* Structured Abstract
Background: Anastomotic insufficiency still remains an unsolved problem in
digestive surgery. Little clinical data, regarding the impact of perioperative volume
management exist, which suggest lower complication rates in intestinal surgery under
restrictive volume regimens. The aim of our study was to investigate the effect of the
extent of intraoperative fluid administration with crystalloids on the stability of
intestinal anastomoses.
Material and methods: 21 rats were randomly assigned to three experimental
groups (n=7 rats/group): control group CO (9 ml kg-1 h-1 crystalloid infusion), volume
restriction group V (-) (3 ml kg-1 h-1) and animals with volume overload V (+) (36 ml
kg-1 h-1 ). After midline incision, all animals received the corresponding infusion for a
30-minute period. Infusion was continued for further 30 minutes while an end-to-end
small bowel anastomosis was performed 15 cm proximal to the Bauhin valve with 8
nonabsorbable interrupted inverting sutures. At reoperation on the 4th postoperative
day, the anastomotic segment was dissected and the bursting pressure [mmHg] was
measured.
As a second parameter for the quality of anastomotic healing,
hydroxyproline concentration was examined with a spectrophotometric method [µg/g
dry tissue]. Histologically, structural changes of the anastomotic segments were
assessed by two pathologists. Data are given as mean ± SEM.
Results: Anastomotic insufficiency was not seen in all animals. Bursting pressure of
CO animals was 102 mmHg ± 8. Bursting pressure was lowest in V (+) with high
volume exposure at 77 mmHg ± 6 and significantly lower than V (-) (112 mmHg ± 9;
p=0.01) while the difference compared to the CO group did not reach significant
values. Hydroxyproline concentration in V (+) (64.4 µg/g dry tissue ± 7.7) was
significantly lower compared to V (-) (91.7 µg/g dry tissue ± 9.1) animals (p<0.05). In
all animals with volume overload a marked submucosal edema was found.
Conclusion: We could demonstrate for the first time in a systematic investigation,
that the quantity of crystalloid infusion, applied intraoperatively, has a significant
impact on functional (bursting pressure) and structural (hydroxyproline) stability of
intestinal anastomoses in the early postoperative period. Since the stability and
quality of an intestinal anastomosis have an impact on insufficiency rates, it should
be noted that volume overload may have deleterious effects on anastomotic healing
and postoperative complications in digestive surgery, possibly due to a marked bowel
wall edema.
* Manuscript (including references and Figure legends)
1
Impact of different crystalloid volume regimes on intestinal
anastomotic stability
Goran Marjanovic M. D.1, Christian Villain 1, Eva Juettner 2, Axel zur Hausen M. D. Ph D 2, Jens
Hoeppner M. D., Ulrich Theodor Hopt M. D 1, Oliver Drognitz M. D. 1, Robert Obermaier M. D.
1
1
Department of General and Digestive Surgery
2
Insitute of Pathology
University of Freiburg
Germany
Corresponding author:
Goran Marjanovic, MD
Department of General and Digestive Surgery
University of Freiburg
Hugstetter Strasse 55
DE - 79106 Freiburg (Germany)
Tel: + 49 761 270 2806 / Fax: + 49 761 270 2804
E-mail: [email protected]
2
Introduction
The debate about correct perioperative fluid management in patients undergoing elective
digestive surgery remains unresolved. Little is known about the influence of intraoperativelyadministered fluid volume on postoperative complications. A few clinical studies in the last
decade compared the effect of restrictive versus liberal perioperative volume regimens on
postoperative recovery time, well-being and complications 1-4. Patients treated with restrictive
fluid management show significantly lower increase in body weight and pass flatus and faeces
earlier 4. However, data of the impact of volume restriction on postoperative hospital stay are
inconsistent 3, 4. The randomized multicenter trial of Brandstrup et al. showed that restricted
fluid management in elective abdominal surgery significantly reduces postoperative mortality
and morbidity. This was expressed in lower cardiopulmonary (i.e. myocardial infarction,
pneumonia) and tissue healing (i. e. anastomotic insufficiency) complications 2. Brandstrup`s
data could be confirmed in a recent prospective randomized controlled trial of a multimodal
perioperative management protocol which included restricted intravenous volume in patients
undergoing elective colorectal resection for cancer 1. However, even if the rather small
subgroups of the studies mentioned above indicate a higher risk for anastomotic insufficiency for
patients with liberal fluid management, these data may be altered in the perioperative setting by
different clinical variables which depend on the patient’s general condition.
Systematic experimental data evaluating the direct impact of intraoperative fluid strategies on the
healing of gastrointestinal anastomoses are lacking. The aim of our study was to evaluate the
direct effect of different intraoperatively-administered amounts of a crystalloid electrolyte
3
solution on the healing and stability of small bowel anastomoses in rats in the early postoperative
period.
Material and methods
Animals
The local Ethics Committee (University of Freiburg) approved all experiments. Male Wistar rats
(Charles River, Sulzfeld) weighing 220 g – 320 g were used for the experiments. The animals
were housed two per cage, fed standard chow and given access to water ad libitum. Twelve hours
before anesthesia, animals were deprived of food but had free access to water. During the first 24
postoperative hours, animals had free access to water but were fed stepwise with a standard
amount of chow in order to minimize the risk of postoperative ileus.
Experimental design
After an observation period of 5-7 days under laboratory conditions (University of Freiburg), the
animals were randomly assigned by the investigator (G. M.) to three different groups (n = 7 /
group). A sample size of 7 in each group will have 80% power to detect a probability of 0,932 of
the expected effect of volume overload on bursting pressure using a Wilcoxon (Mann-Whitney
U) rank-sum test with a 0,050 two-sided significance level. Assuming normal distribution, the
probability of 0.932 refers to a situation of an effect size of 2.11.
The difference between the groups was the intraoperative amount of infusion, which consisted of
a crystalloid isoosmolar electrolyte solution (Jonosteril, Fresenius, Bad Homburg, Germany.
Contents: Na+ 137 mmol/l; K+ 4 mmol/l; Ca2+ 1.65 mmol/l; Mg2+ 1.25 mmol/l; Cl- 110 mmol/l;
CH3COO- 18 mmol/l; pH 5.0-7.0; osmolarity 291 mOsm/l). The CO group received an infusion
flow rate of 9 ml kg-1 h-1, the restrictive V (-) group had a lower rate of 3 ml kg-1 h-1, whereas the
4
animals of the V (+) group were exposed to a high volume charge (36 ml kg-1 h-1). The primary
outcome measure was the bursting pressure [mmHg]. Secondary outcome measures were
hydroxyproline concentration, dry / wet ratio, periopertive weight change and histology.
Operative procedure and infusion
The operative procedure was performed under sterile laboratory conditions. All animals were
operated by the same investigator (G. M.). The fluid administration and the measurement of
bursting pressure were not performed in a blinded manner. After induction of anesthesia with
isoflurane (4% in an oxygen mixture 3 l/min) in a gas box, animals received continuous
isoflurane anesthesia (1.5% in an oxygen mixture 3 l/min) through a mask. A 26G silicon venous
catheter was placed in a tail vein for administration of the infusion. The abdomen was shaved
and disinfected. A 5 cm midline incision was performed. When the abdomen was opened, the
infusion was started in each animal according to the randomization (CO, V (-) or V (+)) and
maintained for 30 min. Then, the anastomotic procedure started and infusion was continued for
further 30 minutes, so that each animal had 60 min infusion time.
A 1-cm control segment for determination of the dry / wet ratio was excised 15 cm proximal to
the caecum. Ileal continuity was restored by performing an end-to-end anastomosis using 8
inverting interrupted sutures (Prolene 8/0, Ethicon, Germany). In order to standardize the suture
technique, a silicon catheter (Heidelberger Verlaengerung, Braun, Melsungen, Germany;
diameter 5mm) was introduced into both ileal ends. After performing the front-wall sutures, the
catheter was removed and the back-wall sutures followed. The distance of the single sutures to
the resection margins and the distance between the single sutures was 1-2 mm. The abdominal
5
wall was closed in two layers – musculoperitoneal and fasciocutaneous layer (Vicryl 4/0 SH+;
Ethicon, Germany).
On the 4th postoperative day (day of operation = day 0) the animals were sacrificed after
induction of anesthesia in a box with isoflurane (4% in an oxygen mixture 3 l/min) by lethal-dose
intracardial potassium injection. The abdomen was opened with a complete midline incision and
a horizontal incision, generating optimal exposure of the abdominal organs. After exploration for
signs of inflammatory complications, adhesions were dissected. A 4-cm long small bowel
segment, containing the anastomosis, was removed and carefully freed from faecal remnants.
Perioperative weight change
Animals were weighed after induction of anesthesia before starting the infusion and after closure
of the abdominal wall and end of the infusion. Differences between preoperative and
postoperative body weight were recorded.
Dry / wet ratio
The measurement of the dry / wet ratio was performed in a blinded manner. The wet weight of
the excised 1-cm long control ileal segment was documented and then it was dried in an oven
(Heraeus electronic UT5042EK, Hanau, Germany) to constant weight, which is defined as dry
weight. Calculations were made to express the dry / wet ratio as a measure of ileal wall water
content.
Bursting pressure
6
One lumen of the anastomotic segment was attached to an infusion pump by a 14 G silicon
catheter filled with isoosmolar saline solution. The other lumen was attached to a digital pressure
transducer (Codman ICP Express, Ethicon, Norderstedt, Germany). The pressure was increased
with an infusion rate of 60 ml/h and digitally monitored – both bursting pressure (mmHg), i.e.
the maximum pressure recorded immediately before sudden loss of pressure, and the site of
rupture were noted (mesenterial or the antimesenterial site). Then the anastomotic segment was
dissected from adhering tissue, opened at the mesenteric site and a 1-cm long segment containing
the complete suture line was excised and washed gently with saline solution. This anastomotic
segment was divided into longitudinal strips, each containing a part of the anastomotic ring. One
strip was stored at – 4°C for the measurement of hydroxyproline concentration. The second strip
was used for HE staining and histopathological examinations.
Hydroxyproline concentration
Tissue hydroxyproline concentration was determined in a blinded manner using the ChloramineT spectrophotometric method as previously described by Reddy et al. 5. The procedure is based
on alkaline hydrolysis of the tissue homogenate and subsequent determination of the free
hydroxyproline in hydrolyzate. Chloramine-T was used to oxidize the free hydroxyproline for
production of a pyrrole. Addition of Ehrlich's reagent resulted in the formation of a chromophore
that can be measured at 550 nm. Calculations were made to express the results as micrograms
hydroxyproline per gram of dry tissue (µg/g dry tissue).
Histological evaluation of edema formation
7
The second strip of the anastomosis was spread out in a cassette for paraffin embedding and
immediately fixed in 4% phosphate-buffered formaldehyde (pH 7.3). Histological sections were
stained with hematoxylin-eosin. Edema formation of the intestinal wall was descriptively
assessed in a blinded manner by two pathologists (E. J. and A. z. H.).
Statistical analysis
All data are expressed as mean ± SEM. Subsequent comparisons between the groups were made
by Mann-Whitney U test. P<0.05 was assumed to be significant. SPSS 14.0.2 for Windows
(Chicago, Illinois) was used.
Results
General
There was no morbidity or mortality in the groups, especially no anastomotic insufficiency was
seen. During the first 30 min of infusion, we could not observe any macroscopic conspicuity, but
while performing the anastomosis at the end of the second 30-min interval, macroscopically we
noted an edematous intestinal wall in the V (+) group with volume overload compared to a
normal bowel wall in the V (-) and the CO group.
Perioperative weight change
To express the perioperative body weight change, the preoperative and the postoperative body
weight of the animals were measured (Fig. 1). The body weight remained nearly stable in CO (0.4g ± 0.4) and in V (-) group (-2g ± 0.7), while it increased significantly in V (+) animals (+8.9g
± 0.9) during the 60-min infusion period (p<0.05).
8
Dry / wet ratio
After the quite short interval of 30 min of infusion, a 1-cm ileal segment was excised before
anastomotic construction. In this segment, the dry / wet ratio was measured to determine
differences of water content of the intestinal wall in the three groups with different fluid volume
regimens. After the period of 30 min, there were no significant differences in dry / wet ratios
between CO (0.27 ± 0.01), V (-) (0.27 ± 0.01) and V (+) animals (0.26 ± 0.01).
Bursting pressure
Mean bursting pressure on the 4th postoperative day in CO animals was 102 ± 8 mmHg, whereas
the values of the V (-) group were not significantly higher (112 ± 9 mmHg; p = 0.6). The
bursting pressure of the animals with volume overload V (+) was significantly decreased (77 ± 6
mmHg; p=0.01) compared to the V (-) animals. The difference to the CO group did not reach
significant values (p = 0.06); (Fig. 2). The site of rupture was equally distributed antimesenterial
or mesenterial throughout the groups – the rupture ratio (n antimesenterial / n mesenterial) was 3
/ 4 in V (-) group, 4 / 3 in CO group and 3 / 4 in V (+) group.
Hydroxyproline concentration
Hydroxyproline concentration was examined to express collagen content of the anastomotic
region. It was 91.7 ± 9.1 µg/g dry tissue in the V (-) group and significantly lower in the V (+)
group (64.4 ± 7.7 µg/g dry tissue; p = 0.04), while it was without statistical significant difference
to CO animals (68.4 ± 4.4 µg/g dry tissue); (Fig. 3).
Histology
9
In all animals with high volume load, we found a marked pale band of the submucosal layer as a
sign of submucosal edema, whereas the submucosa in restrictively-treated animals was narrow
and dense (Fig. 4). Further structural differences were not found in between the groups.
Discussion
We are the first to present experimental data on the direct effect of the intraoperatively-infused
amount of fluid on the stability of small bowel anastomoses, demonstrating the negative impact
of volume overload on anastomotic stability in the early postoperative period.
Historically, there has been discussion about the optimal volume regimen in bowel surgery,
especially as clinical data show that liberal fluid management seems to have various negative
effects on postoperative outcome. Since Holte et Kehlet found that a liberal infusion (40 ml kg-1
h-1 ) of lactated Ringer's solution in healthy volunteers led to a significant decrease in pulmonary
function and a significant weight gain for 24 h 6,7, these findings served as basis information for
some clinical studies of perioperative fluid management strategies 1-4,8. These studies essentially
compared “standard” versus “restrictive” volume regimes, whereas it has to be noted that the
“standard” groups were actually fluid overloaded (liberal) and the “restricted” groups received
the amount of fluid, which was assumed to be the optimal fluid regime.
In a prospective randomized trial of 20 patients with elective colon surgery, Lobo et al. showed
that a positive salt and water balance sufficient to cause 3 kg weight gain after surgery, delayed
the return of gastrointestinal function – measured as gastric emptying time, time to first flatus
and passage of stool – and prolonged hospital stay 8. In the up to now largest trial with 172
10
patients, Brandstrup et al. proved that a restricted regime, aimed at unchanged body weight,
significantly reduced overall complications after elective colorectal resection compared to a
liberal regime with volume overload 2. Similar results were noted by Nisanevich et al., also
constating that a liberal regime caused a significant weight gain of about 2 kg 4, and by Khoo et
al. in a multimodal perioperative management protocol, especially indicating that fluid
restriction reduces postoperative cardiorespiratory and anastomotic complications 1.
Nevertheless, the study by MacKay et al. does not fit in the row, since it fails to show a benefit
of fluid restriction on postoperative outcome 3. Critically discussed, the main reason is that the
patients of MacKay’s standard group, even perioperatively, did not receive more than 3 l of
intravenous fluid a day and were actually treated too “restrictively” to cause a significant weight
gain. This highlights the need to assess the exact definition of volume overload and restriction 9.
In our experimental approach, the restricted group only received one-third of the fluid amount of
the control group, whereas the volume overload animals got an amount which was even twelvefold that of the restrictive group. So, even with a rather short time of infusion, a significant
weight gain was noted in animals treated with volume overload, whereas the body weight of
control and V (-) animals remained stable. Thus, our data are consistent with clinical
manifestations that a significant perioperative weight gain in regimes with high volume load
seems to go parallel with the higher anastomotic complication rates.
In fact, the proof of a direct effect of intravenous volume regimes will be difficult to obtain in
clinical studies, since several factors of patient’s condition like malnutrition, immunodeficiency
or cardiopulmonary comorbidity, have an important impact on anastomotic complication rates
11
10,11
, raising the need for an experimental approach investigating the impact of different fluid
regimes on anastomotic stability. Actually, we did not find anastomotic insufficiency, which was
not surprising, considering the clinically well-known, rather small risk of anastomotic leaks in
small bowel surgery compared to colorectal surgery 12,13. However, the direct perioperative
weight change at index-operation correlated with anastomotic stability on the 4th postoperative
day, which was expressed in a functional (bursting pressure) and a structural (hydroxyproline
concentration) parameter of anastomotic healing. Bursting pressure was shown to be a sensitive
parameter to assess anastomotic strength in the first few postoperative days 10,14,15. The
functional changes of anastomotic stability correlated positively with hydroxyproline
concentration of the anastomotic segment. As collagen is one of the most important structural
proteins in humans, containing a great amount of the amino acid hydroxyproline 16, the amount
and structure of collagen in the submucosa of the intestinal wall is considered to determine
bowel wall strength and suture-holding capacity. In the brief period from 3 to 5 days
postoperative, wound healing, as a fine balance between collagen synthesis and collagenolysis,
requires adequate oxygen delivery at the anastomotic site, with good oxygen supply depending
not only on existing vascular arcades but also on diffusion of oxygen molecules through the
wound tissue 10. Intestinal edema due to high intraoperative volume challenge is well known to
hinder oxygen delivery and compromise anastomotic healing 17. Over two decades ago, Chan et
al. 18 studied the development of edema in rabbits undergoing small intestinal anastomoses after
intraoperative infusion of Hartman’s solution. Even a modest volume challenge significantly
increased edema formation, which persisted for more than five days postoperative, especially at
the anastomotic site, and thus was considered to be deleterious for anastomotic healing 18.
12
In a lecture on physiological and clinical aspects of fluid balance, Lobo proposed a hypothesis
for the effects of salt and water overload on gastrointestinal function. This included the
development of splanchnic edema, increased intra-abdominal pressure and thus decreased
mesenteric blood flow leading to decreased tissue oxygenation and intramucosal acidosis. In
consequence, increased gut permeability and impaired wound healing with potentially
anastomotic dehiscence may evolve 19. In our experiment we could prove this hypothesis to some
extent, even if we could not demonstrate a difference in water content after the first 30 minutes
of infusion which correlated with the subjective macroscopic aspect of the rather “dry” ileal wall
in all animals. During anastomotic construction, the “dry” wall became edematous, but only in
the animals with volume overload. So obviously, the time for determination of the ileal water
fraction in our study seems to be somewhat too early. Nevertheless, in our histologic
examination we could clearly show a submucosal edema persisting four days after surgery in
volume overload animals, as previously demonstrated by Chan et al.18.
Edema formation in small intestine seems to depend not only on the amount of infusion but also
on different infusion types. As shown in a clinical trial during a modified Whipple procedure by
Prien et al. 20, administration of a crystalloid, lactated Ringers solution led to increased bowel
wall water fraction due to decreased colloid osmotic pressure compared to colloid solutions
(10% hydroxyethyl starch HES and 20 % human albumin). Based on clinical and experimental
data, it is known that intravascular volume replacement with HES improves tissue oxygenation
due to improved microcirculation and less endothelial swelling 21-23, reduces the inflammatory
response 24, 25 and improves the quality of postoperative recovery 26. Furthermore, different
crystalloid solutions have varying effects on serum osmolality and renal water and sodium
excretion. In healthy humans, large volumes of a saline solution (0.9%) lead to lower serum pH
13
and significantly slower urine output compared to more balanced solutions 5, 27. In our
experiment, we infused a widely-used, balanced crystalloid solution. Considering the
aforementioned data, it is speculative whether the use of 0.9% saline instead of the balanced
solution would have resulted in a greater magnitude of the shown effects due to higher interstitial
water load. Additionally, according to the data of Prien et al. 20 it remains to be seen whether the
use of a colloid infusion like HES would have contrary effects on anastomotic stability. Up to
now, the available clinical data provide no evidence for the relative benefit between crystalloid
and colloid fluid therapy or between different types of colloid. However, correct dosage,
avoiding volume overload, improves outcome after surgery 28.
In our experimental study, we could clearly demonstrate that intraoperative intravenous
crystalloid fluid overload significantly compromises anastomotic stability of small bowel
anastomoses in the early postoperative period. We hereby confirm the few clinical data and give
a convenient explanation for the higher rates of anastomotic complications in patients with
liberal volume regimens with tendency to volume overload. Further studies regarding the impact
of different types of infusion on anastomotic wound healing, especially in colonic surgery with
potentially higher rates of anastomotic complications, are required and will be of considerable
interest.
14
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16
Figure Legends
Fig. 1
Direct perioperative changes in body weight [g=gram], mean ± SEM. * Significant difference to
CO and V (-) group; p<0.05. The postoperative body weight of the CO (-0.4± 0.4) and V (-)
animals (-2 ± 0.7) remained nearly unchanged. Animals in the group with volume overcharge V
(+) had a significant increase (+8.9 ± 0.9) of body weight. CO = control group with 9 ml kg-1 h-1
infusion rate, V (-) = restricted group with 3 ml kg-1 h-1 infusion rate, V (+) = volume overload
group with 36 ml kg-1 h-1 infusion rate.
Fig. 2
Bursting pressure [mmHg], mean ± SEM. * Significantly higher bursting pressures in V (-)
animals (112 ± 9) compared to the V (+) group (77 ± 6); p<0.05. The CO group (102 ± 8) did not
reach significant values compared to V (+) animals. CO = control group with 9 ml kg-1 h-1
infusion rate, V (-) = restricted group with 3 ml kg-1 h-1 infusion rate, V (+) = volume overload
group with 36 ml kg-1 h-1 infusion rate.
Fig. 3
Hydroxyproline concentration [µg/g dry tissue], mean ± SEM. * Significantly higher
hydroxyproline levels in the restricted V (-) group (91.7 ± 9.1) compared to the V (+) group
(64.4 ± 7.7) as a measure for collagen content in the anastomosis, thus correlating positively with
the bursting pressure (Fig. 2); p<0.05. CO = control group with 9 ml kg-1 h-1 infusion rate, V (-)
= restricted group with 3 ml kg-1 h-1 infusion rate, V (+) = volume overload group with 36 ml kg1 -1
h infusion rate.
Fig. 4
Upper row: an overwiev of the anastomoses in the liberal (A) and volume restricted (B) groups
on 4th postoperative day (HE stain, 25x). Lower row: a higher magnification of intact intestinal
walls in both groups. In animals of the liberal group (C) the submucosal layer is clearly visible as
a pale band (dashed arrow) below the mucosa indicating a submucosal edema, while picture D
shows the same region in an animal of the volume restricted group. Here, the submucosal layer
(bold arrow) is narrow and dense (HE stain, 100x).
Figure 1
Click here to download high resolution imageFig.1_weight change.tif
Figure 2
Click here to download high resolution imageFig.2_bursting pressure.tif
Figure 3
Click here to download high resolution imageFig.3_hydroxyproline concentration.tif
Figure 4
Click here to download high resolution imageFig.4_histology.tif