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\begin{document}

\title{The impact of age on propofol requirement for inducing loss of
consciousness in elderly surgical patients}



\author[1]{Hua Yang}%
\author[1]{Hui-Min Deng}%
\author[1]{Jun-Wei Ji}%
\author[1]{Xin Lv}%
\author[1]{Jin-Chao Song}%
\affil[1]{Affiliation not available}%


\vspace{-1em}



  
  \date{May 16, 2024}


\begingroup
\let\center\flushleft
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\endgroup





\selectlanguage{english}
\begin{abstract}
Aims: It is generally accepted that geriatric patients are more
sensitive to propofol than adults; thus, a dose-adjusted propofol is
recommended for these patients during the induction of anesthesia.
However, for patients aged 75 years and over, established guidelines do
not provide dose references for the anesthesiologists. To this end, we
observed 80 surgical patients (female 39, male 41, American Society of
Anesthesiologists physical status score I \textasciitilde{} II) to access
the appropriate dose of propofol for inducing loss of consciousness
(LOC). Methods: Patients were subdivided into group A (20 patients,
45\textasciitilde{}64 yr), group B (20 patients, 65\textasciitilde{}74
yr), group C (20 patients, 75\textasciitilde{}84 yr), and group D (20
patients, [?] 85 yr). All patients received propofol (at a rate of 0.3
mg/kg/min) alone for inducing LOC, which was defined by loss of both
eyelash reflex and verbal response. Results: Compared with group A, the
propofol requirement for LOC in Group B, C and D decreased by 14.8\%,
25.2\% and 38.5\%, respectively. Bivariate linear correlation analysis
showed that propofol requirement was negatively correlated with age.
After adjusting for potential confounders, age was still an independent
factor affecting propofol requirement. Conclusion: The propofol
requirement for inducing LOC decreased significantly in elderly
patients. We demonstrated that age was an independent factor impacting
propofol requirement for LOC during the induction of general anesthesia,
implying that the propofol dose for anesthesia induction should be
further reduced in elderly surgical patients, especially those aged 75
years and over.%
\end{abstract}%



\sloppy


\textbf{The impact of age on propofol requirement for inducing loss of
consciousness in elderly surgical patients}

\textbf{Running Title} : Impact of age on propofol requirement

Hua Yang\textsuperscript{1}, Hui-Min Deng\textsuperscript{2}, Jun-Wei
Ji\textsuperscript{1}, Xin Lv\textsuperscript{2}, Jin-Chao
Song\textsuperscript{1}

\textsuperscript{1} Department of Anesthesiology, Shidong Hospital of
Shanghai, University of Shanghai for Science and Technology, Shanghai,
China.

\textsuperscript{2} Department of Anesthesiology, Shanghai Pulmonary
Hospital, Tongji University

School of Medicine, Shanghai, China.

Hua Yang, Hui-Min Deng and Jun-Wei Ji contributed equally to this work.

\textbf{Corresponding Author:} Jin-Chao Song, M.D., Department of
Anesthesiology, Shidong Hospital of Shanghai, University of Shanghai for
Science and Technology, 999 Shiguang Road, Shanghai, China. Phone: (86)
21-25066782. Email: sjch2013@163.com; Xin Lv, M.D. Department of
Anesthesiology, Shanghai Pulmonary Hospital, Tongji University School of
Medicine, Shanghai, 200433, China. E-mail: jokul2020@sohu.com.

The authors confirm that the Principal Investigator for this paper
is\textbf{Jin-Chao Song} and that he had direct clinical responsibility
for the patients.

\textbf{Key words:} elderly, anesthetics, propofol, intravenous
anaesthesia, loss of consciousness

\textbf{Word count} : abstract (243), main text (2500)

\textbf{Table count} : 4

\textbf{Figure count} : 2

\textbf{Abstract}

\textbf{Aims:} It is generally accepted that geriatric patients are more
sensitive to propofol than adults; thus, a dose-adjusted propofol is
recommended for these patients during the induction of anesthesia.
However, for patients aged 75 years and over, established guidelines do
not provide dose references for the anesthesiologists. To this end, we
observed 80 surgical patients (female 39, male 41, American Society of
Anesthesiologists physical status score I \textasciitilde{} II) to access
the appropriate dose of propofol for inducing loss of consciousness
(LOC).

\textbf{Methods:} Patients were subdivided into group A (20 patients,
45\textasciitilde{}64 yr), group B (20 patients, 65\textasciitilde{}74
yr), group C (20 patients, 75\textasciitilde{}84 yr), and group D (20
patients, [?] 85 yr). All patients received propofol (at a rate of 0.3
mg/kg/min) alone for inducing LOC, which was defined by loss of both
eyelash reflex and verbal response.

\textbf{Results:} Compared with group A, the propofol requirement for
LOC in Group B, C and D decreased by 14.8\%, 25.2\% and 38.5\%,
respectively. Bivariate linear correlation analysis showed that propofol
requirement was negatively correlated with age. After adjusting for
potential confounders, age was still an independent factor affecting
propofol requirement.

\textbf{Conclusion:} The propofol requirement for inducing LOC decreased
significantly in elderly patients. We demonstrated that age was an
independent factor impacting propofol requirement for LOC during the
induction of general anesthesia, implying that the propofol dose for
anesthesia induction should be further reduced in elderly surgical
patients, especially those aged 75 years and over.

\textbf{What is already known about this subject:}

1. Geriatric patients are more sensitive to propofol than adults.

2. Established guidelines do not provide dose references for patients
aged 75 years and over.

3. We found that elderly patients commonly receive
greater-than-recommended doses of propofol for the induction of general
anesthesia.

\textbf{What this study adds:}

1. The impact of age on propofol requirement for inducing loss of
consciousness in elderly surgical patients are demonstrated.

2. The propofol dose for anesthesia induction should be further reduced
in elderly surgical patients, especially those aged 75 years and over.

\textbf{Introduction}

Advances in surgical techniques and improvement of perioperative
management have led to a larger proportion of elderly patients
presenting to undergo surgical procedures {[}1{]}. Previous studies have
shown that more than half of all surgical procedures were performed on
patients over the age of 65 {[}2{]}. With the deepening of global aging,
this proportion is expected to further increase in the coming decades.
For these patients, anesthesiologists often need to adjust the
anesthetic regimen, including medication selection, dosage optimization
and so on, to adapt to the elderly physiological changes. However,
established guidelines on anesthesia do not provide dose references for
the anesthesiologists' clinical practice {[}3{]}.

Propofol, as an intravenous hypnotic agent, has been widely used for
anesthetic induction and maintenance in surgical patients. It can
provide quick and smooth anesthesia induction. However, a common
side-effect of propofol-based induction is dose-dependent hemodynamic
instability {[}4{]}, such as hypotension and bradycardia, especially in
elderly patients. Compared with the middle-aged adult, the principles of
geriatric physiology are not merely a linear extension {[}1{]}. These
elderly patients represent a unique clinical group, in addition, they
typically suffer from a number of chronic diseases. Although some
studies have recommended that propofol-based induction should be avoided
in these elderly individuals {[}3, 5{]}, many anesthesiologists still
choose to use propofol in clinical anesthesia rather than other drugs
which have little effect on hemodynamics.

Based on the fact that elderly patients have increased sensitivity to
propofol, anesthesiologists are recommended to reduce the dose of
propofol used for induction in patients aged over 65 years from 2-2.5
mg/kg to 1-1.5 mg/kg {[}6{]}. However, for patients over 75 or even 85
years old, it is unclear whether this recommendation is still applicable
and what dose of propofol is appropriate for such patients. To this end,
we designed the current study to access the appropriate dose of propofol
for these patients, and to analyze the role of age on propofol
requirement in the process of loss of consciousness (LOC) induced by
propofol.

\textbf{Patients and Methods}

Participants

We conducted a prospective observational study following the Declaration
of Helsinki from April to August 2020. The study was approved by the
Institutional Research Ethics Committee of Shidong Hospital. Patients
aged 45 years and over scheduled for general surgery or orthopedic
surgery under general anesthesia were considered eligible. Patients were
excluded if they:  American Society of Anesthesiologists (ASA) physical
status score [?]3;  allergic to propofol;  body mass index (BMI) [?]20 or
[?]30 kg/m\textsuperscript{2};  taking hypnotics, opioid analgesic or
antianxiety agents;  known or suspected heart failure (ejection
fraction \textless{}40\%), severe respiratory disease, renal or
metabolic diseases;  could not complete the informed consent procedure
independently. Written informed consent was obtained from all patients.

Study protocol

A total of 80 patients who met the inclusion and the exclusion criteria
were divided into 4 groups, Group A (20 patients, 45\textasciitilde{}64
yr), Group B (20 patients, 65\textasciitilde{}74 yr), Group C (20
patients, 75\textasciitilde{}84 yr), and Group D (20 patients, [?] 85 yr),
according to age. Noninvasive blood pressure, heart rate,
electrocardiogram, pulse oxygen saturation and end-tidal carbon dioxide
were monitored continuously throughout the operation. After 5 minutes of
preoxygenation, propofol was pumped at a rate of 0.3 mg/kg/min until the
LOC occurred. The LOC was defined by loss of both eyelash reflex and
verbal response. The assessment of the loss of eyelash reflex and verbal
response was carried out every 10 seconds after propofol pumping for 1.5
min. An anesthesiologist assistant, who was blinded to the grouping,
performed the above reflex assessment and finally determined the end
point of titration. Meanwhile, the dose of propofol (Propofol
requirement) and the time of reflection disappear (T reflection
disappear) for each patient were recorded. After induction of propofol,
0.4\textasciitilde{}0.6 ug/kg of sufentanil and 0.2 mg/kg of
cisatracurium were administered, and endotracheal intubation was
performed three minutes later.

Perioperative variables included in the analysis were sex, BMI, albumin,
bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase
(AST), serum creatinine (Scr), blood urea nitrogen (BUN), glomerular
filtration rate (GFR) and ejection fraction (EF).

Hemodynamic parameters including mean arterial pressure (MAP) and heart
rate (HR) at 5 different time points (T0, before propofol
administration; T1, LOC; T2, 3 minutes after the administration of
fentanyl and cisatracurium; T3, 1 minute after intubation; T4, 5 minutes
after intubation; T5, 10 minutes after intubation) were recorded.

Statistical analysis

Baseline characteristics of patients were described as mean (standard
deviation, SD) for continuous variables, frequency (percentage) for
categorical variables, or median (interquartile range, IQR) for
continuous variables with skewed distribution. One-way analysis of
variance, Kruskal-Wallis test and \selectlanguage{greek}χ\selectlanguage{english}\textsuperscript{2} test were used to
analyze the demographic data and hemodynamic changes in each group, as
appropriate. For trend analyses, we used the Mantel-Haenszel
\selectlanguage{greek}χ\selectlanguage{english}\textsuperscript{2} test of linear association for categoical variables
and linear regression for continuous variables. Pearson correlation
coefficients were calculated to assess correlations between propofol
requirement and different parameters.

To evaluate the independent association of age with propofol
requirement, multiple linear regression models were constructed. Three
models were fitted, Model I: unadjusted; Model II: adjusted for gender
and BMI; Model III: further adjusted for albumin, bilirubin, ALT, AST and
GFR. Collinearity diagnostics was used to determine whether the
variables in models were highly intercorrelated. In addition, we also
use smooth curve fitting to examine whether the relationship between age
and propofol requirement was linear while adjusting for potential
confounders above. All statistical analyses were performed using SPSS,
version 20.0 (SPSS Inc., Chicago, IL, USA) and R, version 3.6.3 (R
Project for Statistical Computing). A two-side \emph{P} value
\textless{} 0.05 was considered statistically significant.

\textbf{Results}

The baseline characteristics of patients are presented in \textbf{Table
1} . Of the 80 patients (mean age = 74\selectlanguage{ngerman}±12 years, range
45\textasciitilde{}93 years), 39 (48.75\%) were female. No differences
in BMI, ALT, AST, BUN, and EF between age groups. However, GFR was
significantly associated with age (P = 0.014) and the mean difference
(95\%CI) in age between groups A and B was 29.59 (4.60 \textasciitilde{}
54.58). Furthermore, GRF and albumin decreased linearly with age,
whereas Scr and bilirubin were reversed (all P-trends \textless{} 0.05).

Differences in anesthesia effects between ages were shown
in\textbf{Table 2} . Propofol requirement and T reflection disappear
differed significantly between ages (P \textless{} 0.001), and all had
significant linear decreases with age (P-trend \textless{} 0.001).
Compared to group A, group B had a mean reduction in propofol
requirement of 0.20 mg/kg (95\%CI = 0.07 \textasciitilde{} 0.33) and a
mean reduction in T reflection disappear of 32.50 s (95\%CI = 7.28
\textasciitilde{} 57.72). Significant differences were consistent across
all neighboring groups (all P \textless{} 0.05). Additionally, to
further determine whether the relation between age and propofol
requirement was linear, the estimated dose-response curve was fitted.
There was a continuous linear decreasing trend and statistical
significance between propofol requirement and age after adjusting for
gender, BMI, albumin, bilirubin, ALT, AST, and GFR (\textbf{Figure 1} ).

Bivariate linear correlation analysis showed that propofol requirement
was significantly and positively correlated with albumin (r = 0.312;
95\% CI = 0.099 \textasciitilde{} 0.497; P = 0.005) and GRF (r = 0.286;
95\%CI = 0.070 \textasciitilde{} 0.476; P = 0.010), and negatively
correlated with age, such that significant decline in propofol
requirement with increasing age (r = -0.689; 95\%CI = -0.789
\textasciitilde{} -0.553; P \textless{} 0.001). Other kidney and liver
parameters were not significantly correlated with propofol requirements
(\textbf{Table 3} ).

Patient age was an independent and significant factor in propofol
requirement. When propofol requirement entered models as a continuous
variable, advanced age was associated with lower propofol requirements.
In the fully adjusted model, each 1-SD increase in age was associated
with a decrease in propofol requirement of approximately 0.171 (\selectlanguage{greek}β \selectlanguage{english}=
-0.170; 95\%CI = -0.224 \textasciitilde{} -0.117; P \textless{} 0.001).
In the unadjusted model, a high level of age (Group D) was strongly
associated with a lower propofol requirement (\selectlanguage{greek}β \selectlanguage{english}= -0.525; 95\%CI =
-0.648 \textasciitilde{} -0.403; P \textless{} 0.001). Furthermore,
P-trend was calculated using age groups as ordinal variables, and the
results showed a linear trend between age and propofol requirement
(P-trend \textless{} 0.001). The association yielded relatively
consistent results after adjusting for gender and BMI {[}\selectlanguage{greek}β \selectlanguage{english}(95\%CI):
Group B: -0.185 (-0.310 \textasciitilde{} -0.060), P = 0.004; Group C:
-0.348 (-0.470 \textasciitilde{} -0.226), P \textless{} 0.001; Group D:
-0.512 (-0.637 \textasciitilde{} -0.387), P \textless{} 0.001{]} (Model
II). After further adjustment for albumin, bilirubin, ALT, AST, and GFR,
the associations were slightly weakened but still statistically
significant, with \selectlanguage{greek}β \selectlanguage{english}values of -0.158 (95\%CI = -0.289 \textasciitilde{}
-0.027; P = 0.019), -0.321 (95\%CI = -0.457 \textasciitilde{} -0.184; P
\textless{} 0.001) and -0.467 (95\%CI = -0.608 \textasciitilde{} -0.327;
P \textless{} 0.001) for groups B, C, and D, respectively (Model III)
(\textbf{Table 4} ).

After induction of anesthesia, the MAP and HR of patients in each group
began to decrease, especially at T2 (3 minutes after the administration
of fentanyl and cisatracurium). After intubation, MAP and HR rebounded
in different degrees and tended to be stable in 5\textasciitilde{}10
minutes (\textbf{Figure 2} ). However, there was no difference in
percent changes relative to the baseline between the 4 groups (MAP: T1,
P=0.404; T2, P=0.558; T3, P=0.460; T4, P=0.202; T5, P=0.109; HR: T1,
P=0.499; T2, P=0.970; T3, P=0.237; T4, P=0.135; T5, P=0.922).

\textbf{Discussion}

In the present study, we investigated the effective dose of propofol in
surgical patients aged 45 years and over for LOC during the induction of
general anesthesia. We found that the propofol requirement for LOC
decreased significantly with increasing age. Additionally, we
demonstrated that patient age was an independent and significant factor
in propofol requirement for LOC, implying that the propofol dose for
anesthesia induction should be further reduced in elderly surgical
patients, especially those aged 75 years and over.

Increasing aging population paired with age-associated coexisting
diseases and longer life spans have resulted in an increasing proportion
of geriatric surgery. For these elderly patients, age-related changes in
physiology, anatomy and cognitive function have a great impact on both
the pharmacodynamics and pharmacokinetics of administered anesthetics
{[}1, 7, 8{]}. Anesthesiologists have to tailor the anesthetic scheme to
account the changes associated with aging, comorbidities, and patient
medications so as to optimize the perioperative prognosis of these
elderly patients. However, guiding evidence focusing on geriatric
patients remains poor so far. Clinicians tend to adjust the anesthetic
regimen according to their own experience. Additionally, a large
retrospective cohort study has found that the median (IQR) propofol dose
for anesthesia induction in patients aged over 65 years was 1.8
(1.4\textasciitilde{}2.2) mg/kg, greater than recommended doses
(1\textasciitilde{}1.5 mg/kg) {[}3{]}. In our study, the effective dose
of propofol for LOC in patients (65\textasciitilde{}74 years) was 1.15
mk/kg, which is 14.8\% lower than that for patients aged
45\textasciitilde{}64 years. Our findings are in line with previous
studies {[}9, 10{]}. Moreover, our results show that propofol
requirement for LOC in patients aged 75\textasciitilde{}84 years and [?]
85 years are 25.2\% and 38.5\% lower than that for patients aged < 65
years, respectively (\textbf{Table 2} ). Based on age-grouping, we
demonstrate that as age increased by decade, the propofol requirement
for LOC in elderly reduces dramatically (\textbf{Figure 1} ). These
findings confirm the guideline for minimal administration of propofol
and recommend that the dose of propofol for anesthesia induction should
be further reduced for patients aged 75 years and over.

One major purpose of this study was to investigate the impact of age on
the propofol requirement for LOC in elderly during anesthesia induction.
Therefore, we incorporated factors that might have an impact, such as
gender, BMI, albumin, bilirubin, ALT, AST, and GFR into the models
(\textbf{Table 4} ). After adjustment for these factors, age was still
an independent factor. From the perspective of the increased sensitivity
of the elderly to anesthetics, our results do not conflict with previous
studies {[}10-13{]}. However, unlike previous research paradigms, we
focused on elderly surgical population which aged over 65 years, and
tried to eliminate the interference caused by concomitant medication,
comorbidities and renal insufficiency. Remarkably, this geriatric
surgical population represents a special group. They typically suffer
from cardiopulmonary dysfunction, metabolic diseases, and nervous system
dysfunction, etc. {[}1, 7, 14{]}. Increasing age represents the change
within senescent process, rather than a sort of pathological condition.
Correspondingly, this aging process impedes the ability of the body to
maintain homeostasis, especially when the body is under stress {[}1,
15{]}. Meanwhile, studies also have shown that advanced age is an
independent risk factor for prognosis of various surgical procedures
{[}16-19{]}. Therefore, clinicians should be more aware of these changes
caused by aging, so as to provide the most effective perioperative
treatment for these elderly surgical patients.

There are several limitations in our study. First, this was a
single-center observational study, with potential selection biases
including race, type of surgery, propofol infusion rate. Second, our
study only included patients with ASAI\textasciitilde{}II,which could
eliminate the interference caused by some comorbidities, such as
diabetes or hypertension, but it may also limit the universality of our
results. Third, each anesthesiologist has his own induction habit such
as pretreating with midazolam or dexmedetomidine, which leads to great
differences in anesthesia induction.

In addition, some confounding factors that may influence the results
might have been overlooked due to unavailable data, including
inflammation and nutritional status.

In conclusion, our pilot observation study in surgical patients aged 45
years and over demonstrated that age was an independent and significant
factor in propofol requirement for LOC during the induction of general
anesthesia. Propofol dosage should be tailored in elderly patients,
especially those older than 75 years, which may eventually bring benefit
to these individuals. However, due to the limitations of our research
design, further studies are needed to validate this conclusion and to
verify whether this will improve the perioperative prognosis of
patients.

\textbf{Acknowledgements}

The authors thank Dr. Ai-Jun You (Tongji University, Shanghai, China)
for his help for data analysis.

\textbf{Authors' contributions} : Study design: JCS, XL. Data
collection: HY, HMD and JWJ. Statistical analysis: HMD. Manuscript
drafting: HMD and JCS. Supervision: XL and JCS. Project administration:
JCS.

\textbf{Funding}

This work was supported by the 2019 Development Fund of Anesthesiology,
Shanghai Pulmonary Hospital.

\textbf{Conflicts of interest}

All authors declare no conflicts of interest.

\textbf{Data Availability Statement}

The data that support the findings of this study are available from the
corresponding author upon reasonable request.

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\begin{longtable}[]{@{}lllllll@{}}
\toprule
\begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
Group A (n=20)\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
Group B (n=20)\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
Group C (n=20)\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
Group D (n=20)\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\emph{P} value\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\emph{P} trend\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Male, No. (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
9 (45)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
10 (50)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
11 (55)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
11 (55)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.908\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.487\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
BMI, mean (SD), kg/m\textsuperscript{2}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
24.05 (0.61)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
24.40 (0.50)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
24.05 (0.61)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
24.40 (0.50)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.055\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.224\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Liver function\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Albumin, mean (SD), g/L\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
42.15 (7.08)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
41.13 (5.04)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
39.32 (4.00)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
37.76 (7.74)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.121\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{0.016}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Bilirubin, median (IQR), \selectlanguage{greek}μ\selectlanguage{english}mol/L\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
11.50 (9.70-15.78)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
12.90 (10.25-19.83)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
14.85 (12.13-22.45)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
15.30 (11.60-23.18)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.123\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{0.034}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
ALT, median (IQR), U/L\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
18.50 (11.25-26.50)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
18.00 (12.00-22.75)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
12.50 (11.00-18.25)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
14.50 (10.25-24.00)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.358\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.583\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
AST, median (IQR), U/L\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
22.00 (18.00-25.00)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
23.00 (16.00-32.00)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
21.00 (17.00-28.50)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
22.00 (17.25-28.25)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.958\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.168\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Kidney function\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Scr, median (IQR), mg/dl\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.67 (0.55-0.86)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.80 (0.68-0.92)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.80 (0.65-1.01)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.78 (0.62-1.05)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.126\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{0.033}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
BUN, median (IQR), mg/dl\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
14.57 (11.90-16.95)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
15.55 (12.74-19.54)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
13.98 (10.99-17.44)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
15.69 (11.25-20.02)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.746\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.761\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
GFR, mean (SD), mL/min/1.73m\textsuperscript{2}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
136.83 (29.07)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
115.41 (26.87)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
107.24 (28.67)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
111.98 (35.09)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{0.014}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{0.008}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
EF, mean (SD) \%\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
63.65 (2.37)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
62.35 (1.90)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
64.05 (3.32)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
63.10 (3.16)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.239\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.986\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 1.} Baseline characteristics of patients in different age
groups.

BMI, body mass index; ALT, alanine aminotransferase; AST, aspartate
aminotransferase; Scr, serum creatinine, BUN, blood urea nitrogen; GFR,
glomerular filtration rate; EF, ejection fraction.

\emph{P} value in one-way analysis of variance, Kruskal-Wallis test, or
\selectlanguage{greek}χ\selectlanguage{english}2 test; \emph{P} trend in linear regression or Mantel-Haenszel \selectlanguage{greek}χ\selectlanguage{english}2 test.

\textbf{Table 2.} Comparison of anesthetic effects in different age
groups.\selectlanguage{english}
\begin{longtable}[]{@{}lllllll@{}}
\toprule
\begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
Group A (n=20)\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
Group B (n=20)\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
Group C (n=20)\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
Group D (n=20)\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\emph{P} value\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\emph{P} trend\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Propofol requirement, mean (SD), mg/kg\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
1.35 (0.20)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
1.15 (0.20) \textsuperscript{*}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
1.01 (0.21) \textsuperscript{+}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.83 (0.17) \textsuperscript{++§||}\selectlanguage{english}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{\textless{} 0.001}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{\textless{} 0.001}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
T reflection disappear, mean (SD), s\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
262.50 (36.11)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
230.00 (42.43) \textsuperscript{*}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
200.50 (43.34) \textsuperscript{+}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
165.00 (32.36) \textsuperscript{++§||}\selectlanguage{english}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{\textless{} 0.001}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{\textless{} 0.001}\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

* Significant difference between Group A and B, + Significant difference
between Group A and C, ++ Significant difference between Group A and D, \selectlanguage{ngerman}§
Significant difference between Group B and D, \selectlanguage{english}|| Significant difference
between Group C and D.\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
& Propofol requirement, mg/kg & Propofol requirement, mg/kg & Propofol
requirement, mg/kg\tabularnewline
\midrule
\endhead
& r & 95\% CI & \emph{P} value\tabularnewline
Age, yr & -0.689 & -0.789 \textasciitilde{} -0.553 & \textbf{\textless{}
0.001}\tabularnewline
BMI, kg/m\textsuperscript{2} & -0.214 & -0.414 \textasciitilde{} 0.006 &
0.057\tabularnewline
Albumin, g/L & 0.312 & 0.099 \textasciitilde{} 0.497 &
\textbf{0.005}\tabularnewline
Ln (Bilirubin), \selectlanguage{greek}μ\selectlanguage{english}mol/L & -0.169 & -0.375 \textasciitilde{} 0.052 &
0.133\tabularnewline
Ln (ALT), U/L & 0.018 & -0.203 \textasciitilde{} 0.237 &
0.875\tabularnewline
Ln (AST), U/L & -0.145 & -0.353 \textasciitilde{} 0.078 &
0.201\tabularnewline
Ln (Scr), mg/dl & -0.173 & -0.379 \textasciitilde{} 0.048 &
0.124\tabularnewline
Ln (BUN), mg/dl & 0.037 & -0.184 \textasciitilde{} 0.255 &
0.744\tabularnewline
GFR, mL/min/1.73m\textsuperscript{2} & 0.286 & 0.070 \textasciitilde{}
0.476 & \textbf{0.010}\tabularnewline
EF, \% & 0.095 & -0.127 \textasciitilde{} 0.308 & 0.401\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 3} . Correlation coefficients between age and propofol
requirement.

BMI, body mass index; ALT, alanine aminotransferase; AST, aspartate
aminotransferase; Scr, serum creatinine, BUN, blood urea nitrogen; GFR,
glomerular filtration rate; EF, ejection fraction.

\textbf{Table 4} . Effects of age on propofol requirement.\selectlanguage{english}
\begin{longtable}[]{@{}lllllll@{}}
\toprule
Age, yr & Model I & Model I & Model II & Model II & Model III & Model
III\tabularnewline
\midrule
\endhead
& \selectlanguage{greek}β \selectlanguage{english}(95\% CI) & \emph{P} value & \selectlanguage{greek}β \selectlanguage{english}(95\% CI) & \emph{P} value & \selectlanguage{greek}β \selectlanguage{english}(95\%
CI) & \emph{P} value\tabularnewline
Per 1 SD & -0.187 (-0.232 \textasciitilde{} -0.143) &
\textbf{\textless{} 0.001} & -0.185 (-0.230 \textasciitilde{} -0.140) &
\textbf{\textless{} 0.001} & -0.170 (-0.224 \textasciitilde{} -0.117) &
\textbf{\textless{} 0.001}\tabularnewline
Group A & 0.00 {[}reference{]} & & 0.00 {[}reference{]} & & 0.00
{[}reference{]} &\tabularnewline
Group B & -0.201 (-0.323 \textasciitilde{} -0.078) & \textbf{0.002} &
-0.185 (-0.310 \textasciitilde{} -0.060) & \textbf{0.004} & -0.158
(-0.289 \textasciitilde{} -0.027) & \textbf{0.019}\tabularnewline
Group C & -0.344 (-0.466 \textasciitilde{} -0.221) & \textbf{\textless{}
0.001} & -0.348 (-0.470 \textasciitilde{} --0.226) & \textbf{\textless{}
0.001} & -0.321 (-0.457 \textasciitilde{} -0.184) & \textbf{\textless{}
0.001}\tabularnewline
Group D & -0.525 (-0.648 \textasciitilde{} -0.403) & \textbf{\textless{}
0.001} & -0.512 (-0.637 \textasciitilde{} -0.387) & \textbf{\textless{}
0.001} & -0.467 (-0.608 \textasciitilde{} -0.327) & \textbf{\textless{}
0.001}\tabularnewline
Trend & \textbf{\textless{} 0.001} & \textbf{\textless{} 0.001} &
\textbf{\textless{} 0.001} & \textbf{\textless{} 0.001} &
\textbf{\textless{} 0.001} & \textbf{\textless{} 0.001}\tabularnewline
\bottomrule
\end{longtable}

Model I: unadjusted; Model II: adjusted for gender and BMI; Model III:
further adjusted for albumin, bilirubin, ALT, AST, and GFR. One SD is
equal to 12.

BMI, body mass index; ALT, alanine aminotransferase; AST, aspartate
aminotransferase; GFR, glomerular filtration rate.

\textbf{Figure legends}

\textbf{Figure 1} . Adjusted dose-response relationship between propofol
requirement and age. Adjusted for gender, BMI, albumin, bilirubin, ALT,
AST, and GFR. BMI, body mass index; ALT, alanine aminotransferase; AST,
aspartate aminotransferase; GFR, glomerular filtration rate.

\textbf{Figure 2} . The changes of hemodynamic parameters at 5 different
time points during the induction of anesthesia. (\textbf{A} ) Mean
arterial pressure (MAP). (\textbf{B} ) Heart rate (HR). The percent
changes of MAP and HR relative to the baseline between the 4 groups were
compared. All the values are presented as mean. T0, before propofol
administration; T1, LOC; T2, 3 minutes after the administration of
fentanyl and cisatracurium; T3, 1 minute after intubation; T4, 5 minutes
after intubation; T5, 10 minutes after intubation.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Fig-1/Fig-1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Fig-2/Fig-2}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

