Journal of Clinical Anesthesia 38 (2017) 75–80

Contents lists available at ScienceDirect

Journal of Clinical Anesthesia

Original contribution

Pharmacokinetics and pharmacodynamics of cisatracurium in patients

undergoing surgery with two hemodilution methods
Jianrong Guo a,⁎, Xiaohong Yuan b, Xiaofang Zhou a, Xiaoju Jin c
a
Department of Anesthesiology, Gongli Hospital, The Second Military Medical University, Pudong New Area, Shanghai 200135, China
b
Department of Anesthesiology, Zhejiang Tumor Hospital, Hangzhou 310022, China
c
Department of Anesthesiology, Yijishan Hospital of Wannan Medical College, Wuhu 241001, China

a r t i c l e i n f o a b s t r a c t

Article history: Objective: To investigate the pharmacokinetics and pharmacodynamics of cisatracurium in patients undergoing
Received 18 May 2016 surgery under acute normovolemic hemodilution (ANH) and acute hypervolemic hemodilution (AHH).
Received in revised form 3 January 2017 Methods: Ninety patients with orthopedic surgery were divided into ANH, AHH and control groups, which re-
Accepted 9 January 2017 ceived hemodilution by hydroxyethyl starch 130/0.4 transfusion, Voluven transfusion and regular transfusion
Available online xxxx
and infusion during surgery, respectively. Each group was divided into 3 sub-groups, administrated with
cisatracurium at dosage of 0.1, 0.2 and 0.3 mg/kg respectively. The changes in plasma protein, pH and electrolytes
Keywords:
Hemodilution
from the hemodilution beginning to surgery finish were monitored. Before and after cisatracurium administra-
Cisatracurium tion, the phamocodynamic indicators of muscle relaxant were observed, and the plasma drug concentration
Pharmacokinetics was measured.
Pharmacodynamics Results: After hemodilution or regular transfusion, all three groups experienced a distinct drop in total plasma
protein, albumin and pH. Compared with control group, the plasma concentrations of both K+ and Ca2+ in
ANH and AHH groups significantly dropped (P b 0.05), and those in each group after administration of
cisatracurium also dropped, compared with before (P b 0.05). After administration with cisatracurium, the
onset time of muscle relaxation in AHH group was extended notably, compared with AHH and control groups
(P b 0.05), with no distinct difference of residual pharmacodynamics parameters (P N 0.05). In the same hemo-
dilution or regular infusion, with increase of drug dosage, the onset time of muscle relaxation was shortened,
and the period of no response to train-of-four stimulation, muscle relaxation blockade duration and action
time of muscle relaxation blockade in body were extended (P b 0.05).
Conclusion: When using cisatracurium under AHH, the dosage should be increased appropriately, while it need
not be adjusted under ANH.
© 2017 Elsevier Inc. All rights reserved.

1. Introduction
Due to the shortage of blood source, rising awareness of people in
blood transfusion risk and religious belief, the blood protection has be-
come an important part with the development of surgery [1]. Hemodi-
lution, including acute normovolemic hemodilution (ANH) and acute
hypervolemic hemodilution (AHH), is an important measure of blood
protection, which can not only reduce or even avoid the heterologous
blood transfusion, but also avoid the infection and spreading of blood-
borne diseases and other transfusion-related complications [2,3]. Com-
pared with ANH, AHH is easy to operate, economic in manpower and
⁎ Corresponding author at: Department of Anesthesiology, Gongli Hospital, The Second
Military Medical University, Pudong New Area, No. 219 Miaopu Road, Pudong New Area,
Shanghai 200135, China.
E-mail address: guojrpd@163.com (J. Guo).
time, low in cost, and favorable in reducing the chance of blood pollu-
tion, thus boasting more advantages [4,5]. Hemodilution can incur the
changes to the hemodynamics, electrolytes and activity of some en-
zymes in the plasma, and affect the plasma protein binding rate, distri-
bution, elimination and discharge of various muscle relaxants, thereby
influencing their muscle relaxing effect. Different methods of hemodilu-
tion may have different impacts on the muscle relaxant. It is reported
that ANH can extend the elimination half-time of vecuronium bromide
[6], and AHH can shorten the muscle relaxation onset time of
vecuronium bromide in general anesthesia patients and speed up the
recovery of muscle relaxation [7]. The same method of hemodilution
may bring about different action effects on different muscle relaxants.
For example, ANH can enhance the sensitiveness of patients to
vecuronium bromide [8], rocuronium bromide [9] and atracurium
[10], extend the action duration [11], yet weaken the muscle relaxation
effect of pancuronium bromide and obviously shorten the onset time
and action time of pipecuronium bromide [12].

http://dx.doi.org/10.1016/j.jclinane.2017.01.013
0952-8180/© 2017 Elsevier Inc. All rights reserved.
76 J. Guo et al. / Journal of Clinical Anesthesia 38 (2017) 75–80
Cisatracurium Besylate is a cis-enantiomer of atracurium, which can
form a competitive binding with the cholinergic receptor of motor end
plate. It has a muscle relaxing effect similar with atracurium but about
three times of atracurium in intensity of muscle relaxation [13].
Cisatracurium does not bring about a notable change to the hemody-
namics and histamine releasing, which is the greatest advantage that
differs from atracurium [14]. It also has advantages such as quick
onset time, strong action, quick recovery and no accumulation, which
make it a fairly ideal muscle relaxant currently [15]. At present, the im-
pact of hemodilution on pharmacokinetics and pharmacodynamics of
cisatracurium still lacks a systematic research.
This study systematically investigated the changes of blood pH, elec-
trolytes and plasma protein under ANH and AHH and the impacts of
these changes on the pharmacodynamics of cisatracurium during peri-
operative period. The objective was to provide a reference frame for rea-
sonable use of the new muscle relaxant in hemodilution.
2. Patients and methods
2.1. Patients
This study was done in Gongli Hospital, Clinical Medicine of the Sec-
ond Military Medical University (Pudong New Area, Shanghai, China)
from January 2012 to January 2013. 90 patients with lower limbs ortho-
pedic surgery were selected, with ASA grade I-II, ages between 35 and
60, hemoglobin before surgery ≥ 110 g/L, hematocrit (Hct) ≥ 35%, quan-
tity of platelets ≥ 100 × 109 /L, and no abnormality spotted in thrombin,
heart, lung, liver or kidney functions. The design and implementation of
the experiment was in accordance with Helsinki Declaration. This study
was approved by the Ethical Committee of Gongli Hospital, Clinical
Medicine of the Second Military Medical University.
2.2. Grouping
Patients were divided into 3 groups in accordance with the random
number table (n = 30) as follows: ANH group received the ANH, AHH
group received the ANH, and control group received the regular transfu-
sion and infusion. Each group was divided into 3 sub-groups (ANH1,
ANH2, ANH3; AHH1, AHH2, AHH3; Control1, Control2, Control3; n =
10), administrated with cisatracurium (batch number: 20,060,869,
Jiangsu Hengrui Medicine Co., Ltd., Lianyungang, China) at a dosage of
0.1, 0.2 and 0.3 mg/kg, respectively. Double blind was used in the exper-
iment. The participant would be ruled out of the experiment when the
operation time was b 1 h or the participant was accompanied with any
kind of serious complications such as wakening delay and drug allergy.
The flow diagram was shown in Fig. 1.
Fig. 1. Flow chart of patient selection.
2.3. Hemodilution method
Patients did not administrate medicine before the surgery and re-
ceived a regular monitoring. The radial artery was catheterized under
local anesthesia to monitor the blood pressure while right internal jug-
ular vein was catheterized. Before anesthesia induction, the hemospasia
of ANH group was 200–300 ml/10 min, while 6% hydroxyethyl starch
130/0.4 with medium molecular weight (Voluven, batch number:
732,702, Fresenius Company, Berlin, Germany) was injected via periph-
eral vein. The formula for hemospasia [16] was as follows: V = EBV
(H0 − Ht) / H (EBV: estimated blood volume of whole body, 70 ml/kg
for male, 60 ml/kg for female; H0: initial Hct; Ht (constant value): medi-
um dilution, 28%–30%; H: mean of H0 and Ht). If the main hemospasia
surgery was terminated or when necessary, the autologous blood was
transfused within 6 h. In AHH group, 15–20 ml/kg Voluven was trans-
fused at a speed of 30 ml/min to make Hct to drop to medium. Nitroglyc-
erin (Shanghai Soho-Yiming Pharmaceuticals Co., Ltd., Shanghai, China)
was infused with pump to avoid the overload of acute circulation. Dur-
ing the surgery, Voluven and Ringer's solution (Jiangsu Haosen Pharma-
ceutical Co., Ltd., Lianyungang, China) were continued to inject to
ensure a high-circulating blood volume status and the diuresis was in-
duced after the surgery. In control group, the regular transfusion and in-
fusion were conducted.
2.4. General anesthesia and monitoring
After the status in control group was stable or the hemodilution in
hemodilution groups met the standard, the neuromuscular conduction
function of upper limb ulnar nerve and adductor pollicis were moni-
tored (Orgallon muscle relaxation monitor, Holland) in the mode of
train-of-four (TOF) stimulation. The intravenous injection of 0.03–
0.05 mg/kg midazolam, 1–1.5 mg/kg propofol and 1–2 μg/kg
remifentanil was taken for anesthesia induction within 5 s, and the in-
travenous injection of corresponding dosage of cisatracurium was
taken at a single time. After tracheal intubation, the mechanical ventila-
tion was applied. 4–12 mg·kg−1·h−1 propofol and 0.05–0.5 μg·kg−1·-
min−1 remifentanil were pumped to maintain the depth of anesthesia.
During the surgery, the hemodynamics was maintained steady, with
bispectral index value at 45–60 and PETCO2 at 30–35 mm Hg.
2.5. Monitoring of hemodynamics, blood routine and pharmacodynamics
Changes of the body temperature, amount of bleeding, amount of
urine, plasma protein and pH and electrolytes were monitored on 6
measurement time points, namely, before hemodilution or regular
transfusion and infusion (T1) and immediately after hemodilution or
regular transfusion and infusion (T2), completing muscle relaxant injec-
tion (T3), beginning of the surgery (T4), 1 h after surgery beginning (T5)
and completing the surgery (T6). The onset time of muscle relaxation
blockade (time from end of injection to T1 falling to 0), period of no re-
sponse to TOF stimulation (time during which T1 was kept at 0), block-
ade duration (the time from end of injection to T1 restoring to 5%),
muscle relaxation recovery index (the time in which T1 restored from
25% to 75%), action time of muscle relaxation blockade in body (the
time from muscle relaxant injection finished to T1 restored to 95%),
time of TOF to 70% (the time from muscle relaxant injection finished
until TOF ratio was 70%) and time of TOF to 90% (the time muscle relax-
ant injection finished until TOF ratio was 90%).
2.6. Measurement of plasma drug concentration
Blood sample (2 ml) was taken from the vein at 2, 4, 6, 8, 10, 12, 15,
30, 60, 90 and 120 min after the intravenous injection of cisatracurium,
and then was put into anti-coagulant tube, followed by centrifugation at
a speed of 6000 r/min for 5 min to separate plasma. 40 μl sulfuric acid
(pH 3.0, Sigma-Aldrich Corp., MO, USA) was added, and the mixture
 J. Guo et al. / Journal of Clinical Anesthesia 38 (2017) 75–80 77

was stored at −20 °C. 1 ml of plasma was put into the EP tube, added
with 1 ml of acetonitrile, mixed evenly for 1 min, and then centrifuged
at 12000 r/min for 15 min. 100 μl of supernatant was taken, which
was infused into high performance liquid chromatography for analysis.
The measurement was repeated for 5 times and it was rationed with the
internal standard method [17].
Under the chromatographic conditions in the experiment,
cisatracurium was totally separated from other foreign matters, with
nice peak and the retention time of 4.8 ± 0.5 min as well as the reten-
tion time of internal standard peak of 8.0 ± 0.7 min. A total of 6 samples
of 1 ml blank plasma were taken and the reference substances were
added to prepare 25, 50, 100, 500, 1000 and 2000 ng/ml standard plas-
ma samples, 5 samples for each concentration. According to the pre-
treatment method of the samples, the chromatograms were recorded
and a linear regression was made with peak area on the plasma concen-
tration of cisatracurium to get a regression formula: Y = 0.0007×, r =
0.9995, which indicated that the linear relation was good within the
concentration range of 25–2000 ng/ml, with the lowest detection line
being 25 ng/ml. The measurement of plasma sample precision and
recycling rate indicated that the precision of the instrument was good
and the experimental method was reliable.
ANH group, the lowest amount of albumin was 36.6 ± 5.5 g/L at T4,
and that in AHH group was 36.2 ± 5.4 g/L at T5.
pH and electrolyte were basically maintained normal in three
groups. Compared with T1, pH in two hemodilution groups witnessed
a notable drop at T2–T6 (P b 0.05). In ANH group, the lowest pH was
7.35 ± 0.05 at T6, while that in AHH group was 7.35 ± 0.05 at T4. Com-
pared with control group, pH at each time point in two hemodilution
groups dropped notably (P b 0.05), but no statistical difference between
them (P N 0.05).
Compared with T1, the concentration of K+ and Ca2+ in two hemo-
dilution groups at T2-T6 dropped significantly (P b 0.05). In ANH group,
the lowest K+ concentration was 3.10 ± 0.33 mM at T4, while in AHH
group, the lowest value was 3.30 ± 0.26 mM at T5. The concentrations
of Ca2 + in two hemodilution groups reached the lowest level at T3,
which were 1.08 ± 0.06 mM and 1.11 ± 0.04 mM, respectively. The
Na+ concentration in each hemodilution group had no distinct change
before and after hemodilution (P N 0.05). pH and electrolytes in control
group had no obvious change among different time points (P N 0.05)
(Table 2).
3.3. Pharmacodynamics indicators

2.7. Statistical analysis With the same dosage of cisatracurium, the onset time of muscle re-
laxation in AHH group extended notably (low dosage, 7.2 ± 1.0 min;
All statistical analysis was carried out using SPSS 17.0 software (SPSS medium dosage, 3.9 ± 0.5 min, high dosage, 2.81 ± 0.6 min) compared
Inc., Chicago, IL, USA). The measurement data of normal distribution with AHH and control groups (P b 0.05), with no remarkable difference
were expressed as mean ± SD. Intra-group comparison was performed of residual pharmacodynamics indicators (P N 0.05). In the condition of
using paired-sample t-test, and comparison among groups used one- the same hemodilution or regular infusion, with the increase of drug
way analysis of variance. The enumeration data was analyzed used χ2 dosage, the onset time of muscle relaxation was shortened, the period
test. P b 0.05 was considered as statistically significant. of no response to TOF stimulation, muscle relaxation blockade duration
and action time of muscle relaxation blockade in body were extended
3. Results (P b 0.05), while the recovery index and muscle relaxation residual re-
lated time had no distinct change (P N 0.05) (Fig. 2).
3.1. General conditions
3.4. Plasma concentration of cisatracurium
In three groups, every participant completed the experiment and
was involved in statistical analysis. No obvious adverse event or side ef- After administration of medicine, the plasma concentration of
fect was observed. There was no notable difference among three groups cisatracurium of all patients gradually dropped with the extension of
in general conditions including gender, age, body mass index, American time (P b 0.05). After administration of the same dosage of
society of anesthesiologists (ASA) grade and perioperative bleeding cisatracurium, compared with control group, the plasma concentration
amount (P N 0.05). Compared with control group (526 ± 211 ml), the of ANH and AHH groups both dropped, and AHH group dropped more
perioperative urine amount in AHH group (1126 ± 368 ml) and ANH notably (P b 0.05). In the condition of the same hemodilution, the
group (634 ± 168 ml) witnessed a notable increase (P b 0.05), and drop of plasma concentration was related with the dosage of
that in AHH group was significantly higher than ANH group (P b 0.05) cisatracurium (P b 0.05) (Fig. 3).
(Table 1).
4. Discussion
3.2. Plasma protein, pH and electrolytes
Hemodilution, the most important measure of blood protection, can
After hemodilution or regular transfusion, all patients experienced a not only reduce blood loss in surgery, but also improve the supply to
distinct drop in their total plasma protein and albumin (P b 0.05). In the tissue microcirculation, with a definite action of organ protection
ANH group, the lowest amount of protein was 45.1 ± 6.9 g/L at T4, [18]. Hydroxyethyl starch of medium molecules has been extensively
while in AHH group, the lowest amount was 45.5 ± 7.2 g/L at T4. In used in the fields of clinical blood transfusion alternative and volume
therapy. Compared with the old generation of plasma substitute products
Table 1 such as alums and dextran of low molecules, it is favored for the steady
General conditions of patient in three groups. expansion effect and good clinical safety [19]. Compared with HAES-steril,
Index ANH AHH Control the substitution level of Voluven drops from 0.5 to 0.4, and the substitu-
Total (n) 30 30 30
tion mode increases from 5:1 to 9:1, which is closer to “the ideal colloidal
Gender (n, female/male) 10/20 12/18 11/19 solution” [20]. The half-time in the blood vessels is 3 h, the expansion ef-
Age (years) 46 ± 10 47 ± 9 45 ± 11 fect can sustain for around 4 h, up to 6 h at maximum [21]. The dosage and
BMI (kg·m−2) 22.3 ± 2.6 24 ± 1.6 23 ± 3.7 speed adopted in the research has been proved safe and effective.
ASA grade (n, I/II) 17/13 16/14 12/18
In this study, the Hct dropped to 0.28–0.30, which was medium he-
Perioperative bleeding (ml) 681 ± 86.4 702 ± 79.1 678 ± 90.2
Perioperative urine (ml) 634 ± 168⁎ 1126 ± 368⁎,# 526 ± 211 modilution, with steady hemodynamics [22,23]. Hemodilution can
make the concentration of visible components in the plasma to drop.
⁎ P b 0.05 compared with control group.
#
P b 0.05 compared with ANH group. BMI, body mass index; ASA, American society of
Free concentration of muscle relaxant with a high protein binding
anesthesiologists; ANH, acute normovolemic hemodilution; AHH, acute hypervolemic ratio is more sensitive to the change of plasma protein, such as plasma
hemodilution. protein binding ratio for rocuronium bromide, vecuronium bromide
78 J. Guo et al. / Journal of Clinical Anesthesia 38 (2017) 75–80

Table 2
Plasma protein, pH and electrolytes in three groups at different time points.

Variable Time T1 T2 T3 T4 T5 T6

Total protein (g/L) ANH 65.3 ± 6.7 48.5 ± 5.2⁎,+ 46.8 ± 5.5⁎,+ 45.1 ± 6.9⁎,+ 52.6 ± 7.2⁎ 52 ± 6.8⁎,+
AHH 67.3 ± 3.7 47.8 ± 5.6⁎,+ 46.2 ± 6.6⁎,+ 45.5 ± 7.2⁎,+ 46.3 ± 5.6⁎,+ 49.3 ± 5.6⁎
Control 66.1 ± 5.1 55.1 ± 5.3⁎ 54.5 ± 6.8⁎ 53.1 ± 8.1⁎ 50.6 ± 6.1⁎ 47.7 ± 5.5⁎
Albumin (g/L) ANH 47.1 ± 5.2 39.6 ± 4.3⁎,+ 37.9 ± 5.2⁎,+ 36.6 ± 5.5⁎,+ 38.8 ± 5.4⁎ 42.8 ± 5.7⁎,+
AHH 48.5 ± 3.2 42.7 ± 3.6⁎ 40.3 ± 5.3⁎ 40.1 ± 3.6⁎ 36.2 ± 5.4⁎ 39.8 ± 5.9⁎
Control 47.9 ± 3.4 43.5 ± 3.5⁎ 41.2 ± 4.4⁎ 39.7 ± 3.6⁎ 36.5 ± 4.9⁎ 35.9 ± 5.4⁎
pH ANH 7.41 ± 0.04 7.37 ± 0.05⁎,+ 7.36 ± 0.03⁎,+ 7.37 ± 0.05⁎,+ 7.36 ± 0.04⁎,+ 7.35 ± 0.05⁎,+
AHH 7.40 ± 0.03 7.36 ± 0.04⁎,+ 7.36 ± 0.03⁎,+ 7.35 ± 0.05⁎,+ 7.36 ± 0.03⁎,+ 7.36 ± 0.04⁎,+
Control 7.41 ± 0.05 7.40 ± 0.04 7.40 ± 0.03 7.39 ± 0.04 7.42 ± 0.03 7.41 ± 0.05
K+-plasma (mM) ANH 3.60 ± 0.29 3.20 ± 0.32⁎,+ 3.30 ± 0.28⁎,+ 3.10 ± 0.33⁎,+ 3.20 ± 0.34⁎,+ 3.32 ± 0.35⁎,+
AHH 3.70 ± 0.33 3.40 ± 0.29⁎,+ 3.40 ± 0.27⁎,+ 3.50 ± 0.33⁎,+ 3.30 ± 0.26⁎,+ 3.40 ± 0.31⁎,+
Control 3.70 ± 0.26 3.60 ± 0.31 3.70 ± 0.29 3.60 ± 0.33 3.51 ± 0.35 3.60 ± 0.37
Na+-plasma (mM) ANH 138 ± 2 136 ± 3 136 ± 3 137 ± 2 137 ± 2 136 ± 3
AHH 137 ± 2 138 ± 2 137 ± 3 136 ± 2 136 ± 3 137 ± 2
Control 137 ± 3 138 ± 2 136 ± 3 137 ± 3 137 ± 2 136 ± 3
Ca2+-plasma (mM) ANH 1.24 ± 0.06 1.11 ± 0.04⁎,+ 1.08 ± 0.06⁎,+ 1.13 ± 0.04⁎,+ 1.09 ± 0.04⁎,+ 1.14 ± 0.06⁎,+
AHH 1.29 ± 0.05 1.18 ± 0.05⁎,+ 1.11 ± 0.04⁎,+ 1.13 ± 0.05⁎,+ 1.15 ± 0.07⁎,+ 1.13 ± 0.05⁎,+
Control 1.22 ± 0.04 1.24 ± 0.04 1.20 ± 0.06 1.27 ± 0.05 1.25 ± 0.06 1.20 ± 0.04
⁎ P b 0.05 compared with T1.
+
P b 0.05 compared with control group. ANH, acute normovolemic hemodilution; AHH, acute hypervolemic hemodilution.

and atracurium are all above 70%. Hemodilution can make the free med-
icine concentration to rise. Previous research deems that the plasma
protein binding ratio of Cisatracurium is only 38% [24]. After the hemo-
dilution, the free medicine concentration experiences no remarkable
change. The above theory can partially explain why the effect of muscle
relaxation has not changed remarkably under ANH in the research.
Some reports also hold that hemodilution can reduce the plasma pro-
tein binding ratio of the medicine [25,26], but currently no clear conclu-
sion is available.
Previous research indicates that after ANH and AHH, the concentra-
tion of K+, Ca2+ drops notably. The possible reasons are as follows: the
quick injection of Voluven which does not contain the two ions leads to
dilution hypokalemia and hypocalcium [27]; the stress reaction and
light respiratory alkalosis in hemodilution boost the transfer of K+
into the cells; the expansion effect of colloid increases the amount of
urine and the excretion of K+ and Ca2 + via kidneys [28,29]. The two
ions play an important role in the neuro-muscular transmission. The
rapid change in concentration notably influences the response of the
body to the muscle relaxant [7,8,30].
Cisatracurium and atracurium are a bit different in metabolic path-
way. 60% of the atracurium is hydrolyzed through plasma pseudo-cho-
linesterase. Hemodilution can make the activity of plasma pseudo-
cholinesterase to drop [28], which may be one of the reasons why
ANH makes the muscle relaxation time of atracurium to extend. The
Hofmann elimination of cisatracurium takes up about 80%, esterlysis
only takes up a small fraction and the remaining of about 15% is excret-
ed in prototype via the kidneys [31], showing very complicated
influencing factors. Hofmann degradation of cisatracurium within the
body is the key step and mainly affected by the body temperature and
pH value. Under the acid environment and low temperature, the elimi-
nation slows down and the muscle relaxation time and the recovery
time are extended [13,32]. In the experiment, monitoring the body tem-
perature of the patients has revealed no obvious fluctuation, and there-
fore the impact of body temperature change can be excluded. For
Voluven pH 4.0– 5.5, the pH drops after hemodilution [27]. The research
indicates that under AHH, the onset time of muscle relaxation is extend-
ed, which might be a bit related to the drop of pH. We hold that ANH
and AHH are a kind of special physiological status. Under the same

Fig. 2. Pharmacodynamics indicators in three groups. ⁎P b 0.05 compared with control group; + P b 0.05 compared with low dosage (ANH1, AHH1, Control1); △P b 0.05 compared with
medium dosage (ANH2, AHH2, Control2). TOF, train-of-four.
 J. Guo et al. / Journal of Clinical Anesthesia 38 (2017) 75–80
Fig. 3. Changes of cisatracurium plasma concentration after administration. ⁎P b 0.05 compared with control group; △P b 0.05 compared with medium dosage (ANH2, AHH2, Control2).
physiological status and within the dosage of the research (0.1–
0.3 mg/kg), along with the increase of the dosage of cisatracurium, the
onset time of muscle relaxation are all shortened among the patients,
and the period of no response to TOF, duration of muscle relaxation
blockade and the body time are extended. The drop of plasma concen-
tration is related with the dosage. It keeps consistent with the change
of cisatracurium in the two-compartment model under the normal
physiological status.
In this study, the drop of plasma concentration of cisatracurium after
hemodilution is related to the dosage, while it's more notable in the case
of AHH. It's because after hemodilution the blood viscosity drops, the ef-
ficiency of microcirculation is enhanced [33], the cardiac output in-
creases, which can speed up the blood flow and increase the blood
flow volume in the organs and tissues with rich blood supply [2]. Mean-
while the osmotic pressure of plasma colloid drops and the liquid is
transferred out of the blood vessels, so that the distribution volume is
increased notably, which leads to the extension of onset time. The accel-
eration of blood flow speed and the increase of blood flow volume in the
tissues enable more muscle relaxant to redistribute to neuro-muscular
junctions more rapidly, which is consistent with the notable enhance-
ment of the effect of muscle relaxants such as vecuronium bromide,
rocuronium and atracurium [8–10]. However, some researches also
hold that in the hemodynamics changes of ANH, the most prominent
is the redistribution of circulating blood volume [11], namely, the in-
crease of cardiac output is accompanied by notable increase of blood
flow in coronary artery, liver and kidney artery and vertebral artery.
Therefore, in turn, the blood flow fraction in skeletal muscle drops and
the muscle relaxant flowing to the neuro-muscular junction decreases.
Since the plasma concentration of blood flow in skeletal muscle and
the neuro-muscular junction cannot be measured directly, it needs to
be further studied how the change of plasma concentration of muscle
relaxant at the neuro-muscular junction is.
After AHH, the plasma concentration has dropped notably, which
has resulted from the fact that a large amount of infusion has made
the blood volume to increase notably and the expansion of distribution
volume more remarkable. As a result, the drop of initial concentration is
more notable and the onset time of muscle relaxation is extended. The
blood volume has no obvious change under ANH. Plus the following as
reduction of blood viscosity, the change of the blood flow volume and
speed of skeletal muscle, the electrolytes and pH balancing of plasma
and others, it has no notable variation of the efficacy of cisatracurium.
79
However, how the change of the distribution and elimination of
cisatracurium, and what is the relationship between the pharmacology
and metabolism after hemodilution remain problems needed for fur-
ther research.
In conclusion, the AHH makes the muscle relaxation onset time of
cisatracurium to extend while ANH has not notably changed the efficacy
of cisatracurium. Both methods make the plasma concentration of
cisatracurium to drop. When the patients in general anesthesia under
the AHH status are administrated with cisatracurium and to reach an
ideal effect of muscle relaxation and shorten the onset time, the dosage
should be increased appropriately. In the case of ANH, the dosage need
not be adjusted.
Conflict of interest
The authors declare that they have no conflicts of interest.
References
[1] Nagy CJ, Wheeler AS, Archer TL. Acute normovolemic hemodilution, intraoperative
cell salvage and PulseCO hemodynamic monitoring in a Jehovah's Witness with pla-
centa percreta. Int J Obstet Anesth 2008;17:159–63.
[2] Stehling L, Zauder HL. Acute normovolemic hemodilution. Transfusion 1991;31:
857–68.
[3] Mielke LL, Entholzner EK, Kling M, Breinbauer BE, Burgkart R, Hargasser SR, et al.
Preoperative acute hypervolemic hemodilution with hydroxyethylstarch: an alter-
native to acute normovolemic hemodilution. Anesth Analg 1997;84:26–30.
[4] Entholzner E, Mielke L, Plötz W, Malek A, Kling M, Burgkart R, et al. Hypervolemic
hemodilution as a means of preventing homologous blood transfusion. A simple al-
ternative to acute normovolemic hemodilution. Fortschr Med 1994;11:410–4.
[5] Kumar R, Chakraborty I, Sehgal R. A prospective randomized study comparing two
techniques of preoperative blood conservation isovolemic hemodilution and
hypervolemic hemodilution. Anesth Analg 2002;95:1154–61.
[6] Xue FS, Liu Q, Zou Q, An G, Luo L. Pharmacokinetics of vecuronium during acute
isovolemic hemodilution. Br J Anaesth 1997;79:612–6.
[7] Zheng H, Xuan F, Xuan Y. The effects of acute hypervolemia hemodilution on the
onset time and recovery of vecuronium. Chin J Anesth 2008;28:349–52.
[8] Xue FS, Liu JH, Liao X, Tong SY, Li L, Zhang RJ, et al. The influence of acute
normovolemic hemodilution on the dose-response and time course of action of
vecuronium. Anesth Analg 1998;86:861–6.
[9] Dahaba AA, Perelman SI, Moskowitz DM, Bennett HL, Shander A, Oettl K, et al. Influ-
ence of acute normovola- emic haemodilution on the dose-response relationship,
time-course of action and pharmacokinetics of rocuronium bromide. Br J Anaesth
2006;97:482–8.
[10] Xue FS, Liao X, Liu JH, Zhang YM, An G, Luo LK. Influence of acute normovolaemic he-
modilution on the dose-response and time-course of action of atracurium. Acta
Anaesthesiol Scand 2000;44:163–9.
80 J. Guo et al. / Journal of Clinical Anesthesia 38 (2017) 75–80
[11] Zhang LP, Li DS, Gu ZH. The impact of acute moderate normovolaemic hemodilution
on the dose-effect relationship of pancuronium. Chin J Anaesth 1995;15:355–7.
[12] Niu XH, Tian YK, Chen ZJ, Zhang CW. The effect of acute normovolaemic hemodilu-
tion and autologous blood transfusion on the time-course of pipecuronium. Chin J
Anaesth 2003;23:809–11.
[13] Mellinghoff H, Radbruch L, Diefenbach C, Buzello W. A comparison of cisatracurium
and atracurium: onset of neuromuscular block after bolus injection and recovery
after subsequent infusion. Anesth Analg 1996;83:1072–5.
[14] Jirasiritham S, Tantivitayatan K, Jirasiritham S. A comparison of the efficacy of
cisatracurium and atracurium in kidney transplantation operation. J Med Assoc
Thai 2004;87:73–9.
[15] Melloni C, Devivo P, Launo C, Mastronardi P, Novelli GP, Romano E. Cisatracurium
versus vecuronium:a comparative,double blind,randomized, multicenter study in
adult patients under propofol/fentanyl/N2O anesthesia. Minerva Anestesiol 2006;
72:299–308.
[16] Cross JB. Estimating allowable blood loss corrected for dilution. Anesthesiology
1983;58:227–80.
[17] Farenc C, Audran M, Lefrant JY, Mazerm I, Bressolle F. High-performance liquid chro-
matographic method for the determination of atracurium and laudanosine in
human plasma application to pharmacokinetics. J Chromatogr B Biomed Sci Appl
1999;724:117–26.
[18] Licker M, Ellenberger C, Sierra J, Christenson J, Diaper J, Morel D. Cardiovascular re-
sponse to acute normovolemic hemodilution in patients with coronary artery dis-
eases: assessment with transesophageal echocardiography. Crit Care Med 2005;
33:591–7.
[19] Habler O. Clinical fluid therapy in the perioperative setting. Camridge University
Press; 2011 184–8.
[20] Chen G, Yan M, Lu QH, Gong M. Effects of two different hydroxyethyl starch solu-
tions (HES200/0.5 vs.HES130/0.4) on the expression of platelet membrane glyco-
protein. Acta Anaesthesiol Scand 2006;50:1089–94.
[21] Woessner R, Grauer MT, Dieterich HJ, Bepperling F, Baus D, Kahles T, et al. Influence
of a long-term, high-dose volume therapy with 6% hydroxyethyl starch 130/0.4 or
crystalloid solution on hemodynamics, rheology and hemostasis in patients with
acute ischemic stroke. Pathophysiol Haemost Thromb 2003;33:121–6.
[22] Kikuchi K, Konishi A, Terashima M. Hemodynamics during hypervolemic hemodilu-
tion (HH) technique. Masui 1994;43:1701–8.
[23] Mets B. The pharmacokinetics of anesthetic drugs and adjuvants during cardiopul-
monary bypass. Acta Anasethesiol Scand 2000;44:261–73.
[24] Roy JJ, Varin F. Physicochemical properties of neuromuscular blocking agents and
their impact on the pharmacokinetic pharmacodynamic relationship. Br J Anaesth
2004;93:241–8.
[25] Gravenstein D, Suri A, Derendorf HC, Koska AJ. Influence of plasma expansion on
plasma protein binding of ketorolac-analgesia and bleeding. J Clin Anesth 1998;
10:464–8.
[26] Dulvadestin P, Gilton A, Hernigou P, Marty J. The onset time of atracurium is
prolonged in patients with sickle cell disease. Anesth Analg 2008;107:113–6.
[27] Jamnicki M, Zollinger A, Seifert B, Popovic D, Pasch T, Spahn DR. Compromised blood
coagulation: an in vitro comparison of hydroxyethyl starch 130/0.4 and
hydroxyethyl starch 200/0.5 using thrombelastography. Anesth Analg 1998;87:
989–93.
[28] Shrewsbury RP, Hong DD, White LG, Gordon TR. The effect of moderate
haemodilution with Fluosol-DA or Hespan on the nonmicrosomal acetylation of
sulphadimidine in the rat. J Pharm Pharmacol 1992;44:84–8.
[29] Vaughan RS. Potassium in the perioperative period. Br J Anaesth 1991;67:194–200.
[30] Hainaut K, Desmed JE. Effect of dantrolene sodium on calcium movements in single
muscle fibres. Nature 1974;252:728–30.
[31] Imbeault K, Withinqton DE, Varin F. Pharmacokinetics and pharmacodynamics of a
0.1 mg/kg dose of cisatracurium besylate in children during N2O/O2/propofol anes-
thesia. Anesth Analg 2006;102:738–43.
[32] Dahaba AA, Wang G, Xu X, Liu X, Wu X, Bornemann H, et al. Influence of acute
normovolaemic haemodilution on the dose-response relationship and time course
of action of cisatracurium besylate. Br J Anaesth 2007;98:3–6.
[33] Habler OP, Kleen DR. Regional ischemia during hemodilution in flow compromised
myocardium: evidence for incomplete metabolic recovery. Card Surg 1994;9:442–8.