Du trött? Är Du dåsig? Har Du dimsyn? Har Du klåda? Känner Du av andra besvär? Ja Nej Om Ja, i så fall vilka: ……………………………………………………………………… 4) Hur ont hade Du idag (dagen efter operation) när Du kände av operationssmärtan som

mest? (Sätt kryss för det svar Du tycker stämmer bäst) Ingen smärta Obetydlig smärta Mild smärta Måttlig smärta

Rätt svår smärta Svår smärta Mycket svår smärta

5) Hur stora besvär kände Du idag (dagen efter operation) när besvären var som störst? Tänk inte på smärtan efter operationen, utan på hur obehagliga besvären var när de var som värst. (Sätt kryss för det svar Du tycker stämmer bäst)

Inga besvär Obetydliga besvär Milda besvär Måttliga besvär Rätt svåra besvär Svåra besvär Mycket svåra besvär

6) Vad har varit särskilt besvärande? (Sätt kryss i en eller flera rutor.) Inget Illamående/kräkning Huvudvärk Magvärk Dåsighet Trötthet Dimsyn Klåda Andra besvär Ja Nej Om "Ja" vilken/a : ___________________________________________________________

75

7) Beskriv hur ont Du har haft idag (dagen efter operation). Tänk då inte på hur det var när det var som värst, utan försök ge en sammanfattande beskrivning av hur Du upplevt smärtan idag. (Sätt kryss för det svar Du tycker stämmer bäst)

Ingen smärta Obetydlig smärta Mild smärta Måttlig smärta Rätt svår smärta Svår smärta Mycket svår smärta

8) Försök beskriva hur mycket besvär Du haft idag (dagen efter operation). Tänk då inte

på smärtan, utan försök ge en sammanfattande beskrivning av de besvär Du haft. (Sätt kryss för det svar Du tycker stämmer bäst)

Inga besvär Obetydliga besvär Milda besvär Måttliga besvär Rätt svåra besvär Svåra besvär Mycket svåra besvär

9) Vilka besvär tycker Du har varit särskilt obehagliga när Du tänker sammanfattande på

hela dagen? (Sätt kryss i en eller flera rutor.)

Inget Illamående/kräkning Huvudvärk Magvärk Dåsighet Trötthet Dimsyn Klåda Andra besvär Ja Nej Om "Ja" vilken/a : ___________________________________________________________ 10) Har Du kräkts idag? Nej Ja, en gång Ja, flera gånger

11) Hur mycket är klockan när Du fyllt i dessa sidor? __________________

Klockslag

12) Tror Du att vi kommer att få en någorlunda riktig uppfattning om hur Du haft det med smärta och obehag utifrån Dina svar på detta formulär? Ja Nej

Om svaret är nej är vi tacksamma för en kommentar om hur Du tror att det besvarade formuläret ger oss en missuppfattning om hur Du verkligen känt det. …………………………………………………………………………………………………………….………………………………………………………………………………………………………………………………………………………………………………………………