Comprehensive Summaries of Uppsala Dissertationsfrom the Faculty of Medicine 1094

_____________________________ _____________________________

A Laparoscopic Approachin Gastro-Oesophageal Surgery

Experimental and Epidemiological Studies

BY

RUNE SANDBU

ACTA UNIVERSITATIS UPSALIENSISUPPSALA 2001

2

Dissertation for the Degree of Doctor of Philosophy (Faculty of Medicine) in Surgerypresented at Uppsala University in 2001

ABSTRACTSandbu, R. 2001. A Laparoscopic Approach to Gastro-Oesophageal Surgery: Experimentaland Epidemiological Studies. Acta Universitatis Upsaliensis - Comprehensive Summariesof Uppsala Dissertations from the Faculty of Medicine 1094. 87 pp. ISBN 91-554-5155-1.

The extension of laparoscopic procedures into the chest may induce specificpathophysiologic effects. In pigs, we have demonstrated how devastating a combined thoraco-laparoscopicapproach can be for gas exchange. Furthermore, the transmission of elevated pressureintra-cranially is a potential danger. The application of positive end-expiratory pressure(PEEP) was found to improve gas exchange and, more importantly, hypoxemia could beavoided. The application of PEEP did not increase intra-cranial pressure further; nor did itadversely affect cerebral circulation. Even before the introduction of the laparoscopic technique, there was a substantialincrease in the annual number of antireflux procedures. Therefore, the threefold increase ofthe incidence of antireflux surgery recorded during the past decade cannot solely beexplained by the introduction of minimal access surgery. However, a clear shift in thepreferred methodology took place. This change was not scientifically supported at the timeof the transition and, surprisingly, it is still not supported today. In comparison with opensurgery, patients do not seem to derive significant long-term benefits from having theantireflux procedure done laparoscopically. As was demonstrated, laparoscopy might evenbe an inferior approach in some patients. Nevertheless, it is reasonable to assume thatlaparoscopy can yield equally good results as open surgery despite our failure to confirmthat in our studies. Determination of the effectiveness of minimal access surgery in thetreatment of GORD is critical, before minimal access techniques become the standard forantireflux surgery in the community.

Key words: Gastro-oesophageal surgery, fundoplication, laparoscopy, long-term results,pneumothorax, intra-cranial pressure, positive end-expiratory pressure.

Rune Sandbu, Department of Surgical Sciences, Uppsala University Hospital,SE-751-85, Uppsala, Sweden

Rune Sandbu 2001 ISSN 0282-7476 ISBN 91-554-5155-1 Printed in Sweden by Uppsala University, Tryck & Medier, Uppsala, 2001

3

The thesis is based on the following papers, which will be referred to in thetext by their Roman numerals (I-V)

I. Rune Sandbu, Birgitta Birgisdottir, Dag Arvidsson, Ulf Sjöstrand, StenRubertsson. Optimal Positive end-expiratory Pressure (PEEP) settingsin differential lung ventilation during simultaneous unilateralpneumothorax and laparoscopy. An experimental study in pigs.Surg Endosc Published on line 7th September 2001.

II. Rune Sandbu, Ulf Haglund, Harry J. Khamis, Sten Rubertsson. Noadverse effects of PEEP on intracranial pressure or cerebral circulationduring laparoscopy and simultaneous pneumothorax in pigs. Submitted.

III. Rune Sandbu, Ulf Haglund, Dag Arvidsson, Thomas Hallgren.Antireflux Surgery in Sweden, 1987-1997: A Decade of Change.Scand J Gastroenterol 2000; 35: 345-8.

IV. R Sandbu, H Khamis, S Gustavsson, U Haglund. Long-term results ofantireflux surgery: The benefits of the laparoscopic technique underquestion. Accepted for publication, Br J Surg.

V. R Sandbu, H Khamis, S Gustavsson, U Haglund. Laparoscopicantireflux surgery in routine hospital care. Accepted for publication,Scand J Gastroenterol.

Reprints have been made with the permission of the publishers

4

Table of contents

Abbreviations ----------------------------------------------------------------------------------- 5Introduction

Historical background ------------------------------------------------------------------------- 7 Technical principles of minimal access surgery-------------------------------------------- 8 Potential benefits of minimal access surgery ----------------------------------------------- 10 Anatomical considerations -------------------------------------------------------------------- 11 Pathophysiology

Pneumothorax and positive end-expiratory pressure (PEEP)----------------- 12Insufflation pressure and intracranial pressure (ICP):Pneumothorax and PEEP ---------------------------------------------------------- 13

Gastro-oesophageal surgery and minimal access approach: An overview-------------- 14Aims of the thesis ------------------------------------------------------------------------------ 20Material and Methods

A. Experimental studies (Studies I and II) Ethical considerations and animals ---------------------------------------------- 21 Method of anaesthesia ------------------------------------------------------------ 21 Technique for separate lung intubation and differential lung ventilation --- 22

Model for combined positive pressure pneumoperitoneumand unilateral pneumothorax------------------------------------------------------ 23

Experimental design -------------------------------------------------------------- 24Monitoring -------------------------------------------------------------------------- 26

B. Epidemiological studies and survey of long-term results on antireflux surgery (Studies III-V)

Methods of survey------------------------------------------------------------------ 29Study design ------------------------------------------------------------------------ 30Patients and ethical considerations (Studies IV and V) ----------------------- 32

Statistical methods --------------------------------------------------------------------------- 33Results and discussion

Study I ------------------------------------------------------------------------------------------ 35 Study II ----------------------------------------------------------------------------------------- 39 Study III ---------------------------------------------------------------------------------------- 42 Study IV ---------------------------------------------------------------------------------------- 47 Study V ----------------------------------------------------------------------------------------- 51

General discussion ---------------------------------------------------------------------------- 58Conclusions -------------------------------------------------------------------------------------- 66Acknowledgements---------------------------------------------------------------------------- 67References ---------------------------------------------------------------------------------------- 68

5

Abbreviations

BMI body mass indexCNS central nervous systemCO2 carbon dioxideCO cardiac outputc-pH pH in cerebral cortical tissueCPP cerebral perfusion pressureC stat static lung complianceEpC Centre for EpidemiologyETCO2 end-tidal partial pressure of carbon dioxideGORD gastro-oesophageal-reflux-diseaseICP intracranial pressureLDF Laser-Doppler flow signalMAP mean arterial pressurePCWP pulmonary capillary wedge pressurePEEP positive end-expiratory pressurePaCO2 partial pressure of carbon dioxide in arterial bloodPcCO2 partial pressure of carbon dioxide in cerebral cortical tissuePcO2 partial pressure of oxygen in cerebral cortical tissuePjvO2 partial pressure of oxygen in venous blood from the brainPPI proton-pump inhibitorsSaO2 oxygen saturation in arterial bloodSjvO2 oxygen saturation in venous blood from the brainVCO2 CO2 elimination

7

Introduction

Historical background

In 1901, Georg Kelling, a surgeon from Dresden, demonstrated a method he

called “koelioscopie.” The surgeon punctured the peritoneal cavity with a

needle and expanded it with filtered air. He then inserted a trocar into the

abdominal wall and used the trocar to introduce a cystoscope (laparoscope).

This procedure was performed on a live canine during the 73rd Congress of

German Naturalists and Physicians. It was the beginning of the field of

laparoscopy (1-3).

The first major clinical contribution is attributed to the Swedish physician,

Hans Christian Jacobaeus (1910) (4). His initial experience with the

technique was restricted to patients with ascites. He was able to diagnose

syphilis, tuberculosis, cirrhosis and malignancies. Later, Jacobaeus expanded

the limits to include the thoracic cavity (thoracoscopy) (5).

For more than half a century, however, laparoscopy had limited use in clinical

practice. It was chiefly applied in gynaecology as a diagnostic tool and for

tubal ligation. A major problem at that time concerned optics and light

transmission. It was not just a coincidence that the development of general

laparoscopic surgery occurred shortly after the introduction of the computer

chip TV camera. The first reports of successful laparoscopic cholecystectomy

emanated from France in 1987 (6,7).

After 1987, everything happened with incredible speed and a veritable

explosion of laparoscopy into general surgical practice followed. Within a

few years, there was hardly any open intra-abdominal procedure that had not

been attempted laparoscopically (3,8). Enthusiasts predicted by the turn of the

20th century that the majority of general surgery would be performed using

this new approach (9,10). Certainly, for procedures such as cholecystectomy

and Nissen fundoplication, laparoscopy has become the “gold standard”

8

(8,11,12). The matter of securing adequate training and credentialing of

laparoscopic surgeons has become widely debated (13). By contrast, the

question of evaluation of outcomes was virtually bypassed for all procedures

(9,10,14).

When laparoscopy is adopted in the upper abdomen, in particular when the

dissection is extended to the mediastinum, there is substantial risk of

pneumothorax (15-17). The positive insufflation pressure applied in the

abdomen may then be transmitted to the intra-thoracic structures and

fundamentally change the patophysiologic conditions.

This thesis is an attempt to address some of those issues that arise when

laparoscopy is applied in gastro-oesophageal surgery.

Technical principles of minimal access surgery

The denotation “minimal access surgery” refers to all surgical procedures that

apply visualisation through video-endoscopy and limited access, often

through trocars, to perform all or part of the intended procedure.

In this thesis, I will focus on laparoscopy as it is performed at the gastro-

oesophageal junction.

Basic laparoscopic principles and equipment are outlined below:

The main prerequisite for abdominal exposure is establishment of

pneumoperitoneum. Different techniques can be used to gain prime

entrance to the peritoneal cavity: Verres needle, Hasson trocar or

minilaparotomy.

9

Insufflation of carbon dioxide (CO2) is utilised to maintain

pneumoperitoneum. CO2 is a common product of metabolism and its

major advantage is the rapid dissolution in the event of venous gas

embolus. It is also low in cost and highly inflammable. Other gases have

been evaluated (air, O2, He and N2O), but for different reasons they are

less suited for laparoscopy (18-20).

Optimal exposure of the operative field depends on the insufflation

pressure; “the higher pressure, the better view.” However, increased intra-

abdominal pressure is of potential danger to the patient’s safety.

Undesired, but unavoidable side effects, are reduction of the respiratory

minute volume and compression of the vena cava with obstruction of

venous blood return to the heart. Therefore, it is not advisable to apply

pressure higher than 12-15 mm Hg (20-22).

One or several trocars are used to make easy access for the endoscope

and surgical instruments.

Light is transmitted from the light source to the endoscope through light

cables.

Video imaging equipment allows all members of the surgical team to

view the operative field simultaneously.

Most standard abdominal procedures have been translated into equivalent

laparoscopic procedures. Ideally, the difference should be the abdominal

access not the surgical principles.

10

Potential benefits of minimal access surgery

Minimal access surgery offers possibilities to reduce tissue damage because

of the operation. The reduction of surgical stress has been demonstrated in a

decreased inflammatory cytokine response in the early post-operative course

(23-26). The development of post-operative infectious complications (i.e.

wound infections) may be attenuated (27-29).

Patients often experience less pain after laparoscopic procedures and a quick

mobilisation allows for shorter hospital stay. Earlier return to normal

activities and thereby a shorter period of sick leave has repeatedly been

reported for different laparoscopic procedures, i.e. cholecystectomy

(12,30,31), appendectomy (27-29,32,33) and inguinal hernia repair (34-37).

However, when prospective, randomised single-blind comparisons of

laparoscopic versus small-incision cholecystectomy or of laparoscopic versus

open fundoplication have been undertaken, no significant advantages were

found in terms of post-operative recovery (38,39).

A reduced risk of incisional hernia (40,41) and a more acceptable, cosmetic

result may be further arguments in favour of the laparoscopic approach. In

patients in whom one has had the opportunity to inspect intra-peritoneal a

second time, sparse general adhesions have been observed; however, the local

adhesions have often been dense (42,43). It is not known whether the

laparoscopic approach will reduce the risk of post-operative ileus and make

subsequent laparotomy easier. Scientific support for these arguments is

inconclusive.

Economic considerations regarding laparoscopic techniques are not included

in the present thesis.

11

Anatomical considerations

The diaphragm constitutes the boundary between thoracic and abdominal

cavities. On the thoracic side, the diaphragm is lined by the pleura and on

abdominal side by the peritoneum. Although these membranes are extremely

delicate, they define the different anatomic compartments. Several important

organs pass between the thorax and abdomen, i.e. the aorta, the caval vein and

the oesophagus. The opening in the diaphragm where the oesophagus passes

into the abdomen is called the hiatus and the slings of diaphragm muscle,

which curves around the oesophagus from right and left to support the hiatus,

is called the right and left crus. With age, the hiatus often becomes wider and

the gastro-oesophageal junction looses its anchoring in the crura. The

proximal part of the stomach may slide up into the mediastinum, with a hiatal

hernia being the result (Figure 1).

Figure 1: Schematic illustration of the gastro-oesophageal junction and hiatal hernia.

12

During gastro-oesophageal operations, the surgeon regularly opens the

peritoneum in the hiatal region in order to extend the dissection into the

mediastinum. The proximity of surgical manipulations to cardiac and

pulmonary structures is challenging cardiopulmonary functions and the risk of

peri-operative complications increases. In particular, the mediastinal pleura

might be ruptured during dissection (16,44-47).

Pathophysiology

Pneumothorax and positive end-expiratory pressure (PEEP)

If the pleura is opened and communication to the peritoneal cavity

established, inadvertently or as part of the procedure, a pneumothorax will

result and the negative intra-pleural pressure found during normal inspiration

cannot be maintained.

In open surgery this does not normally constitute a problem because the intra-

pleural pressure will be equal to the pressure in the operating room

(atmospheric or zero pressure) and application of a minimal PEEP will force

the lungs to inflate fully. By contrast, the intra-pleural pressure of a

pneumothorax (or, to be precise, a capnothorax) created during laparoscopy

may equalise the positive intra-peritoneal insufflation pressure and thereby

prevent full inflation of the lung during inspiration. Such an event may harm

the gas exchange.

The application of PEEP has been suggested to counterbalance the

insufflation pressure (16,48). Theoretically, PEEP can improve the ventilation

of collapsed and poorly ventilated alveoli, decrease intra-pulmonary shunt

volumes and, finally, increase systemic oxygen saturation (49). On the other

hand, compliance can be reduced during PEEP because of over-distension of

alveoli, alveolar rupture and surfactant inactivation (49). PEEP induced

13

increase in lung volume may cause compression of the small intra-alveolar

vessels, thereby increasing pulmonary resistance (50,51) and decreasing

cardiac output (CO).

It has not been established which combination of insufflation pressure and

PEEP is least harmful for the circulation and gas exchange.

Insufflation pressure and intracranial pressure (ICP):

pneumothorax and PEEP

During laparoscopy, positive-pressure gas insufflation is applied to establish

abdominal distension. This application also induces a significant increase in

intracranial pressure (ICP), a phenomenon which has not been widely

recognised (52-54).

ICP is normally held within narrow limits. The four intracranial

compartments (cerebrospinal fluid, blood, parenchyma, and bone) respond to

changes in one or more of the compartments with reciprocal changes in the

non-osseous compartments to maintain a stable ICP (Monro-Kellie doctrine)

(55). Nevertheless, during rapid increase in one or more compartments,

compensation by the remaining compartments is usually inadequate and ICP

rises. Furthermore, the cranial cavity is not isolated from changes in pressure

of other compartments. Blood and cerebrospinal fluid movements will

transmit changes in intra-abdominal and intra-thoracic pressure intra-

cranially. Elevated intra-abdominal pressure will compress lumbar and

abdominal veins, as well as impair venous return. Central venous pressure

will rise and hence impede venous drainage from the central nervous system

(CNS) with a resulting increase in ICP (53,54,56).

As described in the previous section, application of PEEP is recommended to

correct the negative effects of pneumothorax, if encountered during

laparoscopy. However, potential deleterious effects on the CNS because of

PEEP have been described, though the results from different studies were

14

inconsistent (57-61). In head-injured patients, PEEP resulted in reduction of

mean arterial pressure (MAP) and elevation of ICP, and consequently reduced

cerebral perfusion pressure (CPP) (58). PEEP is thought to increase intra-

thoracic pressure and thereby impair venous return and cardiac filling, which

can lead to reduction of CO and MAP (58-60). These observations were made

in patients or animals with cerebral lesions, where the brain’s ability to

withstand pressure elevations was already challenged.

However, if a communicating pneumothorax is faced during a laparoscopic

procedure in a healthy subject, with reduction of lung compliance and oxygen

saturation, it is not known whether application of PEEP to promote

pulmonary gas exchange would lead to a further increase in ICP and thereby

impairment of cerebral blood flow.

Gastro-oesophageal surgery and minimal access approach:

An overview

Antireflux surgery

Of all gastro-oesophageal surgical procedures, antireflux surgery is at present

the most commonly performed. For this reason, antireflux surgery is best

suited to study how the new technique was implemented in routine hospital

care. The surgical treatment of hiatal hernia is, in principal, the same as for

severe gastro-oesophageal-reflux-disease (GORD). Thus, many of the

following paragraphs can also include the treatment of hiatal hernia.

Two major changes in the management of severe GORD have occurred

during the past decade. For many years, surgical therapy was regarded as

superior (62,63), but with the introduction of proton-pump inhibitors (PPI) in

1989, an alternative and often equally effective medical treatment became

15

available (64-66). The introduction of the laparoscopic technique for

antireflux surgery provided an alternative option. The laparoscopic Nissen

fundoplication was first described in 1991 by both Dallemagne (67) and

Geagea (68). In Sweden, antireflux procedures employing minimal access

surgery were first employed in 1992.

The principles of fundoplication operations include mobilising the lower

oesophagus and to wrapping the fundus of the stomach either partially or

totally around the oesophagus. When the oesophageal hiatus is enlarged, it is

narrowed by sutures in order to preclude the possibility for para-oesophageal

herniation and to prevent the wrap from being pulled up into the chest

(Figures 2A and 2B). The specific techniques for different kinds of

fundoplication and crural closure used in open surgery, i.e. partial anterior

(Watson) or posterior (Toupet) and total fundoplication (Nissen, Nissen-

Rosetti) have been translated into equivalent laparoscopic techniques.

Figure 2: 360 0 (total) Nissen fundoplication with crural closure (A), and

180 0 (partial, posterior) Toupet fundoplication (B).

16

Heading (69) estimated a fundoplication rate (number of antireflux operations

per 100,000 inhabitants) of 10 for Scotland for the 5-year period between

1982 and 1986. The remarkable increase in antireflux surgery in recent years,

noted in several European countries, is often attributed to the change in

surgical modality (70). In contradiction, it is generally held that the

indications for surgery remain unchanged, regardless of the surgical technique

(71). Nevertheless, current trends indicate that laparoscopic fundoplication is

being used increasingly as an alternative to maintenance therapy with proton

PPI (11).

Numerous studies have concluded that the short-term outcome after

laparoscopic antireflux procedures is at least as good as for open procedures.

Accelerated painless recovery is achieved without compromising the efficacy

and clinical outcome of the procedure (11). However, published reports are

almost exclusively from specialised centres (72-79), making it difficult to

draw any firm conclusions from these data and applying them to routine

hospital care. The widespread adoption of laparoscopic antireflux surgery by

generalists without special interests in reflux disease can possibly have a

negative impact on the outcome. It has been repeatedly demonstrated that

laparoscopic antireflux surgery has a long learning curve (80-84). Therefore,

it may be hard to achieve the necessary experience and surgical training in

low-volume hospitals.

To our knowledge, there have only been published results from six controlled

randomised trials comparing the outcome after the two techniques. The Dutch

multicentre study was discontinued because of a high incidence of early

dysphagia in the laparoscopic group (85). In a Swedish study with blind

evaluation of the recovery and discharge periods, patients in both groups

stayed a median of three days post-operatively at hospital and no significant

differences were found in the duration of sick leave (39). Good short-term

results after both laparoscopic and open procedures have been reported from

17

different Finnish groups in three prospective, randomised studies. They

compared complications, outcome, quality of life and patient satisfaction. In

one study, the patients (n=42) were followed for 2 years; the other reports

were based on a 12-month follow-up (86-88). The different procedures seem

to be equally effective, but the number of patients in each study is too small to

allow any firm conclusions. Both Heikkinen and Loustarinen report that new

on-set dysphagia tended to be more frequent among patients who had had the

antireflux procedure made laparoscopically. A similar finding was reported in

a randomised Swedish study (89).

To our knowledge, long-term follow-up studies have not been done.

Surgeons, as well as patients, seem to prefer the laparoscopic technique and

take it for granted that the effectiveness of laparoscopic and conventional

open approach is comparable (43,90,91).

The goal of antireflux surgery is resolution of all symptoms of gastro-

oesophageal reflux with negligible side effects and no further need for

medical therapy (92,93). To evaluate outcome of antireflux surgery it is

therefore paramount to ask the patients whether they are symptom-free and

satisfied with the results. Exclusion of heartburn, which is the cardinal

symptom of GORD, correlates well with post-operative normalisation of 24-

hour pH monitoring (94). Many patients, however, refuse to participate in

post-operative 24-hour pH monitoring. Moreover, this test is both elaborate

and expensive. The absence of heartburn is fairly reliable in predicting normal

acid exposure on pH testing (94). Several investigators have proposed

disease-specific questionnaires as a tool for follow-up surveys after antireflux

surgery (93-95).

18

Cardiomyotomy

The minimal access technique has replaced open surgery in the treatment of

oesophageal achalasia. Laparoscopic Heller myotomy and partial

fundoplication have emerged as the procedure of choice (96,97). From

specialised centres, excellent results have been reported (96,98,99). However,

the disease is seldom occurring and few, if any, units in Sweden will have

enough patients to perform this procedure routinely.

Oesophagectomy

Different techniques for endoscopic oesophagectomy have been employed.

The mediasinoscopic approach to the oesophageus was developed by Buess

and colleagues (100), but its diffusion has remained limited. Several

investigators have reported their experience of oesophagectomy with

thoracoscopy-assisted techniques combined with laparotomy for gastric

mobilisation (101-103). This technique was also adopted at our clinic, but for

the same reasons as reported by others, we abandoned it after a few years

because no reduction in morbidity or mortality could be demonstrated (104-

107). Refinements in technical equipment, i.e. the introduction of a hand-port

system, have made dissection and gastric mobilisation easier to perform

laparoscopically (108). A combined thoracoscopic and laparoscopic technique

was therefore a logical development (109,110). However, contrary to other

advanced surgical endoscopic procedures, endoscopic oesophagectomy has

not yet been convincing and few clinics have included the technique in their

standard repertoire (111).

19

Concerning the oncological issue, we now know that performing a radical

lymphadnectomy by the minimal access technique takes longer operating time

and may increase morbidity (111,112).

Gastric resections

Laparoscopic partial gastrectomy for benign diseases and for palliation has

been accepted as an effective surgical option (113). Laparoscopically assisted

resections for malignancies, however, deserve a word of caution. The CO2

insufflation may stimulate tumour proliferation and the risk for port site

metastases has been addressed in several reports (19,114,115). Further

standardisation is needed as well as the definition of correct indications based

on long-term results. In Sweden, the laparoscopic approach is seldom used for

gastric resections (for benign as well for malign disease).

Bariatric methods

Laparoscopic methods for gastric banding and Roux-en-Y gastric bypass are

widely adopted and the new technique has generated further refinements in

the surgical treatment of obesity.

Prospective, randomised studies comparing equivalent open and laparoscopic

methods are few and the little results available are inconclusive (116,117). In

obese patients morbidity, caused by parietal trauma after laparotomy, occurs

in up to 30% (infections and incisional hernias) of the patients (41). These

complications have been encountered only infrequently when applying

minimal access techniques.

In Sweden, obesity surgery is mostly performed at specialised clinics; all of

these clinics have extensive experience in employing the laparoscopic

approach.

20

Aims of the thesis

This thesis deals with two principally disparate issues.

First, in part one of the thesis pathophysiology specific for the application of

laparoscopic techniques in gastro-oesophageal surgery is investigated. We

evaluated two possible therapeutic actions (differential lung ventilation and

PEEP) to correct for potential harmful effects (Studies I and II). Second, in

part two the widely applied laparoscopic approach for antireflux surgery is

surveyed as regards implementation and outcome (Studies III-V).

The specific aims of part 1 were to study the following issues during

combined pneumoperitoneum and unilateral pneumothorax in anaesthetised

pigs:

- investigate the effects on cardiopulmonary function (Study I)

- determine whether differential ventilation with varying PEEP on each lung

was beneficial (Study I)

- to evaluate the effects of PEEP on ICP and cerebral blood flow (Study II)

The specific aims of part 2 were as follows:

- analyse whether the new therapeutic options (i.e. the introduction of

proton pump inhibitors (PPI) in 1989 and the laparoscopic technique in

1992) altered the surgical treatment of GORD. Specifically, we sought to

study the change in the frequency of antireflux procedures (Study III)

- to compare the long-term results after conventional open and laparoscopic

procedures (Study IV)

- to compare the long-term results after laparoscopic antireflux procedures

at low- and high-volume hospitals (Study V)

21

Material and Methods

A. Experimental studies (Studies I and II)

Ethical considerations and animals

The experimental protocols were reviewed and approved by the Institutional

Review Board of Uppsala University. The animals were treated in conformity

with the Helsinki convention for the use and care of animals (“Principles of

Laboratory Animal Care” and “Guide for the Care and Use of Laboratory

Animals,” National Institute of Health Publication No. 80-23, revised 1985).

Thirty male and female Swedish Landrace piglets 11-14 weeks of age, with a

mean weight of 24 2 kg (range 21-30 kg), were studied. The animals were

fasted overnight with free access to water and delivered by the same supplier

directly to the laboratory on the morning of the experiment. After the

completion of the experiment, when the animals still were anaesthetised,

cardiac arrest was induced with intravenous injection of potassium chloride.

Method of anaesthesia

Anaesthesia was accomplished with an intramuscular injection of 3mg/kg

tiletamine + 3mg/kg zolazepam (6 mg/kg Zoletil®, Virback Lab., France),

2mg/kg xylazine (Rompun®, Bayer, Germany) and atropine 0.04mg/kg

combined with an intravenous bolus injection of 1 mg/kg morphine.

Anaesthesia was maintained with a continuous infusion of 20 mg/kg/h

22

ketamine and 0.48 mg/kg/ h morphine (118). Muscular blockade was

maintained by continuous intravenous infusion of pancuronium bromide, 0.24

mg/kg/h. Tracheotomy was performed and mechanical ventilation initiated

with an I:E ratio of 1:1, FiO2 of 0.4, respiratory rate 25 per minute and PEEP

5 cm H2O (Servo ventilator 900C, Siemens-Elema, Sweden). Minute

ventilation was adjusted to maintain PaCO2 between 5.0 and 5.5 k Pa.

To compensate for fluid losses throughout the study, an intravenous bolus of

50-200 ml dextran 70 (Macrodex ® 6%, Fresenius Kabi AB, Sweden) was

administered before commencement of the interventions, aiming at a

pulmonary capillary wedge pressure (PCWP) of 8-10 mm Hg. This was

followed by a continuous intravenous infusion of a balanced crystalloid

solution with 2.5% glucose, 10 ml/ kg/h.

Technique for separate lung intubation and differential lung ventilation

(Study I)

Each lung was intubated separately. In the pig, the bronchial tree differs from

human anatomy (119). Pigs have a separate bronchial branch to the right

upper lobe, and this branch goes directly from the trachea, proximal to the

carina.

First, the larger 8 mm endotracheal tube was positioned with its tip

immediately above the bronchial branch to the right upper lobe. To achieve

separate intubation and differential ventilation, the left bronchus was

intubated through the wide bore tube with a 5 mm outer diameter

endotracheal tube. This tube was advanced over a 3.5 mm bronchoscope to

ensure optimal placement (Figure 3). After the cuffs were inflated, both tubes

were connected to separate ventilators.

23

Figure 3: Schematic illustration of separate lung intubation in pigs.

Model for combined positive pressure pneumoperitoneum and unilateralpneumothorax (Studies I and II)Two trocars (5 mm) were introduced: one intraperitoneally and the other into

the right pleural space to accommodate gas insufflation. The trocars were

connected to a common gas insufflator (Pelvi-Pneu CO2, WISAP, Germany)

and the pressure was monitored with an aneroid manometer. During the

experimental intervals, CO2 was insufflated with a common pressure applied

to both trocars in the abdomen and in the right haemithorax, and thereby

pneumoperitoneum and unilateral pneumothorax under equal positive

pressure were achieved (Figure 4).

24

Experimental design

Study I

The model for combined positive pressure pneumoperitoneum, unilateral

pneumothorax and differential lung ventilation was used. Different

combinations of PEEP on right and left lung were evaluated. The rationale for

the application of PEEP was to decrease the pressure gradient between the

peritoneal and pleural cavities during inspiration and expiration so that the

lungs inflate completely. We hypothesised that the optimal respiratory

technique would be differential lung ventilation. We assumed that PEEP

applied in the lung with pneumothorax had to be equal to or exceed the CO2

insufflation pressure. To avoid harmful effects that might be related to

prolonged and elevated PEEP, we decreased PEEP on the lung without

pneumothorax.

An experimental cycle was initiated by insufflating CO2 with a pressure of 10

mm Hg applied to both trocars. During this period, right and left PEEP

settings of 10(right)/5(left), 10/10, 15/5, 15/10 cm H2O were used by random

assignment. The same PEEP setting was applied for the next 20 minutes with

no adjustments of the ventilators. Measurements were recorded at the end of

each interval. The gas insufflation was then turned off. The pneumothorax

and the pneumoperitoneum were evacuated and a period of haemodynamic

and respiratory stabilisation was allowed. Thereafter, a new experimental

cycle was started with another combination of PEEP.

In a pilot study, with a PEEP setting of 5/5 cm H2O, extremely high airway

pressures, exceeding 90 cm H2O, were recorded. This resulted in severe

deterioration of blood gases, which was hard to overcome despite long

recovery periods. Therefore, the PEEP combination of 5/5 was always applied

at the end of the experiment. During the study, it became clear that a higher

PEEP on both lungs was favourable, and for the last four animals, an

additional cycle with a PEEP setting of 15/15 was inserted before 5/5.

25

Figure 4: Experimental set-up in Study I (combined right pneumothorax andpneumoperitoneum with differential lung ventilation).

Study II

In this study we examined the changes in ICP and cerebral circulation in a

similar model as described above but without differential lung ventilation. We

hypothesised that application of PEEP to counterbalance the insufflation

pressure would be beneficial for pulmonary gas exchange, but increase ICP

and consequently impair cerebral blood flow.

In the control group (n=11) we analysed changes in ICP, cerebral circulation

and blood gases. Carbon dioxide insufflation pressures of 5, 10, 15 or 20 mm

Hg were randomly assigned and applied for 20 minutes during the

intervention period. PEEP was kept at 5 cm H2O.

In another eight piglets the experiment was similar, except PEEP was adjusted

to a value equal to the insufflation pressure of CO2 during the intervention

periods (PEEP group, n=8).

26

In all animals the experiment consisted of four test intervals with intermediate

recovery periods.

Monitoring

Haemodynamic monitoring (Studies I and II)

Intra-vascular catheters were placed surgically. A catheter (16 G) was inserted

via a branch of the right external carotid artery into the aortic arch for

recording of MAP and sampling for arterial blood gas analysis. A pulmonary

artery catheter (7 Fr) was introduced via the right external jugular vein into

the pulmonary artery for measurements of CO and PCWP. Intra-vascular

pressures and ECG were monitored continuously (Solar 8000, Marqutte

Hellige, USA). Blood samples were analysed in a blood gas analyser (ABL5,

Radiometer, Denmark) and in a Haemoxymeter (OSM3, Radiometer,

Denmark). In Study II a catheter (20 G) was also inserted into the left internal

jugular vein and passed retrogradely into the jugular bulb for blood sampling,

for measurements of oxygen saturation and for partial pressure (SjvO2 and

PjvO2).

Respiratory monitoring (Studies I and II)

A respiratory profile monitor (CO2SMO+, Novametrix Medical Systems, Inc.,

Wallingford, Connecticut, USA) was connected to the ventilator for

monitoring of end-tidal carbon dioxide levels (ETCO2), CO2 elimination

(VCO2) and static compliance (C stat).

In Study I two ventilators with two separate respiratory profile monitors were

used.

Intracranial monitoring (Study II)

Paratrend® catheter: The probe incorporates optical fibres for the

measurements of PCO2 and pH, an electrochemical sensor for PO2, and a

27

thermocouple for measurements of temperature (Paratend-7®, Biomedical

Sensors LTD, High Wycombe, England). The cylindrical construction of the

sensor allows measurements over the entire surface of the probe, the diameter

of which is 0.5 mm. The four sensor components are located at intervals along

the distal 4 cm of the polyethylene probe, which is permeable to O2 and CO2.

The outer surface of the probe is coated with covalently bonded heparin to

prevent deposition of fibrin. The monitor continuously displays pH, PCO2,

PO2 and temperature. Although originally designed for measurement of

arterial blood gases, Paratrend-7® has also been validated for measurements in

cerebral tissue (120-122).

The Paratrend® catheter was inserted through a Camino® bolt (Camino

laboratories, San Diego, USA) fitted into a right parietal burr hole and

positioned 4 cm into the brain for measurement of cerebral cortical tissue

PO2, PCO2, and pH (PcO2, PcCO2 and c-pH) (Figure 5).

Camino® pressure transducer: ICP was measured by a Camino® pressure

transducer inserted through a 2-mm burr hole approximately 1 cm anterior to

the Paratrend® probe (Figure 5).

Periflux® laser-Doppler flowmetre: For continuous measurement of cerebral

cortical blood flow, a Laser-Doppler flow probe (Flexible Straight Probe 320,

Periflux® laser-Doppler flowmetre PF 2B, Perimed, Stockholm, Sweden) was

introduced through a 2-mm burr hole 1 cm anterior to the coronal suture. The

probe was placed on the surface of the brain cortex (Figure 5).

The flow estimate with this technique is based on the Doppler effect induced

by moving erythrocytes to low-power laser light. Light (with a wavelength of

632.8 nm) from a 2-mV helium neon laser is guided to the tissue by a light

conductor, which also serves to transmit the back-scattered light to the

photodetector system. There is a frequency shift when the laser light has

interacted with moving tissue elements. The bandwidth of the Doppler-shifted

28

frequencies increases proportionally to the velocity of erythrocytes. The

signal amplitude reflects the microcirculation.

The Laser-Doppler probe has been validated for flow measurements in the

CNS; good correlation was reported with flow changes detected by the

microsphere technique (123,124). Its accuracy in monitoring changes in

cerebral cortical blood flow has also been validated during the low flow state

after induction of cerebral ischaemia (125).

The Laser-Doppler flow signal (LDF) was registered as online printout. The

measurements of each animal were recorded as a fraction of the steady state

baseline level, which was designated as 1.0.

Cerebral perfusion pressure (CPP) was calculated as the difference between

MAP and ICP (MAP-ICP = CPP).

Figure 5: Schematic illustration of the placement of the Paratrend® catheter (A), Camino®

pressure transducer (B) and Periflux® laser-Doppler flowmetre (C).

29

B. Epidemiological studies and survey of the long-term results

of antireflux surgery

Methods of survey

EpC (Studies III-V)

The Centre for Epidemiology (EpC) at the Swedish National Board of Health

and Welfare administers a register of all in-patient public hospital care in

Sweden (126). This register, which is updated each year, became fully

comprehensive in 1987. Data of all surgical procedures are publicly available

while patient identification numbers are protected. The ICD-9 (WHO)

classification of diagnoses is applied and operations are coded according to

the Swedish Classification of Surgical Procedures.

Questionnaire to the heads of all surgical departments (Study III)

To validate the information obtained from EpC we mailed a questionnaire on

antireflux surgery to the heads of all surgical departments in Sweden. The

question was whether the department performed any antireflux surgery, and,

if so, the number of open and laparoscopic procedures for 1995 and 1996.

Pre-operative evaluation and indications for surgery were not addressed in

this study.

Questionnaire to patients (Studies IV and V)

A questionnaire devised to identify typical symptoms of GORD and post-

operative side effects of antireflux surgery was mailed to all patients included

in the studies.

The questionnaire included items on heartburn, acid regurgitation, medical

treatment, dysphagia, gas bloat, ability to belch and vomit, as well as an

30

overall estimate of satisfaction. We specifically asked about revision surgery

and complaints that could be related to the scars. The usefulness of the

questionnaire was validated on 136 patients before the study was undertaken

(127).

Study design

Study III

Age, gender, county of residence for each patient, information regarding the

numbers and the kind of antireflux procedures, the duration of hospital stay

and the post-operative mortality rate were analysed for the period from 1987

to 1997 using data obtained by the EpC. We have compared the surgical

activity in different health service regions (counties) and among different

hospitals over the years. Fundoplication rates for each county are calculated

and adjustments are made for variations in the population.

Information from the questionnaire that was sent to heads of all surgical

departments was compared with data obtained from EpC in order to validate

the latter.

Study IV

Long-term outcome after laparoscopic and conventional open antireflux

procedures were compared by administering a questionnaire to the patients 4

years after surgery. We hypothesised that the open and the laparoscopic

techniques were equally effective in controlling symptoms and providing

patient satisfaction. The success rate was estimated to be 85-95% (77).

Sample sizes of approximately 180 patients were necessary to detect a

difference of 10% in failure rate in a two-tailed test with a significance level

of 5% and statistical power of 85%. The response rate was estimated to be

between 80 and 90%.

31

The study period took place between 1995 and 1996. In an effort to have

uniform study groups we selected those hospitals where more than 50 patients

had been operated on by one of the techniques. Two random samples of

approximately 230 patients in each group were thus identified for study

purposes.

Study V

Long-term results after laparoscopic antireflux procedures performed at low-

and high-volume hospitals were compared using a questionnaire 4 years after

surgery. The study period was the same as in the previous study, i.e. 1995 and

1996.

We hypothesised that the long-term results were equally good for patients

operated on at low- and high-volume hospitals. Calculation of sample size

was similar to study IV. All 220 patients operated on at low-volume hospitals

and a computerised random sampling of 225 patients operated on at high-

volume hospitals was identified for study purposes.

Definition of treatment failure (Studies IV and V)

The main endpoints in Studies IV and V were treatment failure and patient

satisfaction. Treatment failure was defined by the presence of one or more of

three criteria:

a new antireflux procedure had been required to control symptoms or to

relieve side effects

medication was taken at least once a week specifically to relieve heartburn

or acid regurgitation

patient dissatisfaction with the result of surgery

32

Patients and ethical considerations (Studies IV and V)

The study protocol was approved by the local ethics committee in science at

Uppsala University. Permission to obtain the identification numbers and

addresses was provided by the Centre for Epidemiology (EpC). None of the

patients included in Studies IV and V were treated at the authors’ department.

The questionnaires were treated anonymously and confidentially. The patients

were also informed of their freedom to choose to participate in the study and

that no financial compensation would be given. Non-responders received a

second survey. Heads of those surgical departments that took part were

informed about and approved of the study.

33

Statistical methods

Study I

A Two-way, Randomised Block design was performed for each outcome

variable to determine if the mean outcomes of the four randomised treatments

differed significantly from one another.

In addition, comparisons were made between the mean outcome averaged

over the four randomised procedures, the mean outcome at baseline and the

mean outcome for procedure “5/5.”

For treatment “15/15,” which was applied only for the four last animals, a

purely descriptive comparison of the average outcomes was employed.

Study II

A multivariate repeated measures analysis of variance (MANOVA) was used,

with the different settings of insufflation pressure serving as a within factor

and PEEP serving as a between factor. For SaO2, the standard analysis was

inappropriate because of severe skewness of the data. Therefore, a repeated

measures analysis of variance was performed on the ranks of the SaO2 values,

and the Wilcoxon rank sum test for two independent samples was

subsequently used to compare the median SaO2 values between the two

groups.

Studies I and II: A residual analysis was performed to confirm that the

underlying model assumptions were met by the data. P values of less than 0.05

were defined as significant. The Bonferroni correction was used to ensure that

the overall Type 1 error rate did not exceed 0.05.

34

Study III

In Study III, simple descriptive methods were used, i.e. number, percent,

proportion and median.

Studies IV and V

Comparison of questionnaire items between the groups was conducted using a

logistic regression with sex, age, and body mass index (BMI) serving as the

covariates. The Bonferroni correction was used to control the overall Type 1

error rate at 0.05. Comparisons of age, sex and BMI between the groups were

conducted using t tests and the chi-squared test.

35

Results and discussion

Study I

Results

When a communicating pneumo-pleuro-peritoneum was established with CO2

insufflation pressure of 10 mm Hg in anaesthetised pigs, the following major

observations were noted:

increased PCWP

hypercarbia, respiratory acidosis and increased CO2 elimination

hypoxemia

The hypoxemia could be corrected and the acidosis considerably reduced if

adequate PEEP was applied on both lungs (Figures 6 and 7). The blood gases

were close to normal when PEEP in both lungs exceeded the CO2 insufflation

pressure. If there was a difference in PEEP between the lungs, there was a

tendency to simultaneous decrease in C stat, ETCO2 and VCO2 in the lung

with the lower PEEP, even in the presence of hypercarbia as measured by

blood gas analysis. Haemodynamic outcomes were relatively stable.

36

PEEP settings

Figure 6: Arterial oxygen saturation (SaO2) at baseline and at different

combinations of PEEP in right and left lung (dx/sin).

PEEP settings

Figure 7: pH at baseline and at different combinations of PEEP in right and

left lung (dx/sin).

60

65

70

75

80

85

90

95

100

105

SaO

2 %

Baseline 10\5 10\10 15\5 15\10 15\15 5\5

7,2

7,25

7,3

7,35

7,4

7,45

7,5

7,55

pH

Baseline 10\5 10\10 15\5 15\10 15\15 5\5

37

Discussion

It is well known that CO2 is absorbed transperitoneally during laparoscopy

(128,129). The degree of hypercarbia and acidemia that is induced depends on

CO2 insufflation pressure, peritoneal area available for gas exchange and

respiratory compensation (49). At an insufflation pressure of 10 mm Hg, the

changes are usually moderate and are clinically well tolerated both in humans

(49) and in pigs (130). With a communicating pneumo-pleuro-peritoneum, a

larger surface area will be exposed. More CO2 may be absorbed with a

concomitant increase in hypercarbia and acidosis. With positive pressure in the

pleural cavity, as in our model, a pneumothorax may further aggravate the

condition because of collapse of lung parenchyma and impaired gas exchange.

Shunting of blood in the collapsed lung parenchyma may result in hypoxemia

and CO2 retention (130,132). CO2 is more soluble and crosses from the blood

into the alveoli 25 times faster than oxygen (49). Impaired gas exchange is

therefore first noted in reduced oxygenation rather than increasing hypercarbia,

even in the presence of an abnormal amount of systemically dissolved CO2.

We observed a significant difference in PaO2 between the four randomised

treatments, but not in PaCO2.

Tension pneumothorax refers to a pneumothorax characterised by an increased

intra-pleural pressure that is caused by an opening through the pleura allowing

air to pass in but not out. An increasing intra-thoracic extra-pulmonary

pressure can cause the lung to collapse and even push the structures in

mediastinum to the other side (mediastinal shift). In a strict sense the

pneumothorax of our model is not a tension pneumothorax, but it has a positive

intra-thoracic pressure and thus a tension-like pathophysiology may result.

It is unclear whether cardiovascular collapse observed during tension

pneumothorax is secondary to a direct compressive effect on central venous

structures with reduced preload to the heart, or secondary to grave hypoxemia

38

that is caused by lung parenchymal collapse with shunting of desaturated

blood, or a combination (49,131). In our study severe hypoxemia, hypercarbia

and respiratory acidosis developed without significant changes in HR and

MAP. This finding led us to conclude that hypoxemia is an early sign of

impaired gas exchange in ventilated pigs with pneumothorax. This position is

in accordance with the findings of Barton and colleagues in an experiment with

progressive pneumothorax, where SaO2 decreased immediately and continued

to decline to levels below 50% before cardiovascular collapse (131).

We initially hypothesised that the optimal respiratory technique during

laparoscopy with communicating unilateral pneumothorax would be

differential lung ventilation with different PEEP on left and right lungs. On the

side of the pneumothorax, we thought that PEEP had to equal or exceed the

CO2 insufflation pressure to avoid lung parenchymal collapse and poor

oxygenation. To minimise harmful side effects we tried to keep a lower PEEP

on the contra-lateral lung.

Our hypothesis, however, was not completely supported. To counterbalance

the positive insufflation pressure it seemed correct to apply an equal or larger

PEEP. However, this PEEP had to be applied to both lungs to avoid

deterioration of gas exchange. No beneficial effects of differential application

of PEEP were documented.

39

Study II

Results

This study demonstrated that the establishment of positive pressure

pneumo-pleuro-peritoneum resulted in immediate elevation of ICP. The

magnitude of the increase in ICP was proportional to the increase in

insufflation pressure (Figure 8).

CPP decreased, but LDF remained unchanged (Figures 8 and 9). There

were no obvious metabolic signs of cerebral ischaemia. However, arterial

and venous jugular bulb desaturation developed unless PEEP was matched

to counterbalance the insufflation pressure (Figure 10).

Application of PEEP prevented arterial hypoxemia and hypercapnia;

moreover, a less pronounced decrease in pH was observed (Figures 10 and

11).

Changes in ICP, CPP, and cerebral oxygen extraction ratio did not differ

significantly between the study groups. Hence, PEEP did not adversely

affect ICP or cerebral circulation (Figure 8).

We did not succeed in obtaining reliable and reproducible measurements of

PcO2. The variation between initial baseline values in different animals and

between baseline measurements at different times during the same experiment

was pronounced and unsystematic, often yielding no measurement at all. The

problem with the oxygen sensor of the Paratrend® probe has also been

experienced in similar experiments in our laboratory (133). Nevertheless,

because of regular blood sampling from the left jugular bulb catheter, we

obtained measurements of saturation and partial pressure of oxygen in venous

blood from the brain (SjvO2 and PjvO2). We could then calculate the cerebral

40

oxygen extraction ratio as the ratio of the arterial jugular bulb oxygen content

difference to the arterial oxygen content [(CaO2 – CjvO2)/CaO2].

The Laser-Doppler probe was found sensitive to adjustments in location. In

five animals measurements of cortical blood flow were inaccessible because

we were unable to establish stable baseline values.

41

Figure 8

Figure 9

ICP and CPP in control (-) and PEEP group (+)

0102030405060708090

100

0 5 10 15 20Insufflation pressure (mm Hg)

ICP

and

CPP

(mm

Hg)

ICP -ICP +CPP -CPP +

Laser-Doppler flow (LDF) in control (-) and PEEP group (+)

0

0,5

1

1,5

2

0 5 10 15 20Insufflation pressure (mm Hg)

LDF

(frac

tion

of th

e ba

selin

e)

LDF(-)LDF(+)

42

Figure 10

Figure 11

SaO2 and SjO2 control (-) and PEEP group (+)

0

20

40

60

80

100

0 5 10 15 20Insufflation pressure (mm Hg)

SaO

2 an

d Sj

O2

% SaO2-SaO2+SjO2+SjO2-

a-pH and c-pH in control (-) and PEEP group (+)

6,8

6,9

7

7,1

7,2

7,3

7,4

7,5

0 5 10 15 20Insuff lation pressure (mm Hg)

a-pH

and

c-p

H a-pH-

a-pH+

c-pH-

c-pH+

43

Discussion

In our study the increase of ICP was immediate and proportional to the

increase in insufflation pressure. The difference in PaCO2 between the control

and the PEEP group was significant, but LDF remained at the same level and

the elevation in ICP did not differ between the groups. These results verify the

observations of Halvorsen and co-workers. In their study baseline ICP was 14

(±2) and increased to 30 (±5) mm Hg at 15 mm Hg pneumo-peritoneum. This

increase was independent of changes in PaCO2 and pH (54). It is also in

accordance with the data from Schöb and his colleagues who tested different

insufflation gases in pigs (134). The increase in ICP with increasing

insufflation pressure has been described during laparoscopy in humans

(135,136).

Although the increased ICP constitutes a sign of warning, in clinical practice

the most important factor is whether the cerebral circulation is compromised.

Specifically, brain tissue oxygenation must be ensured. Even a brief period of

inadequate perfusion of brain tissue leads to intense production of lactic acid

(metabolic acidosis) (137). In an experimental study of cardiopulmonary

resuscitation five minutes of cardiac arrest resulted in c-pH of 6.3-6.6 though

a-pH was not below 7.4 (133). In our study the acid-base buffering capacity

of the brain was not exhausted. No cortical metabolic acidosis was detected

because cortical oxygenation was probably sufficient to meet local demands.

Autoregulation of cerebrovascular resistance to blood flow can prevent large

fluctuations in cerebral circulation despite large variations in systemic blood

pressure (137). In the normal cerebrovascular bed cerebral blood flow can be

maintained in the face of rising ICP until the difference between MAP and ICP

falls to about 40 mm Hg (137-139). Moreover, because oxygen supply is

usually superfluous and the cerebral extraction ratio is low, the brain can,

during periods of compromised circulation, increase the oxygen extraction

44

ratio (133,137). Recent studies suggest that SjvO2 correlates better with

cerebral oxygenation than CPP (140-143). Our study verified that cortical

cerebral blood flow could be maintained despite a reduction in CPP.

Nevertheless, in the control group (pneumo-pleuro-peritoneum without

compensatory PEEP), SjvO2 was extremely low and the oxygen extraction

ratio was close to its upper limit when insufflation pressures of 15 and 20 mm

Hg were applied. Jugular venous oxygen saturation below 50% can be

interpreted as a sign of global brain hypoxia (144), indicating that the

compensatory mechanisms were nearly exhausted. PEEP enhanced arterial

oxygenation and thereby could augment the oxygen supply to the brain.

This study was conducted on young and healthy pigs. However, one should be

careful in interpreting the results and then applying them in clinical situations.

Our patients are often elderly with cardiopulmonary impairment, a condition

that renders them far more sensitive to an insult such as combined pneumo-

pleuro-peritoneum. The study verifies that the acute problem of pneumothorax

during ongoing laparoscopic surgery (i.e. fundoplication, cardiomyotomy,

oesophageal resection and bariatric procedures) may be corrected by

application of PEEP. PEEP may help to ensure good oxygenation, CO2

elimination and avoidance of cerebral hypoxemia.

Study III

Results

A good correlation was found between data obtained from EpC and the

answers to the questionnaire from the heads of the surgical departments that

participated in the study. We concluded that the data in EpC were reliable.

Therefore, data collected exclusively from EpC are used in the following

analysis.

45

The increase in the annual number of antireflux procedures was almost

threefold during the study period (Figure 12). In 1987, 456 antireflux

procedures were performed. Ten years later, this figure had risen to 1,303. The

fundoplication rate rose from an average of 5.5 to 12.3/100,000 inhabitants

during a 10-year period.

The variation in operative volume among hospitals was also pronounced; we

found that most hospitals operated on fewer than 15 patients during the study

period.

The length of hospital stay has decreased for both open and laparoscopic

procedures. Mean hospital stay was 12.2 days in 1987, whereas in 1997 it was

3.0 days for laparoscopic and 7.9 days for open surgery. Furthermore, we

observed a large variation among hospitals regarding the length of hospital

stay.

GORD was registered as the diagnosis in 270 procedures (43.9%) among

those patients who had an antireflux procedure or a hiatal hernia repair carried

out in 1987; 406 procedures (66.0%) were diagnosed as hiatal hernia. Thus,

the diagnosis of hiatal hernia was more frequently adopted than GORD. Ten

years later, 1,143 patients (84.4%) were given a diagnosis of reflux and 242

(17.8% were classified as hiatal hernia. Only one (0.03%) laparoscopic

antireflux procedure has been associated with a fatal outcome since its

introduction in 1992.

46

Figure 12: Annual numbers of antrireflux procedures in Sweden, 1987-1997.

Discussion

The annual numbers of surgical procedures performed to correct GORD and

hiatus hernia have changed dramatically and inversely during the study period.

The explanation is more likely a shift in nomenclature than an actual change in

the frequencies of the different diseases.

The increase in the fundoplication rate started before the introduction of

proton-pump inhibitors and continued even more pronounced during the

following few years. The development of laparoscopic antireflux surgery did

not alter the course of this increase. The present study shows that soon after its

introduction the laparoscopic technique replaced the open procedure as the

0200400600800

100012001400

87 88 89 90 91 92 93 94 95 96 97

LaparoscopicOpen

47

preferred method. This change occurred before the proposed benefits of

laparoscopy were clearly documented.

The length of hospital stay has also been considerably reduced during the study

period for open surgery, from 12.2 to 7.9 days, on average, illustrating the

problem with historical controls.

The fundoplication rates varied greatly among health service regions.

However, there is no reason to believe that the prevalence of GORD is

different (145). On the other hand, no one can define the most optimal or even

a reasonable fundoplication rate. It might be that the often quoted annual

number of 10 antireflux operations/100,000 (69) is far too low.

Study IV

Results

Failure and dissatisfaction were significantly more common in the laparoscopy

group than in the laparotomy group. Treatment failure rates were 29.0% in the

laparoscopy group and 14.6% in the laparotomy group (p<0.004). The

dissatisfaction rates were 15.0 and 7.0% in the laparoscopy and laparotomy

group, respectively (p<0.005). We could not recognise any item in which the

patients receiving the open technique had an overall significantly worse

outcome.

An estimated 19.5% of the patients in the laparoscopy group and 8.6% in the

open group reported that they used medication at least once a week specifically

to relieve heartburn or acid regurgitation (p<0.02). Most of them used

medication every day, and in case of medication, 75% used PPI.

Gas bloat or flatulence was reported as the most bothersome abdominal

complaint by 39.7% of all the patients. Only 2.1% (8 patients) considered

48

dysphagia as their most bothersome symptom, although 9.0% (33 patients)

reported daily episodes of difficulties in swallowing food.

Discussion

In this study the high overall failure rate is primarily a result of the high

proportion of patients who continue to use medication to relieve heartburn or

who are dissatisfied. It is obvious that the definition of treatment failure has

influenced the reported results. This is discussed in more detail in a later

section (General Discussion). A more restrictive definition of failure will

reduce the number of procedures that are classified as failures; however, there

will still be a marked difference between the results after laparoscopic and

open procedures.

The results in the laparoscopic group are worse than most of the literature

suggests (72-74,78,79,146), but they are not extreme (43,147-149). It should

also be noted that the results obtained from population-based studies, as ours,

are often inferior to what is reported from selected specialised centres.

At a 2-year follow-up after laparoscopic fundoplication, Soper reported that

26% of the patients had symptoms suggestive of persisting gastro-oesophageal

reflux (43). Anatomic failure of the procedure was documented in 7% and in

2.8% surgical revision was required. The incidence of redo after a primary

laparoscopic approach is usually about 2-6% at short-term follow-up (11).

Most remarkably, the group at Adelaide University noted 12.7% repeat

operations in their 5-year follow-up of 178 consecutive laparoscopically

operated patients (148). More than half of the surgical failures were due to

intra-thoracal herniation. This complication is seldom reported after open

surgery, but is frequently encountered after laparoscopic procedures (42,150).

The design of the present study does not allow us to explore the findings at

49

redo procedures and thus we cannot determine whether intra-thoracal

herniation is a usual cause for surgical failure in Sweden. There are no data

available in the literature to suggest that the surgical failure rate is higher after

laparoscopic fundoplication than after the open approach. In the present study

revision surgery was reported in 5-6% in both groups.

The long learning curve of laparoscopic antireflux surgery may be a

confounding factor (80-83). However, laparoscopic antireflux surgery had

been performed for more than 3 years in Sweden and 950 procedures were

accomplished before the study period (Study III). In addition, the patients were

selected only from those hospitals with high activity in laparoscopic antireflux

surgery. Even though this was an inclusion criteria of the study, it may also be

a bias. An increasing incidence of antireflux surgery may tend to lower the

threshold for accepting patients for surgery (78,90,151). In their enthusiasm

over the new approach, surgeons undertaking laparoscopic procedures may

have operated on patients with less convincing symptoms of GORD. In the

1990s, it was a trend to focus more on technical skills in laparoscopic

handicraft than on the experience of antireflux surgery. Thus, laparoscopic

surgeons at many hospitals took over antireflux surgery from specialised

thoracic and oesophageal surgeons (91). In the beginning, surgeons may have

found it difficult to accomplish an equivalent antireflux procedure by

laparoscopy as in open surgery (152). “Minor” adjustments of the antireflux

procedure could have been made, i.e. omission of hiatal repair and insufficient

mobilisation of the gastric fundus. If so, this may also have had an impact on

outcome after laparoscopic antireflux surgery.

Dysphagia is one of the most troublesome complications of antireflux

surgery. However, there is no standardised and uniformly applied scoring

system and the incidence of persisting dysphagia, as recorded in the literature,

is extremely variable. In several reports laparoscopic fundoplication has been

associated with obstructive complaints such as dysphagia and bloating

50

(85,88). These consequences are believed to be associated with the lack of

tactile feedback and other factors inherent in the laparoscopic technique

(77,153). In a prospective, randomised multicentre trial from the Netherlands

(85), 7 out of 57 patients had persistent dysphagia at a 3-month follow-up

after laparoscopic fundoplication. The dysphagia was severe enough to

require intervention. By comparison, none of the 46 patients having open

surgery experienced dysphagia of this severity. This substantial difference led

to discontinuation of the trial on ethical grounds. Others have not reported

such frequent and severe dysphagia after undergoing laparoscopic surgery.

This observation may be an indication of the impact the individual surgeons

have on the occurrence of dysphagia rather than the specific technique used.

In the present study there was no significant difference in the incidence of

dysphagia or gas bloat among the study groups. Furthermore, severe

dysphagia was seldom encountered. An incidence of approximately 2% of

this problem is exactly the same as Bessell reported in a study on 846

consecutively laparoscopically operated patients (154). In fact, occurrence of

dysphagia among the patients who responded to the questionnaire was

comparable to that found in a normal population (145) and much less

common than that found among patients with GORD (155,156).

Our study does not support the presumption that laparoscopic antireflux

surgery is to be preferred to open procedure. It does suggest, however, that

patients do not derive significant benefit from having the antireflux procedure

made laparoscopically.

51

Study V

Results

Treatment failures were more common among patients operated on at high-

volume hospitals than those operated on at low-volume hospitals. Estimated

treatment failure rates after adjusting for age, sex and BMI were 29.0 and

19.7% at high- and low-volume hospitals, respectively (p<0.0314). However,

because of the number of items that was tested, the p value for the difference in

treatment failure rates was not statistically significant at an overall 0.05 level

(Bonferroni correction).

Nevertheless, with each question regarding the effectiveness of the procedure

to suppress reflux, the patients operated on at low-volume hospitals tended to

have a more favourable outcome. They experienced heartburn and acid

regurgitation less often, needed less medication to relieve such complaints and

revision surgery was undertaken less frequently among these patients.

Gas bloat and flatulence were considered as the most bothersome abdominal

complaints by 46.8% of all patients. Although 7.8% (32 of 408 patients)

reported daily episodes of difficulties in swallowing, only 2.7% (eleven

patients) identified dysphagia as their most troublesome post-operative

symptom. Further, among patients who reported daily episodes of difficulty in

swallowing, gas bloat and flatulence were more often considered as their worst

symptom.

We could adjust for three confounding factors: age, gender and BMI; however,

the difference between the groups was not significant for any of these

variables. Neither age nor gender had a significant influence on outcomes of

the different items. Yet, BMI seemed to have an impact on outcome. As BMI

increased, the more satisfied was the patient with his or her experience after

52

the operation. The correlation was statistically significant (p<0.0006), but the

magnitude of the correlation was small, with a Spearman correlation

coefficient of –0.14. In addition, BMI was almost identical in the high- and

low-volume groups.

The results of Studies IV and V are summarised in Tables 1 and 2.

53

Table 1: The study groups and reasons for exclusion. * The high-volume laparoscopicgroup is compared with the open procedure group.

Laparoscopic procedureOpen procedure

Low-volume High-volume

P value*

Patients identified in

EpC235 220 225

Died 2 1 1

Moved, could not be

traced3 0 5

Excluded

other major procedures

previous surgery

10

16

4

0

1

0

not able to answer

(age, cerebral disease)1 1 1

Final sample size 203 214 217

Response rate 91 % 97 % 92 %

Women 47 % 38 % 40 % 0.135*

Mean age 57.8 51.5 53.5 0.0001*

Mean BMI 26.3 26.4 26.3 0.95*

Median follow-up 4 years 4 years 4 yearsRange

3.4-5.5

54

Table 2: Results of the patient questionnaire. For details, refer to manuscripts IV and V.* The high-volume laparoscopic group is compared with the open procedure group.

Laparoscopic procedureOpen procedure

(n = 185) % Low-volume

(n = 208) %

High-volume

(n = 200) % P value*

A. Effectiveness of the

antireflux procedure

No improvement 2.0 5.3 6.0

Revision surgery 5.4 2.9 6.0

Acid regurgitation 3.7 5.3 8.6

Heartburn 6.0 6.8 11.0

Medication 8.7 11.1 19.5* < 0.02*

Failure 14.6 19.7 29.0* < 0.004*

Dissatisfied 7.0 13.9 15.0* < 0.005*

B: Procedure related

side effects

Difficulties inswallowing food>once a day

(>5 times a day)

9.8 (1.6) 7.7 (1.4) 8.0 ( 2.0)

Difficult or unable to

belch33.1 46.0 29.0

Gas bloat, flatulence

(daily complaints)27.7 39.1 31.8

Suspicion of incisional

hernia4.0 2.4 2.0

Would recommend the

operation92 90 92

55

Discussion:

Because of the great variation in operating volume of laparoscopic antireflux

surgery among hospitals (Study III), we considered Sweden well suited for

studying the impact of operative volume on outcome. To our surprise, the

results suggest that procedures performed at high-volume hospitals were less

successful than procedures done at low-volume hospitals. Different

explanations could help to account for these results. For instance, an

increasing incidence of antireflux surgery may tend to lower the threshold for

accepting patients for surgery, as also was discussed in the previous section.

Furthermore, whereas university and large, county hospitals are educational

institutions with a high number of surgical trainees, the staff at the smaller,

regional hospitals doing fewer procedures may be more experienced. In a

recent report from the USA (VA National Surgical Quality Improvement

Program) it was concluded after assessing the outcomes of eight commonly

performed operations that volume of surgery cannot be used as an alternative

measure of quality in surgical care (157). Moreover, outstanding results can

also be obtained by regional hospitals, despite a low-volume of patients (158).

Nevertheless, a larger hospital volume can provide excellent facilities for

specialisation and refinements in every particular step of treatment and patient

care (79,159). It should be a challenge for units with an interest in

laparoscopic antireflux surgery to demonstrate that the potential advantage of

high-volume is also reflected in better outcome.

When considering the results of the present study, it should be kept in mind

that there are some methodological weaknesses. For instance, this study was

not randomised. However, it is unlikely that patients would submit

themselves to randomisation between high- and low-volume hospitals. It may

even be argued that, despite the relatively large difference between the

median volumes of the hospital groups, neither of the study groups were

frankly high-volume hospital groups in an international context. Other factors

56

may influence the long-term results: in particular, the indication for surgery,

the selection of different techniques, differences in hospital routines and the

experience of the surgeon. These circumstances could not be adjusted for by

other means than a large sample size. Furthermore, the result of a

questionnaire may be different from that obtained by clinical examination on

the same issue. It is then difficult to predict which one is more accurate.

Moreover, because the questionnaires in the present study were handled

anonymously and confidentially and did not involve any of the authors’

patients, there is no danger of the kind of bias that can result when researchers

query their own patients.

Inability to belch or vomit, gas bloat and increased flatulence are often

perceived as surgical side effects but are difficult to evaluate (93), especially

when a pre-operative comparison is lacking as in our study. Interestingly,

47% of the patients regarded gas bloat or increased flatulence as their most

bothersome post-operative symptom. Among the dissatisfied patients 29%

complained above all of gas bloat and increased flatulence. Surgical side

effects are therefore not to be underestimated when indications for surgery

and different therapeutic options are considered.

We have tried to assess the effectiveness of laparoscopic antireflux surgery. If

our results mirror the reality of the situation, laparoscopic antireflux surgery is

questionable as the method of choice for treatment of serious GORD. The

substantial increase in the incidence of antireflux surgery seen in Sweden

during the past few years may not have optimised the treatment of GORD

patients. Medical maintenance therapy with PPI could perhaps be the better

option for some patients and open surgery may have been better than

laparoscopic for others. Results of laparoscopy may also improve if the

indications for antireflux surgery are restricted. A prospective, randomised

57

study to identify different sub-groups of patients who are more likely to

benefit from laparoscopic surgery than PPI is recommended.

General discussion

The uncritical acceptance of laparoscopic technique among patients and

surgeons, enthusiastically supported in mass media, made possible a

revolution in surgical practice within less than a decade. The quick and wide

acceptance occurred despite the fact that it was weakly supported by solid

data (10). The technical equipment of this approach may be ultra-modern, but

the way it was implemented violated traditional scientific principles. At the

time when this approach already was regarded as the method of choice,

minimal access surgery was not modern medicine in the meaning that it was

not evidence-based (160).

Laparoscopy had been applied in gynaecology for decades. Moreover,

substantial knowledge had been collected from experimental and clinical

studies regarding the effect of positive pressure pneumoperitoneum. However,

communicating pneumo-pleuro-peritoneum represents a more complicated

and challenging condition. The experimental work of this thesis was an

attempt to explore that specific pathophysiologic condition in light of the new

surgical approach applied during dissection in the diaphragmatic hiatus.

In pigs we have demonstrated how devastating a combined thoraco-

laparoscopic approach can be for gas exchange. PEEP may then help to

optimise respiratory function. The application of PEEP was found to improve

gas exchange and, more importantly, hypoxemia could be avoided. Yet, no

beneficial effects of differential lung application of PEEP were documented.

To achieve optimal ventilation application of PEEP to both lungs had to

counterbalance the insufflation pressure.

The transmission of elevated pressure intra-cranially during positive pressure

pneumo-pleuro-peritoneum is a potential danger. However, application of

59

PEEP does not seem to increase ICP further; nor does it seem to adversely

affect cerebral circulation. Because PEEP can help to ensure good systemic

oxygenation and CO2 elimination, it may also help to avoid cerebral

hypoxemia.

Pneumothorax, which is a potential complication to laparoscopic surgery in

the upper abdomen (i.e. antireflux procedures, operations for large hiatal

hernia and cardiomyotomies) may be much more frequent than realised

(16,45,161). Many instances of pneumothorax are subclinical (16). Despite

an endoscopical and radiological verified pneumothorax, the clinical

symptoms are often moderate with an increase in airway pressure and ETCO2,

as well as reduced lung compliance. If more pronounced symptoms develop,

hypoxemia will also be present (16,44,47,132). Joris et al. have demonstrated

the therapeutic value of the application of PEEP in patients with

pneumoperitoneum and communicating pneumothorax. What this implies is

that the operative procedure can often be continued without performing tube

thoracostomy or conversion to open surgery (16).

Before applying PEEP, it is necessary to assess the nature of the

pneumothorax and consider differential diagnosis, i.e. endobronchial

intubation, obstruction of the tracheal tube or a bronchus and bronchospasm.

Fiberoptic bronchoscopy and x-ray of the chest can be helpful but such

examinations are often not readily available. Auscultation can reveal

unilateral decreased breath sounds, and combined with increased airway

resistance, elevated ETCO2 and an abrupt decrease in compliance, the

diagnose is fairly reliable. Moreover, the surgical procedure itself can give an

indication of the reason of acute respiratory insufficiency. One should also

keep in mind that the lesion of pleura can operate as a “check-valve,”

whereby tension pneumothorax can develop (162,163). This is a potentially

life-threatening complication and if impairment of cardiopulmonary functions

is encountered, the pneumothorax should immediately be evacuated. Simple

60

desufflation of the abdomen cannot be relied upon in tension pneumothorax;

instead, managing the patient with a chest drain is indicated.

If pneumothorax is encountered during such standard laparoscopic procedures

as fundoplication and hypoxia develops, the first step recommended is an

increase of oxygen concentration in inspired air, followed by increased

ventilation and application of PEEP. The results from Study I indicate that

optimal PEEP is equal to or higher than the abdominal insufflation pressure.

The insufflation pressure should be kept as low as possible because the

negative effects on respiratory function tend to worsen with increasing

pressure (162,164). A tube thoracostomy during the operation may interfere

with maintenance of pneumoperitoneum and hence make it difficult to expose

the surgical field. However, it is paramount that if there are signs of

cardiopulmonary compromise, laparoscopy should be discontinued.

After the operation, when the abdomen has been desufflated, any residual gas

will be quickly absorbed and the pneumothorax will disappear. Therefore,

chest drain is seldom indicated. In any event, a chest X-ray should be

routinely performed post-operatively to rule out any suspicion of tension

pneumothorax.

Diagnostic laparoscopy in trauma patients has proven successful in detection

of occult diaphragmatic lacerations, particular in patients with lower chest

stab wounds (165,166). Such injuries are notoriously difficult to detect by

chest roentenography, computed tomography or diagnostic lavage. Wiedeman

et al. have demonstrated that tension pneumothorax may develop when

pneumoperitoneum is created in the face of a diaphragmatic injury and that

the risk of its development increases with increasing insufflation pressure

(162). Hypoxemia provided an early clue of the pneumothorax, even when

chest X-ray was still normal. The lines of action given above can be applied

during short diagnostic procedures, but if a diaphragmatic lesion were

61

diagnosed, we would not recommend the repair to be done laparoscopically

because of the substantial risk of tension pneumothorax. Further, the lesion is

seldom encountered and a conventional method is to be preferred.

In major oesophageal surgery, i.e. oesophageal resection, one is confronted

with longer operating times and more extended dissection in the mediastinum.

Harmful effects of excessive PEEP applied for too many hours may

predispose for overdistention of lung parenchyma with post-operative

inflammatory reaction and atelectases as a result. Moreover, the patients are

often elderly with cardiopulmonary impairment, rendering them far more

sensitive to an insult such as a combined pneumo-pleuro-peritoneum. At

present, we do not think that a thoraco-laparoscopic approach is to be

recommended for oesophageal resection.

This thesis has demonstrated that the advent of the laparoscopic technique had

a profound impact on the practice of antireflux surgery. However, there was a

substantial increase in the annual number of antireflux procedures even before

the introduction of the laparoscopic technique. The threefold increase of the

incidence of antireflux surgery recorded during the past decade therefore

cannot solely be explained by the advent of the minimal access technique.

Nevertheless, a clear shift in the preferred methodology took place. This

change was not scientifically supported at the time of the transition and,

surprisingly, it is still not supported today. As was demonstrated, laparoscopy

might even be an inferior approach in some patients. However, it is

reasonable to assume that laparoscopic technique can yield equally good

results as open surgery despite our failure to confirm that in this series of

studies. Controlled prospective, randomised studies with adequate patient

enrolment to secure statistical power are needed to settle this issue

conclusively.

62

The development of the minimal access technique has stimulated numerous

innovations of new surgical instruments that can also be utilised in open

surgery, i.e. the Harmonic scalpel technology. In combination with

advancements in the treatment of post-operative pain, this development has

even changed the practice of conventional open surgery. However, before

new trials are undertaken, it is important that properly defined measures to

evaluate short- and long-term outcome are agreed upon.

For instance, one problem is that the criteria to evaluate success or failure are

not well defined (90,93). To equalise reflux control with success rate can give

a false impression (91,92). In a number of reports it is not stated how many

patients are still on antireflux medication (43,72-74,78,95) but if reported,

continuous medical therapy in about 6-8% is usual (77,91,167). There is no

agreement today whether continued use of medication is a sign of failure, as

in this thesis (Studies IV and V), or not. Even patients with objectively

demonstrated anatomical failure of the fundic wrap often do well on PPI (43).

The definition of failure in the present studies was rather demanding, but was

defined in order to achieve the goals of antireflux surgery. For a disease in

which an alternative and often similarly effective medical therapy exists

(168), one has to aim at optimal surgical results and patient satisfaction is

therefore crucial. After all, most patients who submit themselves to surgery

do it because of exacerbating symptoms and not because of objective signs,

i.e. endoscopic findings or results from 24-hour pH monitoring. The Genval

panel of experts accepted the statement, “reflux disease is likely present when

heartburn occurs on two or more days a week on the basis of the negative

impact of this symptom frequency on the health related well being (quality of

life)” (169). It is therefore logical that reasonable symptom control without

the need of frequent medication should be an indicator for surgical success or

failure. Although we are aware that indiscriminate use of acid suppression

therapy does not necessarily represent a technically failed antireflux

63

procedure, we still regard it as a treatment failure because cessation of

medication to suppress the symptoms of GORD is an important aim of

surgery. The questionnaire applied in Studies IV and V was also designed to

detect medication used specifically to suppress reflux symptoms.

Moreover, because the questionnaires were handled anonymously and

confidentially and did not involve any of the authors’ patients, there was no

danger for the kind of bias that can result when researchers query their own

patients.

This thesis did not study the indications for antireflux surgery. The treatment

of severe GORD is unique because medical maintenance therapy with PPI

and antireflux surgery are similarly effective options for most patients.

Surgical indications that were sound before the advent of PPI do not

necessarily stand for trial today. Likewise, the apparently attractiveness of the

laparoscopic approach may influence the patients and doctors’ choice of

treatment. In this respect, we had better have solid knowledge for our

recommendations, rather than merely relying on presumptions. Therefore, a

large prospective, randomised study on the optimal treatment of severe

GORD should ideally compare maintenance therapy with PPI in adequate

doses to surgical treatment with open or laparoscopic procedure. Such a study

should be of national interests; the pharmaceutical industry or medical

suppliers should not fund such a study because the treatment of GORD has

strong implications for the national health economy. Except for the rarely

occurring syndrome of Zollinger-Ellison, GORD is the only commonly

accepted indication for maintenance PPI therapy (FASS). Every year the

Swedish people buy PPI for approximately one hundred million dollars (170).

At the same time, approximately 1,300 patients will be operated on at a cost

of 4,000-7,000 dollars per patient, including sick leave (171).

64

The argument in favour of surgery has been that it offers a definitive

treatment. However, as this thesis has proven, this is a presupposition that has

not been verified. Many patients continue to use antisecretory medication

regularly despite surgery. Furthermore, patients often complain of what they

believe to be side effects of the surgical treatment. In contrast, patients who

never have had the opportunity to discuss different treatment options and

chosen to continue with maintenance therapy may regret they never have been

offered surgery.

A study that compares outcome of medical and surgical treatments will of

course demand close collaboration between surgeons and internists. That may

be as challenging as the problem of funding. The patients will benefit in the

long term when both surgeons and internists can agree upon the treatment.

Depending on what speciality the patients’ doctor happens to promote, the

indications for different therapeutic options should not differ that greatly

(9,11,90,172).

Generally, the laparoscopic approach is also appealing because it offers a

completely new “costume” to old surgical solutions. In particular, younger

surgeons may feel attracted by new technology because it is easy for them to

adopt and in a single, giant leap they may suddenly surpass their “master.”

The ”master,” on the other hand, may feel a regained youthful vigour when he

or she is still able to cope with the new trend. Yes, the fairy tale of HC

Andersen, “The Emperors new cloths” is worth remembering. Why is it that

new surgical techniques can move from “innovations” to widespread use on

the basis of little more than intuition (10,14,173)?

The laparoscopic approach is a major complement of the surgical technique.

There is no reason to deny that fact, but in terms of patient outcome and

overall management of abdominal disease, it has been a small advance

relative to the huge financial investments (10). We need to determine when it

should be used and for whom it would benefit most.

65

When confronted in the future with new therapeutic options, medical

societies, community health care systems and legal authorities should make a

common effort to guarantee that the evaluation and introduction take place

with maintained quality control. Before a new drug is accepted for legal

prescription, it is scrutinised through long and cumbersome experimental and

clinical evaluation. Similarly, there should be a more demanding attitude

toward general implementation of new surgical methods in routine hospital

care. The instrument manufacturers should not be allowed to have any

consequential influence on that process. At an early stage, new techniques

have to undergo clinical testing, and a long time is often needed for follow-up

before a complete picture of risks, side effects and outcomes are known. It

should not be acceptable to let the individual surgeon determine the utility of

new surgical techniques. It is more effective and honest if data on the

usefulness of the techniques were collected systematically and collectively. A

national consulting board for research and supervision of the implementation

of new surgical methods would be welcomed.

66

Conclusions

During laparoscopy, pneumothorax may induce deleterious effects on the

respiratory function.

Application of PEEP may help to ensure good oxygenation and CO2

elimination when accidental pneumothorax is encountered during

laparoscopy (pneumoperitoneum). PEEP did not adversely affect ICP or

cerebral circulation.

To achieve optimal ventilation the PEEP applied to both lungs has to

counterbalance the insufflation pressure. No benefit of differential lung

ventilation was encountered.

Surgical treatment for GORD has increased threefold in 1997 as compared

with 1987.

The laparoscopic approach has replaced the open technique as the method

of choice in antireflux surgery.

In comparison with open surgery, patients do not seem to derive

significant long-term benefits from having the antireflux procedure done

laparoscopically.

Better results after laparoscopic surgery, particularly at hospitals with

larger operating volumes, have to be demonstrated before the method can

be recommended as routine treatment for severe GORD.

We strongly recommend carrying out a randomised controlled trial

between maintenance treatment with adequate doses of PPI and

conventional open or laparoscopic techniques.

67

Acknowledgements

I would like to express my sincere gratitude to all those who have helped mein these studies and especially to:

Ulf Haglund for your consistent support and guidance in scientific andclinical work. You were tolerant and loyal when it was most needed.

Elisabeth Bergquist for your enthusiastic participation in the practicalcompletion of this thesis. It is a pleasure to work with you.

Harry Kahmis for invaluable help with the statistical aspects of my work. Youhave always responded expeditious, even after returning to your position inDayton. Your friendly attitude and educational skills made the statisticalproblems comprehensible.

Sten Rubertsson who has been my human link in the task of comprehendingall of the challenging anaesthesiological issues.

My co-authors, Sven Gustavsson, Dag Arvidsson, Thomas Hallgren, and UlfSjöstrand for providing strong support and inspiring ideas.

Birgitta Birgisdottir and Anders Nordgren who ensured the technical qualityof the laboratory research. You made the work run smoothly and without anyencumbrances. Arne Linder kindly performed the differential bronchialintubation.

Mohana Thiruchelvam for skilful linguistic revision of several of themanuscripts, and Åsa Isacson for highly dependable secretarial assistance.

Gustav Liedberg for brilliant teaching regarding surgical handicraft.

Gudrun, my dear sister, a special thanks to you for always caring for yourfamily, me included.

68

References

1 Kelling, G. ber Oesophagoskopie und Kolieoskopie. Munch

Med Wochenschr 1901; 49: 21.

2 Nadeua OE, Kampmeier OF. Endoscopy of the abdomen:

abdominoscopy. Surg Gynecol Obstet 1925; 41: 259-71.

3 Stellato TA. The history of laparoscopic surgery. In: Operative

laparoscopy and thoracoscopy. MacFadyen BV, Ponsky JL (eds.)

Lippincott-Raven, Philadelphia, Pennsylvania USA. 1996; pp3-12

4 Jacobaeus HC. Ueber die Möglichkeit die Zystoskopie bei

Untersuchung seröser Höhlungen anzuwenden. Munch Med

Wochenschr 1910; 57: 2090-2.

5 Braimbridge MV. The history of thoracoscopic surgery. Ann

Thorac Surg 1993; 56: 610-4.

6 Dubois F, Icard P, Berthelot G, Levard H. Coelioscopic

cholecystectomy. Ann Surg 1990; 211: 60-2.

7 Perissat J. Laparoscopic cholecystectomy; the European

experience. Am J Surg 1993; 165: 444-9.

8 Chae FH, Stiegmann GV. Current laparoscopic gastrointestinal

surgery. Gastrointest Endoscopy 1998; 47, 500-11.

9 Fletcher DR. Preface (Complications and adverse effects of

laparoscopic surgery) Sem Lap Surg 1997, 4: 133-4.

10 Johnson A. Laparoscopic surgery. Lancet 1997; 349: 631-5.

11 Cuschieri A. Preface (Laparoscopic surgery of the Foregut: Part I)

Sem Lap Surg 1999, 6: 175-6.

69

12 Kalser SC, Bray EA, Burton BT, et al. National Institutes of

Health consensus development conference statement on gallstone

and laparoscopic cholecystectomy. Am J Surg 1993; 165: 390-8.

13 Dent TL. Training and Credentialing. In: Operative laparoscopy

and thoracoscopy. MacFadyen BV, Ponsky JL (eds.) Lippincott-

Raven, Philadelphia, Pennsylvania USA. 1996; pp 27-34.

14 Cuschieri A. Whither minimal access surgery: tribulations and

expectations. Am J Surg 1995; 169: 9-19

15 Anvari M. Complications of laparoscopic Nissen fundoplication.

Sem Lap Surg 1997, 4: 154-61.

16 Joris JL, Chiche J-D, Lamy ML. Pneumothorax during

laparoscopic fundoplication: diagnosis and treatment with positive

end-expiratory pressure. Anesth Analg 1995; 81: 993-1000.

17 Yee R, Hyde PR, Currie JS. Pneumothorax during laparoscopic

Nissen fundopliction. Anesth Intens Care 1996; 24: 93-6.

18 Holthausen UH, Nagelschmidt M, Troidl H. CO2

pneumoperitoneum: What do we need to know. World J Surg

1999; 23: 794-800.

19 Menes T, Spivak H: Laparoscopy. Searching for the proper

insufflation gas. Surg Endosc 2000; 14: 1050-6

20 Paolucci V, Schaeff B, Gutt CN, Litynski GS. Exposure of the

operative field in laparoscopic surgery. Surg Endosc 1997; 11:

856-63.

21 Warner PM, Andrus CH. Hemodynamic and pulmonary

implications and complications in laparoscopic surgery. Sem Lap

Surg 1997; 4: 135-8.

70

22 Rasmussen I, Berggern U, Arvidsson D, Ljungdahl M, Haglund U.

Effects of pneumoperitoneum on splanchnic hemodynamics. An

experimental study in pigs. Eur J Surg 1995; 161: 819- 26.

23 Sietses C, Wiezer MJ, Eijsbouts QA, Beelen RH, van Leeuwen

PA, von Blomberg BM, Meijer S, Cuesta MA. A prospective

randomized study of the systemic immune response after

laparoscopic and conventional Nissen fundoplication. Surgery

1999, 126: 5-9.

24 Sietses C, Wiezer MJ, Eijsbouts QA, van Leeuwen PA, Beelen

RH, Meijer S, Cuesta MA. The influence of surgery on

postoperative polymorphonuclear leukocyte function. Surg Endosc

2000; 14: 812-6.

25 Perttila J, Salo M, Ovaska J, Gronroos J, Lavonius M, Katila A,

Lahteenmaki M, Pulkki K. Immune response after laparoscopic

and conventional Nissen fundplication. Eur J Surg 1999; 165: 21-

8.

26 Juul P, Schultz K, Bendtzen K, Nielsen OH. Systemic

inflammatory responses during laparoscopic and open inguinal

hernia repair: a randomised prospective study. Eur J Surg 2000;

166: 540-4.

27 Ortega AH, Hunter JG, Peters JH, Swanstrom LL, Schirmer B. A

prospective, randomized comparison of laparoscopic

appendectomy with open appendectomy. Am J Surg 1995; 169:

208-12.

28 McCall JL, Sharples K, Jadallah F. Systematic review of

randomized control trials comparing laparoscopic with open

appendiectomy. Br J Surg 1997; 84: 1045-50.

71

29 Pedersen AG, Petersen OB, Wara P, Ronning H, Qvist N,

Laurberg . Randomized clinical trial of laparoscopic versus open

appendectomy. Br J Surg 2001; 88: 200-5.

30 McMahon AJ, Russel IT, Baxter JN, Ross S, Anderson JR,

Morran CG, et al. Laparoscopic versus mini-laparotomy

cholecystectomy: a randomised trial. Lancet 1994; 343: 135-8.

31 Lam D, Miranda R, Hom SJ. Laparoscopic cholecystectomy as an

outpatient procedure. J Am Coll Surg 1997; 185: 152-5.

32 Hellberg A, Rudberg C, Kullman E, Enochsson L, Fenyo G,

Graffner H, Hallerback B, Anderberg B, Wenner J, Ringqvist I,

Sörensen S. Prospective randomized multicentre study of

laparoscopic versus open appendectopmy. Br J Surg 1999; 86: 48-

53.

33 Heikkinen TJ, Haukipuro K, Hulkko A. Cost-effective

appendectomy. Open or laparoscopic? A prospective randomized

study. Surg Endosc 1998; 12: 1204-8.

34 Kald A, Anderberg B, Carlsson P, Park PO, Smedh K. Surgical

outcome and cost-minimisation-analyses of laparoscopic and open

hernia repair: a randomised prospective trial with one year follow

up. Eur J Surg 1997; 163: 505-10.

35 Johansson B, Hallerback B, Glise H, Anesten B, Smedberg S,

Roman J. Laparoscopic mesh versus open preperitoneal technique

for inguinal hernia repair: a randomized multicenter trial (SCUR

Hernia Repair Study). Ann Surg 1999; 230: 225-31.

36 The MRC Laparoscopic Groin Hernia Trial Group. Laparoscopic

versus open repair of groin hernia: a random comparison. Lancet

1999; 354: 185-90.

72

37 Juul P, Christensen K. Randomized clinical trial of laparoscopic

versus open inguinal hernia repair. Br J Surg 1999; 86: 316-9.

38 Majeed AW, Troy G, Nicholl JP, Smythe A, Reed MWR,

Stoddard CJ, Peacock J, Johnson AG. Randomised, prospective,

single-blind comparison of laparoscopic versus small-incision

cholecystectomy. Lancet 1996; 347: 989-94.

39 Nilsson G, Larsson S, Johnsson F. Randomized clinical trial of

laparoscopic versus open fundoplication: blind evaluation of

recovery and discharge period. Br J Surg 2000; 87: 873-78.

40 Pelgrims N, Closset J, Sperduto N, Gelin M, Houben JJ. What did

the laparoscopic Nissen approach of the gastro-oesophageal reflux

really change for the patients 8 years later? Acta Chir Belg 2001;

101: 68-72.

41 Cadière G-B, Himpens J, Vertruyen M, Germay O, Favretti F,

Segato G. Laparoscopic gastroplasty (adjustable silicone gastric

banding). Sem Lap Surg 2000; 7: 55-65.

42 Hunter JG, Smith CD, Branum GD, Waring JP, Trus TL, Cornwall

M, Galloway K. Laparoscopic fundoplication failures. Patterns of

failure and response to fundoplication revision. Ann Surg 1999;

230: 595-606.

43 Soper NJ, Dunnegan D. Anatomic fundoplication failure after

laparoscopic antireflux surgery. Ann Surg 1999; 229: 669-77.

44 Wahba R, Tessler M, Kleiman S. Acute ventilatory complications

during laparoscopic upper abdominal surgery. Can J Anaesth

1996; 43: 77- 83.

45 Clements Rh, Reddy S, Holzman MD, Sharp KW, Olsen D,

Holcom GW, Ricards WO. Incidence and significance of

73

pneumomediastinum after laparoscopic esophageal surgery. Surg

Endos 2000; 14: 553-5.

46 Mangar D, Kirchoff GT, Leal JJ, Laborde R, Fu E. Pneumothorax

during laparoscopic Nissen fundoplication. Can J Anaesth

1994;41: 854-6.

47 Coelho JC, Wiederkehr JC, Campos AC, Anderigueto PC.

Conversion and complications of laparoscopic treatment of

gastroesophageal reflux disease. J Am Coll Surg 1999; 189: 356-

61.

48 Chiche JD, Joris J, Hamoir E, Lamy M. PEEP corrects

haemodynamic changes induced by pneumothorax during

laparoscopy (Abstract). Br J Anesth 1995; 74: 54 (A175).

49 Stegerwald S, Bockhorn H, Denhardt R () Respiratory changes

during carbon dioxide pneumoperitoneum. In: Rosenthal RJ,

Friedman RL, Phillips EH (eds) The pathophysiology of

pneumoperitoneum. Springer, Berlin 1998; pp 70-77.

50 Benumof JL. One-lung ventilation and hypoxic pulmonary

vasoconstriction: implications for the anaesthetic management.

Anesth Analg 1985; 64: 821-833.

51 Horswell JL. Anesthetic techniques for thoracoscopy. Ann Thorac

Surg 1993; 65: 624-629.

52 Josephs LG, Este-McDonald JR, Birkett DH, Hirsch EF.

Diagnostic laparoscopy increases intracranial pressure. J Trauma

1994; 36: 815-9.

53 Bloomfield GL, Ridings PC, Blocher CR, Marmarou A, Sugerman

HJ. Effects of increased intra-abdominal pressure upon intracranial

74

and cerebral perfusion pressure before and after volume

expansion. J Trauma 1996; 40: 936-42.

54 Halverson A, Buchanan R, Jacobs L, Shayani V, Hunt T, Riedel

C, Sackier J. Evaluation of mechanism of increased intracranial

pressure with insufflation. Surg Endosc 1998; 12: 266-9.

55 Shalmon E, Caron MJ, Becker DP. Intracranial pressure:

Pathology and Pathophysiology. In: Tindall GT, Cooper PR,

Barrow DI (eds): The Practice of neurosurgery. Baltimore,

Williams and Wikings, 1996, pp 45-70.

56 Rosenthal RJ, Hiatt JR, Phillips EH, Hewitt W, Demetriou AA,

Grode M.: Intracranial pressure. Effects of pneumoperitoneum in a

large-animal model. Surg Endosc 1997; 11: 376-80.

57 Feldman Z, Robertson CS, Contant CF, Gopinath SP, Grossman

RG. Positive end-expiratory pressure reduces intracranial

compliance in the rabbit. J Neurosurg Anesth 1997; 9: 175-9.

58 Shapiro HM, Marshall LF. Intracranial pressure responses to

PEEP in head-injured patients. J Trauma 1978; 18: 254-6.

59 Moffa SM, Quinn JV, Slotman GJ. Hemodynamic effects of

carbon dioxide pneumoperitoneum during mechanical ventilation

and positive end-expiratory pressure. J Trauma 1993; 35: 613-8.

60 Adinis SJ, Lafferty J, Shapiro HM. Intracranial responses to

PEEP. Anesthesiology 1976; 45: 275-86.

61 Tyler DC. Positive end-expiratory pressure: A review. Crit Care

Med 1983; 11: 300-8.

62 DeMeester TR, Bonavina L, Albertucci M. Nissen fundoplication

for gastroesophageal reflux disease. Ann Surg 1986; 204: 9-20.

75

63 Spechler SJ, and The Department of Veterans Affairs

Gastroesophageal Reflux Disease Study Group. Comparison of

medical and surgical therapy for complicated gastroesophageal

reflux disease in veterans. N Engl J Med 1992; 326: 786-92.

64 Dent J. Australian clinical trials of omeprazole in the management

of reflux oesophagitis. Digestion 1990; 47 (suppl 1): 69-71.

65 Klinkenberg-Knol EC, Festen HPM, Jansen JBMJ, Lambers

CBHW, Nelis F, Snel P, et al. Long-term treatment with

omeprazole for refractory reflux esophagitis: efficacy and safety.

Ann Intern Med 1994;121:161-7.

66 Lundell L, Miettinen P, Myrvold HE, Pedersen SA, Liedman B,

Hatlebakk JG, et al. Continued (5-year) follow-up of a randomized

clinical study comparing antireflux surgery and omeprazole in

gastroesophageal reflux disease. J Am Coll Surg 2001; 192 (2):

172-9.

67 Dallemagne B, Weerts JM, Jehaes C, Markiewicz S, Lombard R.

Laparoscopic Nissen fundoplication: preliminary report. Surg

Laparosc Endosc 1991; 1: 138-43.

68 Geagea T. Laparoscopic Nissen´s fundoplication: preliminary

report on ten cases. Surg Endosc 1991; 5: 170-3.

69 Heading RC. Epidemiology of oesophageal reflux disease. Scand J

Gastroenterol 1989; 24(suppl 168): 33-7.

70 Viljakka M, Luostarinen M, Isolauri J. Incidence of antireflux

surgery in Finland 1988-1993. Scand J Gastroenterol 1997; 32:

415-18.

71 Eypasch E, Neugebauer E, Fischer F, Troidl H. Laparoscopic

antireflux surgery for gastroesophageal reflux disease (GERD).

76

Results from a consensus development conference. Surg Endosc

1997; 11: 413- 26.

72 Hinder RA, Filipi CJ, Wetscher G, Neary P, DeMeester TR,

Perdikis G. Laparoscopic Nissen fundoplication is an effective

treatment for gastroesophageal reflux disease. Ann Surg 1994;

220: 472-83.

73 Anvari M, Allen C. Laparoscopic fundoplication. Two-year

comprehensive follow-up of a technique of minimal

paraesophageal dissection. Ann Surg 1998; 227: 25-32.

74 Dallemagne B, Weerts JM, Jeahes C, Markiewicz S. Results of

laparoscopic Nissen fundoplication. Hepatogastroenterol 1998; 45:

1338-43.

75 Peters DI, Demeester TR, Crookes P, Oberg S, de Vos Shoop M,

Hagen JA, et al. The treatment of gastroesophageal reflux disease

with laparoscopic Nissen fundoplication. Ann Surg 1998; 228: 40-

50.

76 Kamolz T, Bammer T, Granderath FA, Pasiut M, Pointner R.

Quality of life and surgical outcome after laparoscopic antireflux

surgery in the elderly gastroesophageal reflux disease patient.

Scand J Gastroenterol; 36: 116-120.

77 Watson DI, Jamieson GG. Antireflux in the laparoscopic era. Br J

Surg 1998; 85: 1173-84.

78 Valiati W, Fuchs KH, Valiati L, Freys SM, Fein M, Maroske J, et

al. Laparoscopic fundoplication - short- and long-term outcome.

Langenbecks Arch Surg 2000: 385; 324-28.

79 Frantzides CT, Richards C. A study of 362 consecutive

laparoscopic Nissen fundoplications. Surgery 1998; 124: 651-5.

77

80 Harris SC. Laparoscopic antireflux surgery. Am J Surg 1996; 171:

482-4.

81 Watson DI, Baigrie RJ, Jamieson GG. A learning curve for

laparoscopic fundoplication. Definable, avoidable, or a waste of

time? Ann Surg 1996; 224: 198-203.

82 Soot SJ, Eshraghi N, Farahmand M, Sheppard BC, Deveney CW.

Transition from open to laparoscopic fundoplication. The learning

curve. Arch Surg 1999; 134: 278-81.

83 Voitk A, Joffe J, Alvarez C, Rosenthal G. Factors contributing to

laparoscopic failure during the learning curve for laparoscopic

Nissen fundoplication in a community hospital. J

Lapraoendoscopic Advanced Surg Tech 1999; 9: 243-8.

84 Luostarinen MES and Isolauri JO. Surgical experience improves

the long-term results of Nissen fundoplication. Scan J

Gastroenterol 1999; 34: 117-20.

85 Bais JE, Bartelsman JFWM, Bonjer HJ, Cuesta MA, Go PMNYH,

Klinkenberg-Knol EC, et al, (The Netherlands Antireflux Surgery

Study Group) Laparoscopic or conventional Nissen fundoplication

for gastro-oesophageal reflux disease: randomised clinical trial.

Lancet 2000; 355: 170-74.

86 Laine S, Rantala A, Gullichsen R, Ovaska J. Laparoscopic vs

conventional Nissen fundoplication. A prospective randomized

study. Surg Endosc 1997; 11: 441-4.

87 Heikkinen TJ, Haukipuro K, Bringman S, Ramel S, Sorasto A,

Hulkko A. Comparison of laparoscopic and open Nissen

fundoplication 2 years after operation. A prospective randomized

trial. Surg Endoc 2000; 14: 1019-23.

78

88 Loustarinen M et al: Dysphagia and oesophageal clearance after

laparoscopic versus open Nissen fundoplication. Scand J

Gastroenterol 2001; 36: 565-71.

89 Franzén T, Anderberg B, Tibbling L, Johansson K-E. A report

from a randomized study of open and laparoscopic 3600

fundoplication. Surg Endosc 1998; 582 (Abstract 159).

90 Hogan WJ, Shaker R. Life after antireflux surgery. Am J Med

2000; 108(4A): 181S-191S.

91 Landreneau RJ, Wiechmann RJ, Hazelrigg SR, Santucci TS, Boley

TM, Magee MJ, et al. Success of laparoscopic fundoplication for

gastroesophageal reflux disease. Ann Thorac Surg 1998; 66:1886-

93.

92 Stein HJ, Feussner H, Siewert JR. Antireflux surgery: a current

comparison of open and laparoscopic approaches. Hepato-

Gastroenterology 1998;.45:1328-37.

93 Pope CE. The Quality of life following antireflux surgery. World J

Surg 1992; 16: 355-58.

94 Eubanks TR, Omelanczuk P, Richards C, Phol D, Pellegrini CA.

Outcomes of laparoscopic antireflux procedures. Am J Surg 2000;

179: 391-95.

95 Velanovich V, Karmy-Jones R. Measuring gastroesophageal

reflux disease. Relationship between the Health-Related Quality of

Life Score and physiologic parameters. Am Surg 1998; 64: 649-

53.

96 Patti M, Tamburini A, Pellegrini CA. Cardiomyotomy. Sem Lap

Surg 1999; 6: 186-93.

79

97 Spiess AE, Kahrilas PJ. Treating achalasia. From whalebone to

laparoscope. JAMA 1998; 280: 638-42.

98 Ancona E, Anselmino M, Zaninotto G, et al. Esophageal

achalasia: Laparoscopic versus conventional open Heller-Dor

operation. Am J Surg 1995; 170: 265-70.

99 Vogt D, Curet M, Pitcher D, et al. Successful treatment of

esophageal achalasia with laparoscopic Heller myotomy and

toupet fundoplication. Am J Surg 1997; 174: 709-14.

100 Becker R, Buess G, Mentges B, et al. Endoscopic esophagectomy.

Adv Surg 1993; 26: 397-410.

101 Cuschieri A. Thoacoscopic subtotal oesophagectomy. Endosc Surg

Allied Technol 1994; 2: 21-25.

102 Gossot D, Ghnassia MD, Debiolles H, Chourrout Y, Bonnichon

JM, Sarfati E, Celerier M, Revillon Y. Thoracoscopic dissection of

the esophagus: an experimental study. Surg Endosc 1992; 6: 59-

61.

103 Law S, Fok M, Chu KM, Wong J. Thoracoscopic esophaectomy

for esophageal cancer. Surgery 1997; 122: 8-14.

104 Sandbu R, Arvidsson D, Gustavsson S, Haglund U. Thoracoskopi-

assisteread esofagusresektion – preliminära resultat. Svenska

kirurgveckan 1996; pp 68(Abstract 43).

105 Gossot D, Cattan P, Fritsch S, Halimi B, Sarfati E, Celerier M.

Can The morbidity of esophagectomy be reduced by the

thoracoscopic approach? Surg Endosc 1995; 9: 1113-15.

106 Collard JM, Lengele B, Otte JB, Kestens PJ. En bloc and standard

esophagectomies by thoracoscopy. Ann Thorac Surg 1993; 56:

675-9.

80

107 Peracchia A, Rosati R, Fumagalli U, Bona S, Chella B.

Thoracoscopic Esophagectomy: are there benefits? Sem Surg

Oncol 1997; 13: 259-62.

108 The HALS study group: Litwin DEM, Darzi A, Jakimowicz J,

Kelly JJ, Arvidsson D, Hansen P, Callery MP, Denis R, Fowler

DL, Medich DS, O’Reilly MJ, Atlas H, Himpens JM, Swanstrom

LL, Arous EJ, Pattyn P, Yodd SM, Ricciardi R, Sandor A, Meyers

W (2000) Hand-Assisted Laparoscopic Surgery (HALS) with the

HandPort System. Initial experience with 68 patients. Ann Surg

231: 715-723.

109 Watson D, Davies N Jamieson G. Totally endoscopic Ivor Lewis

esophagectomy. Surg Endosc 1999; 13: 293-297.

110 Swanstrom LL, Hansen P. Laparoscopic total esophagectomy.

Arch Surg 1997; 132: 943-7.

111 Gossot D, Toledo L, Cortes A. Minimal access esophagectomy:

where are we up to? Semin Lapa Surg 2000; 7: 2-8.

112 Collard J. A role of videoassisted surgery in the treatment of

oesophageal cancer. Ann Chir Gynaecol 1995; 84: 209-14.

113 Huscher C, Anastasi A, Crafa F, Recher A, Lirici M. Laparoscopic

gastric resections. Sem Lap Surg 2000; 7: 26-54.

114 Kuntz C, Wunsch A, Bödeker C, Bay F, Rosch R, Windeler J,

Herfarth C. Effect of pressure and gas type on intrabdominal,

subcutaneous, and blood pH in laparoscopy. Surg Endosc 2000;

14: 367-71.

115 Jacobi CA, Sabat R, Böhm B, zieren HU, Muller JM.

Pneumoperitoneum with carbon dioxide stimulates growth of

malignant colonic cells. Surgery 1997; 121: 72-78.

81

116 Westling A, Gustavsson S. Laparoscopic vs open Rouxen-Y-

gastric bypass- a prospective randomized trial. Obesity Surgery

2001; 11: 284-92.

117 de Witt LT, Mathus-Vliegen L, Hey C, Rademaker B, Gouma DJ,

Obertop H. Open versus laparoscopic adjustable silicone gastric

banding: a prospective randomized trial for treatment of morbid

obesity. Ann Surg 1999; 230: 800-5.

118 Boschert K, Flecknell PA, Fosse RT, Framstad T, Ganter M,

Sjöstrand U, Stevens J, Thurmon J. Ketamine Consensus Working

Group: Ketamine and its use in the pig. Lab Anim 1996; 30: 209-

19.

119 Nickel R, Schummer A, Seiferle E. Respiratory system. In: The

viscera of the domestic mammals. 2nd revised edition by

Schummer A, Nickel R (eds) Verlag Paul Parey, Berlin1979; pp

211-281.

120 Venkatesh B, Clutton Brock TH, Hendry SP. A multiparameter

sensor for continuous intra-arterial blood gas monitoring: A

prospective evaluation. Crit Care Med 1994; 22: 588-94.

121 Zauner A, Bullock R, Di X, Young HF. Brain oxygen, CO2, pH,

and temperature monitoring: Evaluation in the feline brain.

Neurosurg 1995; 37: 1168-77.

122 Hoffman WE, Charbel FT, Edelman G. Brain tissue oxygen,

carbon dioxide, and pH in neurosurgical patients at risk for

ischemia. Anesth Analg 1996; 82: 582-6.

123 Carter LP. Surface monitoring of cerebral cortical blood flow.

Cerebrovasc Brain Met Rev 1991; 3: 246-61.

82

124 Lindsberg PJ, O’Neill JT, Paakkari IA, Hallenbeck JM,

Feuertstein G. Validation of laser-Doppler flowmetry in

measurement of spinal cord blood flow. Am J Physiol 1989; 257:

H674-H680.

125 Dirnagel U, Kaplan B, Jacewicz M, Pulsinelli W. Continuous

measurement of cerebral cortical blood flow by Laser-Doppler

flowmetry in a rat stroke model. J Cereb Blood Flow Metab 1989;

9: 589-96.

126 EpC: Internet http://www.sos.se/epc/par

127 Sandbu R, Trana R, Haglund U, Gustavsson S. Antirefluxkirurgi

och patientselektion. 5. Kirurgveckan, Östersund, Sweden, 2000;

(F 128),189-90.

128 Leighton T, Pianim N, Liu S-Y, Kono M, Klein S, Bongard F.

Effectors of hypercarbia during experimental pneumoperitoneum.

Am Surg 1992; 58: 717-721.

129 Lister DR, Rudston-Brown B, Warriner B, McEwen J, Chan M,

Walley KR. Carbon dioxide absorption is not linearly related to

intraperitoneal carbon dioxide insufflation pressure in pigs.

Anesthesiology 1994; 80: 129-136.

130 Ho HS, Gunther RA, Wolfe BM. Intraperitoneal Carbon Dioxide

insufflation and Cardiopulmonary Functions. Laparoscopic

Cholecystectomy in Pigs. Arch Surg 1992; 127: 928-933.

131 Barton ED, Rhee P, Hutton KC, Rosen P. The pathophysiology of

tension pneumothorax in ventilated swine. J Emerg Med 1997; 15:

147-153.

83

132 Marcus DR, Lau WM, Swanstrom LL. Carbon dioxide

pneumothorax in laparoscopic surgery. Am J Surg 1996; 171: 464-

466.

133 Nozari A, Rubertsson S, Wiklund L. Improved cerebral blood

supply and oxygenation by aortic balloon occlusion combined

with intra-aortic vasopressin administration during experimental

cardiopulmonary resuscitation. Acta Anaesthesiol Scand 2000; 44:

1209-19.

134 Schöb OM, Allen DC, Benzel E, Curet MJ, Adams MS, Baldwin

NG, et al: A comparison of the pathophysiologic effects of carbon

dioxide, nitous oxide, and helium pneumoperitoneum on

intracranial pressure. Am J Surg 1996; 172: 248-53.

135 Iragu I, Koyfman Y, Tikellis JI. Elective intraoperative

intracranial pressure monitoring during laparoscopic

cholecystectomy. Arch Surg 1995; 130: 1011-3.

136 Uzzo RG, Bilsky M, Mininberg DT, Poppas DP. Laparoscopic

surgery in children with ventriculoperitoneal shunts: effect of

pneumoperitoneum on intracranial pressure - preliminary

experience. Urology 1997; 49: 753-7.

137 Lassen NA, Christensen MS. Physiology of cerebral blood flow.

Br J Anaesth 1976; 48: 719-34.

138 Harper AM. Physiology of cerebral blood flow. Br J Anaesth

1965; 37: 225-35.

139 Miller JD. Intracranial pressure monitoring. Br J Hospital Med

1978; 497-503.

84

140 Hans P, Franssen C, Damas F, Born JD, Lamy M. Continuous

measurement of jugular venous bulb oxygen saturation in

neurological patients. Acta Anaesth Belg 1991; 42: 213-8.

141 Robertson C. Desaturation episodes after severe head injury:

influence on outcome. Acta Neurochir 1993; S59: 98-101.

142 van Helden A, Scheider GH, Unterberg A, Lanksch WR.

Monitoring of jugular oxygen saturation in comatose patients with

subarachnoid haemorrhage and intracranial haematomas. Acta

Neurochir 1993; S59: 102-6.

143 Cruz J, Miner ME, Allen SJ, Alves WM, Gennarelli TA:

Continuous monitoring of cerebral oxygenation in acute brain

injury: assessment of cerebral hemodynamic reserve.

Neurosurgery 1991: 29: 743-9.

144 Gopinath SP, Robertson CS, Contant CF, Hayes C, Feldman Z,

Narayan RK. Grossman RG. Jugular venous desaturation and

outcome after head injury. J Neurol Neurosurg Psych 1994; 57:

717-23.

145 Isolauri J, Laippala P. Prevalence of symptoms suggestive of

gastro-oesophageal reflux disease in an adult population. Ann

Med 1995; 27: 67-70.

146 Gotley DC, Smithers BM, Rhodes M, Menzies B, Branicki FJ,

Nathanson L. Laparoscopic Nissen fundoplication - 200

consecutive cases. Gut 1996; 38: 487-91.

147 Rantanen TK, Halme TV, Luostarinen ME, Karhumäki LM,

Könönen EO, Isolauri JO. The long term results of open antireflux

surgery in a community-based health care centre. Am J

Gastroenterol 1999; 94: 1777-81.

85

148 Lafullarde T, Watson DI, Jamieson GG, Myers JC, Game PA,

Devitt PG. Laparoscopic Nissen fundoplication: five-year results

and beyond. Arch Surg 2001; 136: 180-4.

149 Horvath KD, Jobe BA, Herron DM, Swanstrom LL. Laparoscopic

Toupet fundoplication is an inadequate procedure for patients with

severe reflux disease. J Gastrointest Surg 1999; 3: 583-91.

150 Horgan S, Pohl D, Bogetti D, Eubanks T, Pellegrini C. Failed

antireflux surgery. What have we learned from reoperations? Arch

Surg 1999; 134: 809-17.

151 So JBY, Zeitels SM, Rattner DW. Outcomes of atypical symptoms

attributed to gastroesophageal reflux treated by laparoscopic

fundoplication. Surgery 1998; 124: 28-32.

152 Collard JM, de Gheldere CA, De Kock M, Otte JB, Kestens PJ.

Laparoscopic antireflux surgery. What is real progress? Ann Surg

1994; 220: 146-54.

153 Lundell L. Antireflux surgery in the laparoscopic area. Baillièr’s

Clin Gastrenterol 2000;14: 793-810.

154 Bessell JR, Gotley DC, Smithers BM, Nathanson L, Menzies B.

Chronic dysphagia following laparoscopic fundoplication. Br J

Surg 2000; 87: 1341-45.

155 Patti MG, Feo CV, De Pinto M, Arcerito M, Tong J, Gantert W, et

al. Results of laparoscopic antireflux surgery for dysphagia and

gastroesophageal reflux disease. Am J Surg 1998; 176: 564-68.

156 Wetscher GJ, Glaser K, Gadenstaetter M, Profanter C, Hinder RA.

The effect of medical therapy and antireflux surgery on dysphagia

in patients with gastroesophageal reflux disease without

esophageal stricture. Am J Surg 1999; 177: 189-92.

86

157 Khuri SF, Daley J, Henderson W, Hur K, Hossain M, Soybel D, et

al. Relation of surgical volume to outcome in eight common

operations. Results from the VA National Surgical Quality

Improvement Program. Ann Surg 1999; 230: 414-32.

158 Reasbeck PG. Treatment of oesophageal carcinoma at a small

rural hospital. J R Coll Surg Edinb 1998; 43: 314-7.

159 Smedh K, Olsson L, Johansson H, Åberg C, Andersson M.

Reduction of postoperative morbidity and mortality in patients

with rectal cancer following the introduction of a colorectal unit.

Br J Surg 2001; 88: 273-7.

160 Sackett DL, Rosenberg WMC, Gray JAM, Haynes RB,

Richardsson WS. Evidence based medicine: what it is and what it

isn’t. BMJ 1996; 71: 312.

161 Pohl D, Eubanks TR, Omelanczuk PE, Pellegrini CA.

Management and outcome of complications after laparoscopic

antireflux operations. Arch Surg 2001; 136: 399-404.

162 Wiedeman JE, Knolmayer TJ, Bowyer MW. Is pneumothorax a

threat in trauma laparoscopy? J Trauma: injury, infection, and

critical care 1998; 45: 677-83.

163 Sternberg DM, Petrick AT, Gharagozloo F, Hannallah MS.

Tension pneumothorax precluding laparoscopic repair of

diaphragmatic hernia. Surg Laparosc Endosc 1997; 7: 429-31.

164 Power M, McCoy D, Cunningham A. Laparoscopic-assisted repair

of traumatic ruptured diaphragm. Anesth Analg 1194; 78: 1187-9.

165 Fabian TC, Croce MA, Stewert RM, Pritchard FE, Minard G,

Kudsk KA. A prospective analysis of diagnostic laparoscopy in

trauma. Ann Surg 1993; 217: 557-65.

87

166 Murray JA, Demetriades D, Asensio JA, Cornwell EE, Velmahos

GC, Belzberg H, Berne TV. Occult injuries to the diaphragm:

prospective evaluation of laparoscopy in penetrating injuries to left

lower chest. J Am Coll Surg 1998; 187: 626-30.

167 Lundell L, Dalenbäck J, Hattlebakk J, Janatuinen E, Levander K,

Miettinen P, et al. The Nordic GORD-study group. Outcome of

open antireflux surgery as assessed in a Nordic multicentre

prospective clinical trial. Eur J Surg 1998; 164: 751-57.

168 Lundell L, Miettinen P, Myrvold HE, Pedersen SA, Liedman B,

Hatlebakk JG, et al. Continued (5-year) followup of a randomized

clinical study comparing antireflux surgery and omeprazole in

gastroesophageal reflux disease. J Am Coll Surg 2001; 192 (2):

172-9.

169 Dent J, Brun J, Fendrick AM, Fennerty MB, Janssens J, Kahrilas

PJ, Lauritsen K, Reynolds JC, Shaw M, Talley NJ on behalf of the

Genval Workshop Group. An evidence- based appraisal of reflux

disease management- the Genval Workshop report. Gut 1999; 44

(suppl 2): S1-S16.

170 Svensk läkemedelsstatistik 2000, Apoteket AB, Stockholm.

171 Blomquist AM, Lonroth H, Dalenback J, Lundell L. Laparoscopic

or open fundoplication? A complete cost analysis. Surg Endosc

1998; 12: 1209-12.

172 Kahrilas PJ. Laparoscopic antireflux surgery: silver bullet or the

emperor’s new clothes? Am J Gastroenterol 1999;94: 1721-3.

173 Gillett G. Ethics of surgical innovation. Br J Surg 2001; 88: 897-8.