The Effects of Short-Term Propofol and

Dexmedetomidine on Lung Mechanics, Histology, and

Biological Markers in Experimental Obesity
Luciana Boavista Barros Heil, MD,* Cntia L. Santos, PhD,* Raquel S. Santos, PhD,*
Cynthia S. Samary, PhD,* Vinicius C. M. Cavalcanti, MD, MSc,* Mariana M. P. N. Arajo, MD,*
Hananda Poggio, PhD,* Lgia de A. Maia, PhD,* Isis Hara Trevenzoli, PhD, Paolo Pelosi, MD, FERS,
Fatima C. Fernandes, MD, PhD, Nivaldo R. Villela, MD, PhD, Pedro L. Silva, PhD,* and
Patricia R. M. Rocco, MD, PhD*

BACKGROUND: Administering anesthetics to the obese population requires caution because of

a variety of reasons including possible interactions with the inflammatory process observed in
obese patients. Propofol and dexmedetomidine have protective effects on pulmonary function
and are widely used in short- and long-term sedation, particularly in intensive care unit settings
in lean and obese subjects. However, the functional and biological effects of these drugs in
obesity require further elucidation. In a model of diet-induced obesity, we compared the short-
term effects of dexmedetomidine versus propofol on lung mechanics and histology, as well as
biological markers of inflammation and oxidative stress modulation in obesity.
METHODS: Wistar rats (n = 56) were randomly fed a standard diet (lean) or experimental diet
(obese) for 12 weeks. After this period, obese animals received sodium thiopental intraperito-
neally and were randomly allocated into 4 subgroups: (1) nonventilated (n = 4) for molecular
biology analysis only (control); (2) sodium thiopental (n = 8); (3) propofol (n = 8); and (4) dex-
medetomidine (n = 8), which received continuous IV administration of the corresponding agents
and were mechanically ventilated (tidal volume = 6 mL/kg body weight, fraction of inspired
oxygen = 0.4, positive end-expiratory pressure = 3 cm H2O) for 1 hour.
RESULTS: Compared with lean animals, obese rats did not present increased body weight but had
higher total body and trunk fat percentages, airway resistance, and interleukin-6 levels in the lung
tissue (P = 0.02, P = 0.0027, and P = 0.01, respectively). In obese rats, propofol, but not dexme-
detomidine, yielded increased airway resistance, bronchoconstriction index (P = 0.016, P = 0.02,
respectively), tumor necrosis factor-, and interleukin-6 levels, as well as lower levels of nuclear fac-
tor-erythroid 2related factor-2 and glutathione peroxidase (P = 0.001, Bonferroni-corrected t test).
CONCLUSIONS: In this model of diet-induced obesity, a 1-hour propofol infusion yielded increased
airway resistance, atelectasis, and lung inflammation, with depletion of antioxidative enzymes.
However, unlike sodium thiopental and propofol, short-term infusion of dexmedetomidine had no
impact on lung morphofunctional and biological variables. (Anesth Analg 2016;122:101523)

O
besity is increasing and is one of our most important
health issues. This metabolic disorder is commonly
associated with increased systemic inflammation,1,2
From the *Laboratory of Pulmonary Investigation, Carlos Chagas Filho
Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro,
Brazil; Department of Surgical and Sciences, Federal University of Rio
de Janeiro, Rio de Janeiro, Brazil; Faculty of Medicine, Laboratory of
Experimental Surgery, Federal University of Rio de Janeiro, Rio de Janeiro,
Brazil; Laboratory of Molecular Endocrinology, Federal University of Rio
de Janeiro, Rio de Janeiro, Brazil; Department of Surgical Sciences and
Integrated Diagnostics, IRCCS AOU San Martino-IST, University of Genoa,
Genoa, Italy; and Division of Anesthesiology, Department of Surgery, State
University of Rio de Janeiro, Rio de Janeiro, Brazil.
Accepted for publication November 3, 2015.
Funding: Brazilian Council for Scientific and Technological Development
(CNPq), Rio de Janeiro State Research Foundation (FAPERJ), Coordination for
the Improvement of Higher Education Personnel (CAPES), and Department
of Science and Technology (DECIT)/Ministry of Health.
The authors declare no conflicts of interest.
Supplemental digital content is available for this article. Direct URL citations
appear in the printed text and are provided in the HTML and PDF versions of
this article on the journals website (www.anesthesia-analgesia.org).
Reprints will not be available from the authors.
Address correspondence to Patricia R. M. Rocco, MD, PhD, Laboratory of
Pulmonary Investigation, Carlos Chagas Filho Biophysics Institute, Federal
University of Rio de Janeiro, Sl G01-014, Ilha do Fundo, Rio de Janeiro, RJ,
Brazil 21941. Address e-mail to prmrocco@gmail.com.
Copyright 2015 International Anesthesia Research Society
DOI: 10.1213/ANE.0000000000001114
which may lead to major adverse events when obese indi-
viduals undergo surgical procedures. Anesthetics may
influence immune function and the inflammatory process,
requiring caution when choosing these agents. Propofol
(PRO) and dexmedetomidine (DEX) have a favorable phar-
macokinetic profile for anesthesia and sedation and are used
for surgical procedures and long-term sedation in inten-
sive care units in the obese population.35 In lean animals,
PRO decreases airway resistance and lung inflammation
in experimental acute lung injury induced by endotoxin,6,7
ischemiareperfusion,8 or oleic acid.9 Similarly, in lean
human subjects, PRO improves lung mechanics,10 reduces
inflammation,11 and modulates oxidative stress.12 Likewise,
DEX has shown beneficial effects on lung mechanics,13
inflammation,14,15 and oxidative stress16 in lean animals and
humans. Conversely, in septic patients with intraabdominal
hypertension, PRO, but not DEX , increased tumor necrosis
factor (TNF)- and interleukin (IL)-6 levels.17 However, the
impact of these anesthetic/sedative agents on obese popula-
tions during short-term procedures is not well established.
In this study, we hypothesized that both PRO and DEX
infusion would decrease lung inflammation in obese pop-
ulations. For this purpose, we compared the short-term
effects of DEX versus PRO on lung mechanics and histol-
ogy, as well as biological markers related to inflammation

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 Propofol Versus Dexmedetomidine in Obesity
and oxidative stress modulation in a model of diet-induced
obesity.
METHODS
This study was approved by the Research Ethics Committee
of the Federal University of Rio de Janeiro Health Science
Centre (CEUA-CCS-019). All animals received humane care
in compliance with the Principles of Laboratory Animal Care
formulated by the National Society for Medical Research
and the United States National Academy of Sciences Guide
for the Care and Use of Laboratory Animals.
Animal Preparation and Experimental Protocol
Only clinically healthy male animals were selected for inclu-
sion in the study. Fifty-six male Wistar rats (age, 4 weeks;
weight, 100150 g) were randomly assigned to 2 groups:
(1) lean (n = 28), where animals received a conventional
diet (commercial rodent chow, Purina, So Paulo, Brazil)
for 12 weeks; and (2) obese group ([Ob] n = 28), in which
animals received the experimental diet for the same period.
The experimental diet was developed by supplementation
of the conventional diet with a tablet, a confectionery prod-
uct made from sweetened condensed milk (Supplemental
Digital Content 1, Supplemental Table 1, http://links.lww.
com/AA/B340). To control the environment and reduce
potential spread of infectious agents, 3 animals from each
group were housed in a microisolator cage (filter tops).
All animals were maintained without physical activities,
on a 12:12 h lightdark cycle, under controlled tempera-
ture conditions, and had unrestricted access to food and
water. Food intake was measured every 3 days, and body
weight gain was measured once a week. The general char-
acteristics associated with obesity, such as progression of
food intake (grams per week), energy intake (kilocalories
per week), final body weight (FBW; grams), nasalanal
length (centimeters), and FBW/length (grams per centime-
ter), were evaluated and did not differ between lean and
Ob groups (Supplemental Digital Content 1, Supplemental
Table 2, http://links.lww.com/AA/B340). After 12 weeks,
animals from the Ob groups received sodium thiopental
([THIO]Thiopentax, Cristlia, Itapira, So Paulo, Brazil)
intraperitoneally (50 mg/kg) before undergoing any other
procedures. The level of sedation was evaluated by the
response to light touch with a fingertip to the rats whiskers
(0 = awake, fully responsive to surroundings, 1 = not respon-
sive to surroundings, rapid response to whisker stimula-
tion, 2 = slow response, and 3 = unresponsive to whisker
stimulation).18 Animals were then placed and kept in the
supine position throughout the experiment. The tail vein
was cannulated with a 24-gauge catheter, and Ob animals
were randomly allocated into 4 subgroups: (1) nonven-
tilated (NV) group (n = 4) for molecular biology analy-
sis only (control); (2) THIO group ( n = 8); 3); PROgroup
( n = 8); and (4) DEX group (n = 8). In the THIO, PRO, and DEX
groups, continuous IV administration of sodium THIO (5
mg/kg/h), PRO (Propovan, Cristlia; 100200 g/kg/min obtained by one of the authors, blinded to group assignment.
for 10 min until an adequate depth of anesthesia was
achieved, followed by 75100 g/kg/min), or DEX
(Precedex, Hospira, Lake Forest, IL; 1 g/kg/min bolus
over 10 minutes, followed by 0.5 g/kg/h for maintenance)
were administered, respectively. The plane of anesthesia
1016
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was assessed by evaluation of pupil diameter, position, and
response to light; position of the nictitating membrane; and
movement in response to tail stimulation. The experiments
were started when responses to a noise stimulus (handclap),
as well as whisker stimulation and tail clamp response,
were absent. A 14-gauge cannula was used for tracheos-
tomy, and a fluid-filled tube was inserted in the esophagus
for esophageal pressure measurements. A polyethylene
catheter (PE-50) was inserted into the right carotid artery
for blood sampling and monitoring of mean arterial blood
pressure (MAP). THIO, PRO, and DEX animals lungs were
mechanically ventilated (Servo-i, Maquet, Solna, Sweden)
with the following variables: tidal volume (VT) = 6 mL/kg
actual body weight, respiratory rate = 80 breaths/min ,
fraction of inspired oxygen (Fio2) = 1.0, and positive end-
expiratory pressure (PEEP) = 0 cm H2O zero end-expiratory
pressure (ZEEP) during the first 5 minutes to evaluate the
effects of obesity on lung function without the interference
of mechanical ventilation. Blood (300 L) was drawn into
a heparinized syringe to determine arterial oxygen partial
pressure (Pao2), arterial partial pressure of carbon dioxide
(Paco2), and arterial pH (pHa; Radiometer ABL80 FLEX,
Copenhagen NV, Denmark). Heart rate, MAP, and rec-
tal temperature were continuously recorded (Networked
Multiparameter Veterinary Monitor LifeWindow 6000V;
Digicare Animal Health, Boynton Beach, FL; baseline
ZEEP). Body temperature was maintained at 37.5C 1C
by using a heating blanket. Fio2 was then adjusted to 0.4,
PEEP was increased to 3 cm H2O, and functional data were
further measured (baseline PEEP). For 1 hour, the anesthe-
sia requirements were adjusted to ensure a similar level
of anesthesia in all groups based on maintenance of MAP
>70 mm Hg. At the end of the experimental protocol (1
hour), animals were killed by exsanguination, and the
lungs were then removed. The exsanguination technique of
euthanasia does not interfere with lung histology or with
biological markers of inflammation (Supplemental Digital
Content 2, Supplemental Figure 1, http://links.lww.com/
AA/B334). All experiments were replicated 3 times.
Body Composition Measurements In VivoDual-
Energy X-Ray Absorptiometry
After 11 weeks of feeding (1 week before the anesthetic pro-
tocol), dual-energy X-ray absorptiometry19 measurements
were performed in a Lunar DXA 200368 GE scanner (GE
Healthcare, Lunar, WI) using specific software (encore 2008
version 12.20, GE Healthcare) on rats anesthetized by intra-
peritoneal injection of a 2:1 solution of ketamine hydrochlo-
ride (50 mg/mL ketamine, Cristlia) and 20 mg/mL xylazine
hydrochloride (Rompun Bayer, Animal Health, So Paulo,
So Paulo, Brazil). Evaluation was performed in a blind
fashion, because the dual-energy X-ray absorptiometry tech-
nician was unaware of the experimental protocol. Total fat
(% body weight) and trunk fat (% visceral fat) were measured
in each animal. All body composition measurements were
Data Acquisition and Processing
Airflow, volume, and airway and esophageal pressures
were measured. Airway pressure (Paw) was measured with
a SCIREQ differential pressure transducer (UT-PDP-75,
anesthesia & analgesia
 SCIREQ, Montreal, Canada). The changes in esophageal
pressure (Pes), which reflect changes in chest wall pres-
sure, were measured with a 30-cm long water-filled catheter
(PE205) with side holes at the tip connected to a SCIREQ dif-
ferential pressure transducer (UT-PL-400, SCIREQ). The cath-
eter was passed into the stomach and then slowly returned
into the esophagus. Its proper positioning was assessed using
the occlusion test.20 Values were continuously recorded using
LabView-based software (National Instruments, Austin, TX).
All signals were filtered (100 Hz), amplified in a 4-channel
conditioner (SC-24; SCIREQ) and sampled at 200 Hz with
a 12-bit analog-to-digital converter (National Instruments).
Static lung elastance (Est,L) and airway resistance (Raw) were
measured by the end-inflation occlusion method and com-
puted offline using a routine written in MATLAB (version
R2007a; The Mathworks Inc., Natick, MA).16 All analyses
were performed in a blinded manner, i.e., the observer was
unaware of the experimental protocol.
Postmortem Analysis
Heparin (1000 IU) was injected into the tail vein, the trachea
clamped at PEEP 3 cm H2O, and blood aspirated through
the arterial line for further analysis, yielding a massive
hypovolemia that quickly killed the animals. Lungs were
prepared for histological and molecular biology analysis.
The retroperitoneal, epididymal, and inguinal adipose tis-
sue compartments were dissected and weighed. Visceral
adiposity was estimated by the sum of retroperitoneal and
epididymal depot mass and subcutaneous adiposity by the
inguinal depot mass.
Lung Histology
Lungs were removed en bloc at PEEP = 3 cm H2O in all
groups. Lung tissue samples were taken longitudinally from
the central zone of the left lung. Sections (4 m thick) were
stained with hematoxylin and eosin. Lung morphometric
analysis was performed using an integrating eyepiece with
a coherent system consisting of a grid with 100 points and 50
lines of known length coupled to a conventional light micro-
scope (OlympusBX51, Olympus Latin America Inc., So
Paulo, SP, Brazil). The volume fractions of the lung occupied
by collapsed alveoli (alveoli with rough or plicate walls),
hyperinflated structures (alveolar ducts, alveolar sacs, or
alveoli wider than 120 m), and normal pulmonary areas
(those not exhibiting overdistended or plicate walls) were
determined by the point-counting technique at a magnifica-
tion of 200 across 10 random, noncoincident microscopic
fields.21 Four intraparenchymatous airways from each ani-
mal were viewed at a magnification of 400. The number of
points (NP) falling on the airway lumen and the number of
intercepts (NI) of the lines with epithelial basal membrane
were counted. Because the NI of the lines with the epithelial
basal membrane is proportional to the airway area, the mag-
nitude of bronchoconstriction (contraction index) was com-
puted as contraction index = NI/NP.22 Lung morphometric
analysis was performed in a blinded fashion.
Metabolic and Hormonal Analysis
Serum was separated by centrifugation at 5000 rpm for
10 minutes and stored at 80C. An enzymatic colorimetric
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kit (Bioclin, Belo Horizonte, Brazil) was used to measure
total triglycerides and total cholesterol in accordance with
manufacturer recommendations. Serum insulin and leptin
were measured by enzyme-linked immunosorbent assay
using commercial kits (EDM, Millipore, Corporation, MA).
The assay sensitivity was 0.1 ng/dL for rat insulin and 0.08
ng/dL for leptin, and the intraassay coefficients of varia-
tion were <3% and <10%, respectively. All metabolic and
hormonal analyses were performed by one of the authors,
blinded to group assignment.
Biological Markers of Proinflammatory and
Oxidative Stress Activity in Lung and Adipose
Tissue
Quantitative real-time reverse transcription polymerase chain
reaction (PCR) was performed to measure biological markers
associated with inflammation (TNF- and IL-6) and oxida-
tive stress (nuclear factor erythroid 2-derived factor-2 [Nrf2],
catalase [CAT], and glutathione peroxidase [GPx]) in the lung
tissue and IL-6 in the adipose tissue. Acidic ribosomal phos-
phoprotein P0 (36B4) was used as a housekeeping gene.23
Central slices of right lung and visceral adipose tissue were
cut, collected in cryotubes, quick frozen by immersion in liquid
nitrogen, and stored at 80C. Total RNA was extracted from
frozen tissues using the Quantitec Reverse Transcription total
RNA Isolation System (Qiagen Corporation, Valencia, CA),
following manufacturer recommendations. RNA concentra-
tion was measured by spectrophotometry in a Nanodrop
ND-1000 system (Thermo Fisher Scientific, Wilmington, DE).
First-strand complementary DNA was synthesized from
total RNA using the GoTaq 2-STEP RT-Quantitative PCR
System (Promega Corporation, Fitchburg, WI). The primers
(Invitrogen, Carlsbad, CA) used for gene amplification are
listed in Supplemental Digital Content 1, Supplemental Table
3 (http://links.lww.com/AA/B340). Relative mRNA levels
were measured with a SYBR green detection system in an
ABI 7500 Real-Time PCR system (Applied Biosystems, Foster
City, CA). Samples were measured in triplicate. Relative
gene expression was calculated as a ratio of the average gene
expression levels compared with the reference gene (36B4)
using the 2,Ct method, where Ct = Ct (reference gene)
Ct (target gene) and expressed as fold changes relative to
NV animals (Ob NV) before the start of anesthesia protocols.
Lung biological analyses were performed in a blinded fash-
ion by one of the authors.
Statistical Analyses
The sample size calculation for testing the primary hypoth-
esis was based on the decrease in lung inflammation as
measured by mRNA expression of IL-6 after DEX infusion
in endotoxin-induced shock in rats. The mean (SD) of IL-6
mRNA expression was 1 (0.64) in lean animals and 300 (240)
in animals subjected to endotoxin-induced shock.14
Accordingly, adjusting the error probability to 5%
and the statistical power to 95%, we obtained a sample size
of 8 animals per group. This sample size would provide
the appropriate power (1 = 0.95) to identify significant
( = 0.05) differences in IL-6 gene expression, consider-
ing an effect size d = 1.76, a 2-sided test, and a sample size
ratio = 1 (G*Power 3.1.9.2, University of Dsseldorf, Germany).
 Propofol Versus Dexmedetomidine in Obesity
Random allocation was performed by simple random-
ization using computer-generated sequence. To characterize
the model of obesity, data from lean animals were com-
pared with those obtained for Ob rats using the Student
t test. Concerning the effects of sodium THIO, PRO, or DEX
in Ob rats, different variables were compared using 1-way
analysis of variance followed by the Bonferroni post hoc test.
For molecular biology analyses, Student t tests with P val-
ues adjusted for multiple comparisons (n = 3, * = 0.0167, *
Bonferroni-adjusted test) were performed among the 3 drugs
versus NV animals. We used Kolmogorov-Smirnov test with
Lilliefors correction and Levene median test to assess normal-
ity and the equality of variance, respectively, to all of the anal-
ysis of variance residuals, with all P values 0.17. Parametric
data were expressed as mean (SD) and nonparametric data as
median (interquartile range). All tests were performed using
GraphPad Prism version 5.00 (GraphPad Software, La Jolla,
CA). Significance was established at P < 0.05.
RESULTS
All animals survived the 12-week dietary intervention
period and the anesthetic experimental protocol.
Comparison Between Lean and Obese Animals
Body and trunk fat percentages were higher in Ob ani-
mal groups compared with lean animals (Supplemental
Digital Content 1, Supplemental Table 4, http://links.lww.
com/AA/B340). Furthermore, Ob animal groups showed
higher triglyceride, total cholesterol, insulin, and leptin lev-
els (Supplemental Digital Content 1, Supplemental Table
5, http://links.lww.com/AA/B340). Although no differ-
ences were observed in general characteristics, such as body
weight (Supplemental Digital Content 1, Supplemental Table
2, http://links.lww.com/AA/B340), adipose tissue com-
partments normalized by FBW were significantly greater in
Ob compared with lean animals (P = 0.0001) (Supplemental
Digital Content 1, Supplemental Table 6, http://links.lww.
com/AA/B340). Est,L did not differ significantly between
lean and Ob animals (P = 0.17). Raw was higher in Ob animal
groups compared with lean animals (P = 0.0027). Alveolar
collapse was greater in Ob animal groups than in lean rats
(Supplemental Digital Content 1, Supplemental Table 7,
http://links.lww.com/AA/B340). In addition, mRNA
expression of IL-6 in lung and adipose tissues was higher
in Ob animal groups than in lean animals (P = 0.01; Fig. 1).
Effects of Sodium Thiopental, Propofol, and
Dexmedetomidine in Obese Rats
No differences were observed in MAP (Supplemental Digital
Content 3, Supplemental Figure 2, http://links.lww.com/
1018
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AA/B341). Likewise, blood gas analyses were comparable
among Ob groups at baseline ZEEP (Supplemental Digital
Content 1, Supplemental Table 8, http://links.lww.com/
AA/B340). Furthermore, Est,L and Raw were also similar in
all groups at baseline PEEP (Supplemental Digital Content
1, Supplemental Table 9, http://links.lww.com/AA/B340).
After 1 hour of drug infusion and mechanical ventila-
tion, Est,L did not differ across groups administered dif-
ferent agents (THIO: 1.9 0.7; PRO: 2.3 0.5; DEX: 2.1
0.3). Conversely, Ob PRO animals demonstrated a higher
Raw compared with Ob THIO (P = 0.001) and Ob DEX
(P = 0.016) animals (Lilliefors correction, P = 0.854; Levene
median test, P = 0.732; Fig.2). After drug infusion, alveo-
lar collapse was greater in Ob PRO animals compared with
Ob DEX animals, and the bronchoconstriction index was
higher in Ob PRO animals compared with Ob THIO and
Ob DEX animals (P = 0.04; all P 0.17 for Lilliefors cor-
rection and Levene median test; Table1). Figure3 depicts
light micrographs of representative animals in each group,
clearly showing a reduction in airway diameter in the Ob
PRO group.
Biological Markers Associated with Inflammation
and Oxidative Stress After Propofol or
Dexmedetomidine Administration in Obese Rats
Figures 4 and 5 show the expression of markers associated
with inflammation and oxidative stress, respectively, in the
Ob groups. PRO led to higher mRNA expression of IL-6
and TNF- and lower expression of GPx, an antioxidative
enzyme, than in the NV group (Figs. 4 and 5). Regarding
modulation of oxidative stress, the THIO group exhibited
lower mRNA expression of Nrf2 and CAT compared with
NV group (Fig. 5). Unlike PRO and THIO, DEX infusion did
not modify the biological variables related to inflammation
and oxidative stress modulation (Figs. 4 and 5).
DISCUSSION
In our model of diet-induced obesity, a 1-hour PRO infusion
yielded increased airway resistance, atelectasis, and lung
inflammation with depletion of antioxidative enzymes. As
a short-term infusion, DEX had no impact on lung mechani-
cal and histology, as well as biological variables, unlike
sodium THIO and PRO.
Relevance of the Diet-Induced Obesity Model
We developed a model of obesity that features increased
total body fat content, central adiposity, and a metabolic
profile such as increased leptinemia, insulinemia, and dys-
lipidemia,24 yet did not increase body weight compared with
lean animals. Furthermore, our model featured increased
Figure 1. Interleukin (IL)-6 gene expression
in (A) lung and (B) adipose tissue in animals
exposed to standard diet (lean) and experi-
mental diet to induce obesity (Ob) and not
exposed to anesthetic agents (nonventilated
[NV]). Relative gene expression was expressed
as fold change relative to the respective lean
NV group. Data are presented as mean (SD)
of n = 4 animals/group. Comparisons among
groups were performed using Student t test.
*P = 0.01 versus lean NV.
anesthesia & analgesia

Figure 2. Airway resistance (Raw) at 1 hour. Obese animals received
sodium thiopental (THIO), propofol (PRO), or dexmedetomidine
(DEX). Data are presented as mean (SD) of n = 8 animals/group.
Comparisons among groups were performed using 1-way analysis of
variance followed by Bonferroni post hoc test.
Table 1.Lung Morphometry in Obese Animals
Variables THIO PRO DEX
Normal (%) 75.5 6.5 65.9 14.2 78.8 8.2
Collapse (%) 24.5 6.1 34.1 14.2 21.2 8.2*
Bronchoconstriction 2.8 0.3* 3.1 0.3 2.8 0.2*
index
Values are mean (SD) of 8 rats/group. All values were computed in 10
random, noncoincident microscopic fields per rat. Normal: volume fraction
of the lung occupied by normal alveoli. Collapse: volume fraction of the lung
occupied by collapsed alveoli. Obese animals were randomized to receive
sodium THIO, PRO, or DEX for 1 h. Comparisons across Ob groups were
performed using 1-way ANOVA followed by Bonferroni post hoc test.
ANOVA = analysis of variance; DEX = dexmedetomidine; Ob = obese;
PRO = propofol; THIO = thiopental.
*P < 0.05 compared with Ob PRO.
expression of IL-6 in lung and adipose tissues, suggesting
systemic inflammation associated with obesity.25
Experimental Protocol
At the start of the experimental protocol, sodium THIO
was administered in all groups to prevent discomfort asso-
ciated with surgical manipulation. In addition, sodium
THIO does not affect baseline airway tone,26 lung mechan-
ics, or histology.16,26 A protective ventilatory strategy was
used to discard possible biological effects associated with
mechanical ventilation, which may yield confounding
results. Infusion rates of sodium THIO, PRO, and DEX
were based on experimental studies that reported negli-
gible effects of these agents on hemodynamic variables in
rats6,14,16 when given for 1 hour. Although the initial bolus
dose of DEX is considered high compared with that rec-
ommended for humans, animals reached an adequate
anesthesia level not observed with lower doses, without
autonomic derangements or cardiovascular compromise.
Because obesity may affect drug metabolism, depth of
anesthesia and hemodynamic variables were strictly
controlled.
Choice of Anesthetic Agent
There has been controversy concerning the optimal seda-
tive/anesthetic agent for use in short-term procedures in
the obese population.3,5,27 PRO and DEX have been used
because they have favorable pharmacokinetic proper-
ties, allow easy titration of sedation/anesthesia and
maintenance of steady-state drug levels, and yield rapid
recovery.27
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Effects of Propofol and Dexmedetomidine on
Lung Mechanics and Histology
PRO increased Raw compared with sodium THIO and
DEX in Ob animals, in contrast to what has been observed
in in vitro studies,28 animals without obesity,29 and lean
humans.30 PRO can trigger bronchospasm during anes-
thetic induction, which is associated with the effects of
metabisulfite preservative on neurally mediated and
direct airway smooth muscle-induced bronchoconstric-
tion.31 In Ob animals, the release of proinflammatory
mediators produced in adipose tissue contributes to
a state of systemic and lung inflammation,25 which, in
association with PRO or its preservative, may exacerbate
airway obstruction.32 The exact mechanism of broncho-
constriction induced by PRO (2,6-diisopropylphenol) or
its excipients is not completely understood and might
include activation of tracheobronchial irritant receptors
and stimulation of a cholinergic reflex33 or nonallergic
bronchospasm.34 In our study, the PRO used (produced
by Cristlia) did not contain EDTA or sodium metabi-
sulfite, but the following additives were listed: soybean
oil, egg lecithin, glycerol, oleic acid, sodium hydroxide,
and water. These cannot be excluded as factors leading to
worsening of airway resistance.
Inflammation and Oxidative Stress After
Propofol and Dexmedetomidine Administration
in Obesity
The proinflammatory cytokines, TNF-2 and IL-6,25,35
exert important roles in the immune mechanisms linked
to obesity. TNF- is important concerning the expansion
of adipose tissue mass through macrophage recruitment
and is implicated in induction of airway hyperresponsive-
ness.36 IL-6, important in the regulation of inflammatory
and immune responses,35 is considered a marker of vis-
ceral adiposity.37 Nrf2 regulates antioxidant defenses that
protect against inflammation by inhibiting oxidative tis-
sue injury.38 GPx acts as a reducing system for H2O2 and
detoxifies several toxic peroxides, preventing lipid per-
oxidation.39 CAT catalyzes H2O2 dismutation and protects
cells against the harmful effects of H2O2.40 After confirm-
ing lung and systemic inflammation in our obesity model
by measuring IL-6 expression, we normalized molecular
biology analyses by a NV (Ob NV) group. IL-6 and TNF-
expressions were higher in Ob PRO compared with NV
animals, which may have been because of the interac-
tion between increased leptin levels and PRO exposure.
In our study, the higher levels of leptin may have con-
tributed to the release of proinflammatory mediators
through epithelial cells, airway smooth muscle cells, and
macrophages,41 which express the leptin receptor. PRO
and its intralipid diluent considerably depress neutrophil
chemotaxis42 and function at 50%.43 We hypothesize that
by decreasing neutrophil function, these cells (epithelial
cells, airway smooth muscle cells, and macrophages) may
activate the nuclear factor-B pathway to keep the neutro-
phil activity requirement in the setting of obesity. DEX did
not affect the expression of IL-6 and TNF-, and subjects
responses to it resembled those to sodium THIO. These
findings stand in contrast to what has been reported in
 Propofol Versus Dexmedetomidine in Obesity

Figure 3. Representative photomicrographs of airways and lung parenchyma in obese (Ob) animals treated with sodium thiopental (THIO) (A),
propofol (PRO) (B), or dexmedetomidine (DEX) (C). Note the presence of airway constriction (arrow) and alveolar collapse (asterisk) in Ob PRO
group. Hematoxylin-eosin staining. Original magnification 400. Bars = 100 m.

Figure 4. Expression of biological markers associated with inflammation: (A) interleukin (IL)-6 and (B) tumor necrosis factor (TNF)-. Relative
gene expression was calculated as a ratio of the average gene expression levels compared with the reference gene (36B4) and expressed as
fold change relative to nonventilated (NV) animals. Obese animals were treated with sodium thiopental (THIO), propofol (PRO), or dexmedeto-
midine (DEX) for 1 hour. Values are depicted as box plots (median, interquartile range, and minimum and maximum). Comparisons among
groups were performed using the Kruskal-Wallis test and corrected by Bonferroni procedure.

experimental sepsis14,15 and in clinical studies44 in which
DEX inhibited inflammation because of its sympatholytic
effects, resulting in downregulation of proinflammatory
cytokines.45
GPx activity is decreased in obese compared with non-
obese subjects.46 PRO reduced GPx expression, which was
not affected by DEX and sodium THIO. This is in contrast
to previous reports, because the PRO structure contains a
phenolic hydroxyl group, important for free radical scav-
enging activities and considered a peroxynitrite-mediated
oxidative stress scavenger in healthy subjects, with estab-
lished antioxidant properties.47 The increased oxidative
stress because of the association between PRO and obesity
may be explained by higher leptin levels in Ob animals,
because leptin is directly related to increased oxidative
stress in different tissues and cells in response to inflam-
matory stress.48
Limitations
This study has some limitations: (1) The effects of PRO
on different models of lung inflammation differ accord-
ing to dose.6,49 In our study, results were based on an
adequate level of anesthesia and hemodynamics, rather
than the dose in Ob animals. No study has evaluated the

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Copyright 2015 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited.

dose adjustment of PRO or DEX in obese rats. Analysis of
a progressive drug dose response or plasma concentra-
tion at the effect site should be better evaluated in future
research. (2) All Ob animals lungs were ventilated with
VT = 6 mL/kg actual body weight, PEEP = 3 cm H2O, and
no recruitment maneuvers. In animal species, although
lean body mass or species-specific adjusted body weight
may be appropriate variables, additional studies to deter-
mine excess lean body mass associated with adiposity in
small animals would help define body weightadjusted
dosing strategies.50 In this study, VT was set according to
actual body weight, because body weight did not differ
between lean and Ob animals and there is no validated
body mass index for rats. The PEEP level was set based
on the pilot studies in Ob animals; however, we cannot
exclude that different results could have been obtained
at higher or lower PEEP levels and/or with associated
recruitment maneuvers. (3) Our results cannot be directly
extrapolated to the clinical setting or other obesity mod-
els. (4) Observation time was relatively short (1 hour of
anesthetic infusion); however, a longer time course may
result in confounding data because of fluid requirement to
maintain MAP at adequate levels, which affects inflamma-
tory markers. (5) We focused on specific inflammatory and
oxidative stress mediators involved in obesity-associated
systemic inflammation. Another study is required to detail
the mechanisms associated with individual gene activa-
tion and the possible mechanisms of action of PRO in the
setting of obesity.
Before a clinical study is undertaken to evaluate the role
of PRO in obese patients, further experimental studies are
required to clarify the interactions between PRO and hyper-
leptinemia or adipocytokines in obesity.
CONCLUSIONS
In a model of diet-induced obesity, a 1-hour PRO infusion
yielded increased airway resistance, atelectasis, and lung
inflammation, with depletion of antioxidative enzymes.
Unlike sodium THIO and PRO, short-term infusion of DEX
April 2016 Volume 122 Number 4 www.anesthesia-analgesia.org 1021
Copyright 2015 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited.
Figure 5. Expression of biological markers
associated with oxidative stress: (A) gluta-
thione peroxidase (GPx), (B) nuclear factor
erythroid-2 related factor 2 (Nrf2), and (C)
catalase. Relative gene expression was
calculated as a ratio of the average gene
expression levels compared with the refer-
ence gene (36B4) and expressed as fold
change relative to the obese (Ob), non-
anesthetized, nonventilated (NV) group.
Ob animals were treated with sodium
thiopental (THIO), propofol (PRO), or dex-
medetomidine (DEX) for 1 hour. Values are
depicted as box plots (median, interquar-
tile range, and minimum and maximum).
Comparisons among groups were per-
formed using the Kruskal-Wallis test and
corrected by Bonferroni procedure.
had no impact on lung morphofunctional and biological
variables. E
DISCLOSURES
Name: Luciana Boavista Barros Heil, MD.
Contribution: This author helped design the study, conduct the
study, collect the data, analyze the data, and prepare the manuscript.
Attestation: Luciana Boavista Barros Heil approved the final
manuscript, attests to the integrity of the original data and the
analysis reported in this manuscript, and is the archival author.
Name: Cntia L. Santos, PhD.
Contribution: This author helped design the study, conduct
the study, collect the data, analyze the data, and prepare the
manuscript.
Attestation: Cntia L. Santos approved the final manuscript
and attests to the integrity of the original data and the analysis
reported in this manuscript.
Name: Raquel S. Santos, PhD.
Contribution: This author helped design the study, conduct the
study, collect the data, and analyze the data.
Attestation: Raquel S. Santos approved the final manuscript
and attests to the integrity of the original data and the analysis
reported in this manuscript.
Name: Cynthia S. Samary, PhD.
Contribution: This author helped design the study, conduct the
study, and collect the data.
Attestation: Cynthia S. Samary approved the final manuscript
and attests to the integrity of the original data and the analysis
reported in this manuscript.
Name: Vinicius C. M. Cavalcanti, MD, MSc.
Contribution: This author helped conduct the study and collect
the data.
Attestation: Vinicius C. M. Cavalcanti approved the final man-
uscript and attests to the integrity of the original data and the
analysis reported in this manuscript.
Name: Mariana M. P. N. Arajo, MD.
Contribution: This author helped conduct the study and collect
the data.
Attestation: Mariana M. P. N. Arajo approved the final manu-
script and attests to the integrity of the original data and the
analysis reported in this manuscript.
 Propofol Versus Dexmedetomidine in Obesity
Name: Hananda Poggio, PhD.
Contribution: This author helped conduct the study, collect the
data, and analyze the data.
Attestation: Hananda Poggio approved the final manuscript
and attests to the integrity of the original data and the analysis
reported in this manuscript.
Name: Lgia de A. Maia, PhD.
Contribution: This author helped collect the data, analyze the
data, and prepare the manuscript.
Attestation: Lgia de A. Maia approved the final manuscript
and attests to the integrity of the original data and the analysis
reported in this manuscript.
Name: Isis Hara Trevenzoli, PhD.
Contribution: This author helped conduct the study, analyze
the data, and prepare the manuscript.
Attestation: Isis Hara Trevenzoli approved the final manuscript
and attests to the integrity of the original data and the analysis
reported in this manuscript.
Name: Paolo Pelosi, MD, FERS.
Contribution: This author helped design the study, analyze the
data, and prepare the manuscript.
Attestation: Paolo Pelosi approved the final manuscript and
attests to the integrity of the original data and the analysis
reported in this manuscript.
Name: Fatima C. Fernandes, MD, PhD.
Contribution: This author helped design the study and analyze
the data.
Attestation: Fatima C. Fernandes approved the final manu-
script and attests to the integrity of the original data and the
analysis reported in this manuscript.
Name: Nivaldo R. Villela, MD, PhD.
Contribution: This author helped design the study and analyze
the data.
Attestation: Nivaldo R. Villela approved the final manuscript
and attests to the integrity of the original data and the analysis
reported in this manuscript.
Name: Pedro L. Silva, PhD.
Contribution: This author helped design the study, conduct
the study, collect the data, analyze the data, and prepare the
manuscript.
Attestation: Pedro L. Silva approved the final manuscript and
attests to the integrity of the original data and the analysis
reported in this manuscript.
Name: Patricia R. M. Rocco, MD, PhD.
Contribution: This author helped design the study, conduct the
study, analyze the data, and prepare the manuscript.
Attestation: Patricia R. M. Rocco approved the final manuscript
and attests to the integrity of the original data and the analysis
reported in this manuscript.
This manuscript was handled by: Markus W. Hollmann, MD,
PhD, DEAA.
ACKNOWLEDGMENTS
The authors thank Mr. Andre Benedito da Silva for animal care;
Mrs. Ana Lucia Neves da Silva for her help with microscopy;
Professor Ronir Raggio Luiz, PhD (Institute of Public Health
Studies, Federal University of Rio de Janeiro) for his help
with statistics; and MAQUET (So Paulo, Brazil) for technical
support.
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