1Cardiovasand Research

2DepartmeTurkey.

3DepartmeResearch Hosp

Correspondcular Surgery,Street, Altinda

Ann Vasc Surghttp://dx.doi.or� 2014 Elsevi

Manuscript rec

2013.

Effect of Conditioning on Visceral Organsduring Indirect Ischemia/Reperfusion Injury

A. Tulga Ulus,1 Soner Yavas,1 Ali Sapmaz,2 Ziysan Sakao�gullari,3 Erdal Simsek,1

Siyar Ersoz,2 and Cuneyt Koksoy,2 Ankara, Turkey

Background: The mortality and morbidity rates of even extensive thoracoabdominal replace-ment have improved markedly in recent years. We investigated the effects of a temporary occlu-sion of the aorta as a direct precondition and temporary occlusion of the axillary artery for remotepreconditioning to determine any effects that preconditioning may have on indirect (nonische-mic) injuries to visceral organs (indirect effects of remote ischemia/reperfusion injury).Methods: Thirty-seven New Zealand white rabbits were divided into five groups: controls(sham-operated; group 1); direct ischemia to the infrarenal aorta without preconditioning (group2); direct ischemic preconditioning to the infrarenal aorta (group 3); remote ischemic precondi-tioning before clamping the infrarenal aorta (group 4); and simultaneous direct aortic and remoteischemic preconditioning before the clamping and during clamping of the infrarenal aorta (group5). We used a 30-minute ischemia period for aortic occlusion for spinal cord ischemia/reperfu-sion. The axillary artery was used for remote preconditioning. After 24 hours, tissue specimensof the internal organs were obtained.Results: Myocardial congestion was the main pathology detected in all groups. Histopathologicevaluation of tissue samples taken from the hearts showed no significant differences in terms ofthe degree of polymorphonuclear leukocyte (PMNL) infiltration and edema between the groups.Lung congestion and pneumonic cell infiltration were detected in all the groups. Pneumonic cellinfiltration was significantly high in groups 2 and 3. Cell infiltration was lowest in group 4 at 71.4%of normal values, which differed from the normal values of 25e33.3% in the other groups(P < 0.05). Although there is a difference between the groups in case of renal congestion, thereis not any difference as tubular damage and PMN. There was a significant difference with regardto renal congestion between groups 2 and 3. Renal congestion was normal in 80% of the kidneysin group 3. This differed from the normal values observed in the other groups (14.3e57.1%,P < 0.05). Liver congestion was detected in all groups.Conclusions: Different preconditioning methods may play an important role in distinct organinjuries during aortic cross-clamping. The visceral organs that exhibited positive and construc-tive results with direct and remote preconditioning included the lungs and kidneys during indirectischemia/reperfusion injury. Remote ischemic conditioning was determined to be especiallyadvantageous as a protection method, due to the fact that it is easy to use and effective for indi-rect ischemia/reperfusion injury.

cular Surgery Clinic, Turkiye Yuksek Ihtisas EducationHospital, Ankara, Turkey.

nt of General Surgery, University of Ankara, Ankara,

nt of Pathology, Turkiye Yuksek Ihtsas Education andital, Ankara, Turkey.

ence to: Erdal Simsek, MD, Department of Cardiovas-Yuksek Ihtisas Training and Research Hospital, Kızılay�g, Ankara, Turkey; E-mail: erdaldr@yahoo.com

2014; 28: 437–444g/10.1016/j.avsg.2013.06.027er Inc. All rights reserved.

eived: December 2, 2012; manuscript accepted: June 14,

INTRODUCTION

The mortality and morbidity rates of even extensive

thoracoabdominal replacements have improved

markedly in recent years.1 Visceral organ dysfunc-

tion, however, is still associated with a significant

risk of postoperative mortality or morbidity after

thoracabdominal aortic aneurysm (TAAA) repair.

In 1986, the concept of ischemic preconditioning

was first introduced as a potent, endogenous form

of cardioprotection against ischemia/reperfusion

(I/R) injuries.2 Ischemic preconditioning (IPC) is

437

438 Ulus et al. Annals of Vascular Surgery

a counter intuitive phenomenon, involving induc-

tion of brief periods of ischemia, which protects

various organs from subsequent episodes of more

protracted or sustained ischemia. Initially described

by Murry et al. in a canine model of myocardial

ischemia, IPC occurs in many species, including

humans, and in various organs, including the liver,

lungs, intestine, and kidneys.2e6

Wepreviously investigated the effects of precondi-

tioning on the spinal cord using the same I/R model

with the same experimental setup to determine

spinal cord functional and pathologic outcomes.

Because I/R injury is thought to be a systemic

reaction, we investigated the effects of temporary

occlusion of the aorta as direct preconditioning

and the axillary artery for remote preconditioning

to determine the effects that preconditioning may

have on injury to visceral organs (indirect effects

of remote ischemia/reperfusion injury).

METHODS

The study was carried out according to the ‘‘Princi-

ples of Laboratory Animal Care’’ and The Guide for

the Care and Use of Laboratory Animals (NIH Publica-

tion No. 80-23, revised 1985), after approval from

the ethics committee of out institution. This investi-

gation was performed for the purpose of evaluating

distal organs and is the second part of this research is

related to spinal cord ischemia.

Thirty-sevenNewZealandwhite rabbitswereused

in the study and the (meanweight 2.7 ± 0.2 kg, range

2.5e3.5kg). Theanimalswere allowedaccess to stan-

dard rabbit chow and tap water ad libitum.

The Rabbits were divided into five groups as

follows:

Group 1: controls (sham-operated).

Group 2: direct ischemia to the infrarenal aorta

without preconditioning.

Group 3: direct ischemic preconditioning to the

infrarenal aorta.

Group 4: remote ischemic preconditioning,

before clamping of the infrarenal aorta.

Group 5: simultaneous direct aortic ischemia

and remote ischemic perconditioning before

clamping and during clamping of the infrarenal

aorta.

Surgical Procedure

The animals were administered ketamine (50mg/kg)

and xylazine (10 mg/kg) intramuscularly for in-

duction of anesthesia and allowed to breathe

spontaneously without mechanical ventilation.

Intravenous xylazine was used for anesthesia main-

tenance, if needed. An ear vein catheter was placed

for the administration of intravenous fluids and addi-

tional medications. An ear arterial catheter was

placed to obtain blood samples.

After sterile surgical preparation, the abdomen

was opened with a 4-cm midline laparotomy inci-

sion and the retroperitoneal abdominal aorta was

exposed. In group 1 (sham, 6 animals), the abdomen

was provisionally closed to avoid excessive heat or

fluid loss and kept this way for 30 minutes without

clamping. In group 2 (9 animals), after positioning

of the abdominal aorta with tape, 50 IU/kg heparin

sodium was administered intravenously and the

aorta was cross-clamped using an atraumatic

vascular clamp immediately caudal to the origin of

the left renal artery and above the aortic bifurcation.

The use of application of 30 minutes of ischemic

insult is based on the results of previous experi-

ments using this model.7e9 After occluding the

aorta, the abdomen was provisionally closed to

avoid excessive heat or fluid loss. After removal

of the cross-clamp, distal reperfusion was observed

visually. In group 3 (6 animals), in this direct

preconditioning group, after the three 5-minute

periods of clamping of the aorta, 30 minutes of

clampingwas done. In group 4 (8 animals), the right

axillary artery was exposed via a 3-cm-long axillary

incision and controlled with vascular tape. The axil-

lary artery was clamped three times for 5-minute

periods with 5-minute clamp removal periods.

During these clamping periods, the abdomen was

opened with a 4-cm midline laparotomy incision

and the retroperitoneal abdominal aorta was

exposed and controlled with vascular tape. After

clamping and reperfusing the axillary artery a third

time, the abdominal aorta was cross-clamped using

an atraumatic vascular clamp immediately caudal

to the origin of the left renal artery and above the

aortic bifurcation, and the abdomen was provision-

ally closed to avoid excessive heat or fluid loss and

kept this way for 30minutes. In group 5 (8 animals),

the axillary artery and abdominal aorta were

clamped simultaneously. Although the axillary

arterywas clamped three times for 5-minute periods

with 5-minute clamp removal periods, the abdom-

inal aortawas clamped continuously for 30minutes.

Upon completion of the procedures, incisions

were closed with sutures and all catheters were

removed. The animals were allowed to recover

from anesthesia before they were returned to the

holding area, where they could move freely in their

cages, and were provided with food and water ad

libitum and permitted to remain alive for 24 hours.

Vol. 28, No. 2, February 2014 Conditioning of visceral organs in I/R 439

At that point, all animals were euthanized with

intravenous sodium pentobarbital (50 mg/kg) and

tissue specimens were obtained.

Histopathologic Assessment

Fig. 1. Remote organ injuries (lung and liver) in the

study groups (P > 0.05).

Histopathologic assessment of the tissue samples

was conducted through the use of standard histo-

logic techniques, including formalin fixation, dehy-

dration, embedding into paraffin blocks, obtaining

serial transverse sections (4 mm), and hematoxy-

lineeosin staining.10,11 The histopathologic studies

were carried out by the same pathologist using

a light microscope. The histopathologic parameters

of I/R injury were defined for the kidneys as tubular

injury, congestion, polymorphonuclear leukocyte

(PMNL) count; for the heart as PMNL count, edema,

and congestion; for the lungs as pneumonic infiltra-

tion, edema, and congestion; and for the liver as

necrosis, congestion, and vacuolar degeneration.

Degrees of I/R injury were graded and expressed as

+, ++, +++, or ++++ by the pathologist. The

observers evaluated the samples blindly.

Statistical Analysis

Data are presented as mean and standard deviation

or as percentages, as appropriate. Chi-squared test,

independent-samples t-test, or one-way analysis of

variance (ANOVA)were used to compare test values

where necessary. P < 0.05 was considered signifi-

cant. Confidence intervals (CIs) were calculated at

the 95% level.

RESULTS

Animals in all groups were evaluated in terms of

organ damage (Table I). Between-group statistical

differences were assessed (Table II).

Myocardial congestion was the main pathologic

finding, which was detected in all groups. It was

observed in the myocardial biopsy taken from

1 animal in the control group. Although there was

no significant difference in terms of congestion

between the groups, the second group was affected

adversely. Histopathologic evaluation of the tissue

samples taken from the hearts showed no significant

differences in terms of the degree of PMNL infiltra-

tion and edema between groups (P > 0.05).

Lung congestion and pneumonic cell infiltration

were detected in all groups (Fig. 2). Pneumonic

cell infiltration was significantly high in groups

2 and 3 (P< 0.05). Lung edema was not determined

in controls (group 1) and group 3, but was assessed

in the other groups. No statistically significant

difference was observed between groups in terms

of lung edema and congestion (P > 0.05; Fig. 1).

Renal congestion was found but renal PMN and

tubular damage was not seen in any of the groups

(Fig. 3). There was a significant difference con-

cerning renal congestion between groups 2 and 3

(P < 0.05). Damage was more extensive in group 2.

Liver congestion was detected in all groups. Liver

necrosis occurred in 1 rabbit in the control group.

Vacuolar degeneration of the liver was seen in all

groups except group 4, at various levels. The pres-

ence and the degree of vacuolar degeneration,

congestion, and necrosis reflected the level of I/R-

originated damage of the liver. There was no signif-

icant difference between groups in terms of liver

congestion, necrosis, and vacuolar degeneration

(P > 0.05) (Table I).

DISCUSSION

Organ failure is a common cause of death and is a

well-known complication of I/R after major

aortic surgery. In this study we attempted to inves-

tigate the effects of different ischemic conditioning

methods on remote organ injuries after aortic

ischemia. For this purpose, we investigated the

effects of both local (in situ) and remote repeated

intermittent ischemia in aortic clamping. The most

important morphologic findings from the present

study demonstrate that local and remote ischemic

stimuli may reduce remote organ injury after aortic

clamping.

Ischemia occurs after the end of blood flow; when

reperfusion takes place, I/R destruction develops.

Research concerning this issue has a long history.

Earlier studies showed that remote ischemic precon-

ditioning is an effective method to reduce the area of

cardiac ischemia.12 The mechanism of how this

works is still not known; however, if its workings

do come to light, then major treatment advances

Table I. Comparison of remote organ injuries and mortality between groups

Group 1 Group 2 Group 3 Group 4 Group 5 P

Exitus % (n) 0 22.2 (2) 0 0 0 0.160

Myocardial congestion 0.839

0 75.0 (3) 42.9 (3) 60.0 (3) 62.5 (5) 57.1 (4)

1+ 25.0 (1) 42.9 (3) 40.0 (2) 37.5 (3) 42.9 (3)

2+ 0 14.3 (1) 0 0 0

Myocardial PMN -

0 100.0 (4) 100.0 (7) 100.0 (5) 100.0 (8) 100.0 (7)

1+ 0 0 0 0 0

Myocardial edema -

0 100.0 (4) 100.0 (7) 100.0 (5) 100.0 (8) 100.0 (7)

1+ 0 0 0 0 0

Lung congestion 0.830

0 50.0 (2) 75.0 (3) 50.0 (3) 28.6 (2) 40.0 (2)

1+ 50.0 (2) 25.0 (1) 33.3 (2) 57.1 (4) 60.0 (3)

2+ 0 0 16.7 (1) 14.3 (1) 0

Lung pneumonic

immune cell

infiltration

0.234

0 25.0 (1) 25.0 (1) 33.3 (2) 71.4 (5) 33.3 (2)

1+ 50.0 (2) 75.0 (3) 66.7 (4) 0 33.3 (2)

2+ 25.0 (1) 0 0 28.6 (2) 33.3 (2)

Lung edema 0.638

0 100.0 (4) 75.0 (3) 100.0 (6) 85.7 (6) 66.7 (4)

1+ 0 25.0 (1) 0 14.3 (1) 16.7 (1)

2+ 0 0 0 0 16.7 (1)

Renal congestion 0.152

0 25.0 (1) 14.3 (1) 80.0 (4) 33.3 (2) 57.1 (4)

1+ 50.0 (2) 85.7 (6) 0 66.7 (4) 28.6 (2)

2+ 25.0 (1) 0 20.0 (1) 0 14.3 (2)

Renal PMN -

0 100.0 (4) 100.0 (7) 100.0 (5) 100.0 (6) 100.0 (7)

1+ 0 0 0 0 0

Renal tubular injury -

0 100.0 (4) 100.0 (7) 100.0 (5) 100.0 (6) 100.0 (7)

1+ 0 0 0 0 0

Liver congestion 0.633

0 40.0 (2) 57.1 (4) 80.0 (4) 50.0 (2) 33.3 (2)

1+ 40.0 (2) 42.9 (3) 20.0 (1) 25.0 (1) 50.0 (3)

2+ 0 0 0 0 16.7 (1)

3+ 20.0 (1) 0 0 25.0 (1) 0

Liver necrosis 0.242

0 75.0 (3) 100.0 (7) 100.0 (5) 100.0 (4) 100.0 (5)

1+ 25.0 (1) 0 0 0 0

Liver vacuolar

degeneration

0.516

0 60.0 (3) 57.1 (4) 60.0 (3) 100.0 (4) 66.7 (4)

1+ 20.0 (1) 42.9 (3) 40.0 (2) 0 33.3 (2)

2+ 20.0 (1) 0 0 0 0

440 Ulus et al. Annals of Vascular Surgery

may be developed.13 According to one theory, aden-

osine and bradykinin are secreted from the other

tissues and, accordingly, catecholamine secretion,

sympatheticnerve stimulation, andfinallyprotection

is provided.13 According to the neural hypothesis,

adenosine, bradykinin, and calcitonin-generated

peptide (CGRP) provide protection by stimulating

the regional afferent neural pathway; in the humoral

hypothesis, adenosine, bradykinin, opioids, CGRP,

endocannabinoids, and other humoral factors

Table II. P values between groups

Groups

1 vs 2 1 vs 3 1 vs 4 1 vs 5 2 vs 3 2 vs 4 2 vs 5 3 vs 4 3 vs 5 4 vs 5

Lung pneumonic

immune cell

infiltration

0.549 0.435 0.104 0.870 0.778 0.025* 0.329 0.027* 0.264 0.199

Renal congestion 0.308 0.155 0.435 0.588 0.013* 0.416 0.091 0.060 0.424 0.321

Group 1: sham; group 2: pure ischemia, group 3: direct preconditioning, group 4: remote preconditioning, group 5: direct and remote

preconditioning.

*P < 0.05.

Fig. 2. Histopathologic appearance of lung. (A) Normal lung (�400). In (B), the asterisk indicates the congested area of

the lung (�400). In (C), the asterisk indicates alveolar inflammation of the lung (�400).

Vol. 28, No. 2, February 2014 Conditioning of visceral organs in I/R 441

secreted from the distant tissues generate a precondi-

tioning effect in the target tissues. According to

the systemic response hypothesis, systemic antiin-

flammatory and antiapoptotic effects provide the

protection. In a study on rabbits, remote ischemic

preconditioning was performed in the lower

extremity muscle and the cardiac infarction area

was decreased by 65%.14

Themechanisms induced by preconditioning and

after direct and indirect I/R injury have been poorly

investigated. The effects of the substances released

and circulating in the peripheral blood after precon-

ditioning may be beneficial. The known mecha-

nisms of preconditioning should be classified into

three pathway categories, humeral, neural, or

a combination of the two, and involving the

kinases.15 Zitta and colleagues described protection

of human intestinal cells from hypoxia-induced

injury by using serum derived from patients having

undergone preconditioning.16 They suggested the

role for matrix metalloproteinase (MMP)-2/-9emediated protection in the model.

Reperfusion of acutely ischemic abdominal

organs is one of the many factors that cause local

and distant organ damage that may contribute to

highmorbidity andmortality.17 Systemic inflamma-

tory response is an important component of visceral

I/R damage, as shown in animal studies.18,19 A

similar phenomenon after aortic surgery could

contribute to the high morbidity and mortality asso-

ciated with this procedure. The primary goal of is to

minimize damage after I/R. Remote ischemia pre-

conditioning is the body’s defense mechanism.

The fundamental effects of conditioning on the

progressionof I/R injuriesof visceral organs ina rabbit

model of aortic occlusion have been thoroughly

Fig. 3. Histopathologic appearance of the kidney. (A)

Normal kidney (�400). In (B), the asterisk indicates the

severely congested kidney area (�400).

442 Ulus et al. Annals of Vascular Surgery

examined. It was identified that, in the aftermath of

aortic aneurysm repair, significant complications

may occur and visceral damage can be a severe,

even lethal pathology. One study showed a very

high rate (34.5%) of visceral organ damage (multi-

system organ failure) among 29 patients with thora-

coabdominal aortic aneurysm repair (TAAA).20 In

that study, the mortality rate was 17.2%, myocardial

infarction rate was 6.9%, pulmonary failure was

44.8%, renal failure was 34.5%, hepatic failure was

24.1%, hematopoietic failure was 41.4%, and spinal

cord injurywas 10.3%.20 Aortic aneurysm repair still

seems to be a great challenge. The most common

causes death include multisystem organ failure,

hemorrhagic shock, and cardiac damage. The most

overwhelming complication is paraplegia. It is

known that surgery for TAAA repair affects all major

organs, including the heart, lung, liver, kidneys,

intestines, and spinal cord.20,21

Throughout TAAA repair, the heart must regu-

late not only the immediate afterload augmentation

due to cross-clamping of the aorta but also the

inflammatory response due to visceral I/R injury.

We acknowledge the fact that aortic cross-

clamping clearly causes proximal systemic hyper-

tension and left ventricular distention. Increased

wall stress and decreased subendocardial perfusion

may also be observed due to left ventricular disten-

tion. Harward and colleagues reported a myocardial

infarction (MI) rate of 6.9% in this setting.20 Cam-

bria et al. evaluated 337 patients undergoing

TAAA repair over a 15-year period and described

a 13.8% rate of cardiac complications.22 In our

study, we observed no differences among groups

with regard to pathology of the heart.

Similar to the heart, although proximal to the

cross-clamp, pulmonary dysfunction after TAAA

repair is firmly associated with I/R injury and

systemic inflammatory response syndrome. The

incidence rates of pulmonary complications fol-

lowing TAAA repair varies between 20% and 50%.

Advanced age, longer aortic cross-clamp time,

number of packed red blood cells transfused, and

tobacco are considered common predictors of pro-

longed postoperative respiratory failure.23 Unlike

all other organs in the human body, the lung has

two blood supply networks with widespread anasto-

motic connections and a total of three likely sources

of lung tissue oxygenationdwhich has resulted in

comprehensive research into addressing the role of

neutrophils and other inflammatory mediators.24

However, these mediators seem to have only a

limited role in lung I/R injury.24,25 Another report

indicated that the rate of pulmonary dysfunction

was 44.8% after TAAA repair, 25% when cross-

clamp time was <40 minutes and 59% when cross-

clamp time was�40minutes.17 After aortic surgery,

a systemic inflammatory response, as detected by

a consistent increase in cytokine plasma concentra-

tion (tumor necrosis factor-a and interleukin-6),

was observed; nevertheless, there was no specific

evidence of a relationship between cytokine plasma

concentrations and clinical outcome after aortic

surgery. Thus, the clinical details associated with

the transient systemic inflammatory response re-

main unclear.26 In our investigation, according to

lung pneumonic immune cell infiltration findings,

the remote preconditioning group (group 4) showed

better results than groups 2 and 3. This may be

an important finding with regard to lung protec-

tion, although we studied only a small number of

animals.

Necrosis, congestion, and vacuolar degeneration

have been considered histopathologic parameters in

liver I/R injury.27 After 48 hours of reperfusion,

eminent microcirculatory destruction has been

Vol. 28, No. 2, February 2014 Conditioning of visceral organs in I/R 443

shown to take place, decreasing liver perfusion.26

Biopsies taken 24 hours postoperatively showed no

severe damage to liver tissues. Furthermore, we

observed no statistical difference between groups

with respect to biochemical or histopathologic

parameters, although vacuolar degeneration was

seen in 1 animal in group 3.

One of the most common complications of aortic

surgery is acute renal failure (ARF),28 with an inci-

dence rate of between 3% and 34.5%.13,18,26 It has

been asserted that the renal flow pattern diverts

the cortical nephrons even though the aorta is

cross-clamped infrarenally.29 Ultimately, regardless

of where the cross-clamp is placed, renal perfusion

decreases and the release of inflammatorymediators

leads to vasoconstriction, redistribution of the flow

pattern, and increased vascular permeability.

Finally, cytokines, forskolin, proteases, myeloper-

oxidase, and other enzymes that reduce damage

are absolved by the activated neutrophils.30 In our

study, the direct preconditioning group showed

the best results with regard to renal congestion.

There was a significant difference between groups,

particularly when comparing the ischemic group

and the direct preconditioning group. Precondition-

ing has major effect on renal injuries.

In conclusion, these present results suggest that

aortic cross-clamping causes remote organ injury.

Different ischemic conditioning methods may play

major roles in distinct organ injury during aortic

cross-clamping for aortic aneurysms. The organs

protected by direct and remote preconditioning

were the lungs and renal systems. Remote precondi-

tioning is considered an especially advantageous

protection method because it is easy to use and

effective during aortic surgery.

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