Efficacy and safety of different doses of ropivacaine for laparoscopy-assisted infiltration analgesia in patients undergoing laparoscopic cholecystectomy: A prospective randomized control trial

Abstract

Background:
Wound infiltration analgesia provides effective postoperative pain control in patients undergoing laparoscopic cholecystectomy (LC). However, the efficacy and safety of wound infiltration with different doses of ropivacaine is not well defined. This study investigated the analgesic effects and pharmacokinetic profile of varying concentrations of ropivacaine at port sites under laparoscopy assistance.

Methods:
In this randomized, double-blinded study, 132 patients were assigned to 4 groups: Group H: in which patients were infiltrated with 0.75% ropivacaine; Group M: 0.5% ropivacaine; Group L: 0.2% ropivacaine; and Group C: 0.9% normal saline only. The primary outcome was pain intensity estimated using numeric rating scale (NRS) at discharging from PACU and at 4 hours, 6 hours, 8 hours, and 24 hours after infiltration. Secondary outcomes included plasma concentrations of ropivacaine at 30 minutes after wound infiltration, rescue analgesia requirements after surgery, perioperative vital signs changes, and side effects.

Results:
The NRS in Group C was significantly higher at rest, and when coughing upon leaving PACU and at 4 hours, 6 hours, 8 hours, and 24 hours after infiltration (P < .05) and rescue analgesic consumption was significantly higher. Notably, these parameters were not significantly different between Groups H, Group M and Group L (P > .05). Intra-operative consumption of sevoflurane and remifentanil, HR at skin incision and MAP at skin incision, as well as 5 minutes after skin incision were significantly higher in Group C than in the other 3 groups (P < .01). In contrast, these parameters were not significantly different between Groups H, Group M and Group L (P > .05). The concentration of ropivacaine at 30 minutes after infiltration in Group H was significantly higher than that of Group L and Group M (P < .05). No significant differences were observed in the occurrence of side effects among the 4 groups (P > .05).

Conclusions:
Laparoscopy-assisted wound infiltration with ropivacaine successfully decreases pain intensity in patients undergoing LC regardless of the doses used. Infiltration with higher doses results in higher plasma concentrations, but below the systematic toxicity threshold.

Full text

Efficacy and safety of different doses of
ropivacaine for laparoscopy-assisted infiltration
analgesia in patients undergoing laparoscopic
cholecystectomy
A prospective randomized control trial
Min Liang, MD
a,b
, Yijiao Chen, MM
a
, Wenchao Zhu, MM
b
, Dachun Zhou, MM
a,∗
Abstract
Background: Wound infiltration analgesia provides effective postoperative pain control in patients undergoing laparoscopic
cholecystectomy (LC). However, the efficacy and safety of wound infiltration with different doses of ropivacaine is not well defined.
This study investigated the analgesic effects and pharmacokinetic profile of varying concentrations of ropivacaine at port sites under
laparoscopy assistance.
Methods: In this randomized, double-blinded study, 132 patients were assigned to 4 groups: Group H: in which patients were
infiltrated with 0.75% ropivacaine; Group M: 0.5% ropivacaine; Group L: 0.2% ropivacaine; and Group C: 0.9% normal saline only.
The primary outcome was pain intensity estimated using numeric rating scale (NRS) at discharging from PACU and at 4 hours, 6
hours, 8 hours, and 24 hours after infiltration. Secondary outcomes included plasma concentrations of ropivacaine at 30 minutes after
wound infiltration, rescue analgesia requirements after surgery, perioperative vital signs changes, and side effects.
Results: The NRS in Group C was significantly higher at rest, and when coughing upon leaving PACU and at 4 hours, 6 hours, 8
hours, and 24 hours after infiltration (P<.05) and rescue analgesic consumption was significantly higher. Notably, these parameters
were not significantly different between Groups H, Group M and Group L (P>.05). Intra-operative consumption of sevoflurane and
remifentanil, HR at skin incision and MAP at skin incision, as well as 5 minutes after skin incision were significantly higher in Group C
than in the other 3 groups (P<.01). In contrast, these parameters were not significantly different between Groups H, Group M and
Group L (P>.05). The concentration of ropivacaine at 30 minutes after infiltration in Group H was significantly higher than that of
Group L and Group M (P<.05). No significant differences were observed in the occurrence of side effects among the 4 groups
(P>.05).
Conclusions: Laparoscopy-assisted wound infiltration with ropivacaine successfully decreases pain intensity in patients
undergoing LC regardless of the doses used. Infiltration with higher doses results in higher plasma concentrations, but below the
systematic toxicity threshold.
Abbreviations: ERAS =enhance recovery after surgery, HR =heart rate, LC =Laparoscopic cholecystectomy, MAP =mean
arterial pressure, NRS =numerical rating scale, PONV =postoperative nausea and vomiting, TAP =transversus abdominis plane
block.
Keywords: laparoscopic cholecystectomy, local infiltration, ropivacaine, systematic concentration
Editor: Joho Tokumine.
The authors have no conflicts of interests to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
a
Department of Anesthesia, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou,
b
Department of Anesthesia, Liaocheng People’s Hospital,
Liaocheng, PR China.
∗
Correspondence: DaChun Zhou, Department of Anesthesia, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, PR China
(e-mail: 3192028@zju.edu.cn).
Copyright ©2020 the Author(s). Published by Wolters Kluwer Health, Inc.
This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to
download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal.
How to cite this article: Liang M, Chen Y, Zhu W, Zhou D. Efficacy and safety of different doses of ropivacaine for laparoscopy-assisted infiltration analgesia in patients
undergoing laparoscopic cholecystectomy: a prospective randomized control trial. Medicine 2020;99:46(e22540).
Received: 14 April 2020 / Received in final form: 31 July 2020 / Accepted: 3 September 2020
http://dx.doi.org/10.1097/MD.0000000000022540
Clinical Trial/Experimental Study Medicine®
OPEN
1

1. Introduction
Laparoscopic cholecystectomy (LC) is the mainstay approach for
the treatment of cholelithiasis. This is because it is considered to
be minimally invasive and accelerates recovery.
[1]
However, this
approach is associated with high post-operative pain intensity,
especially in the early period.
[2,3]
Effective pain control is crucial
for enhancing recovery after surgery (ERAS).
[4,5]
Studies have
shown that traditional pain management using opioids often lead
to side effects, such as postoperative nausea, vomiting (PONV),
and respiratory depression.
[6]
Previous studies have shown that multimodal analgesic
strategies with local infiltration not only provide strong analgesic
effects but also reduce incidence of opioid-related side effects,
resulting in faster recovery and shorter hospital stay.
[7–9]
Several
clinical studies have shown that local infiltration with ropiva-
caine effectively control postoperative pain and thus has been
widely adopted in recent years.
Ropivacaine at 0.75%, 0.5%, or 0.2% doses have been applied
for postoperative pain management, but no study has compared
the analgesic effects of different doses of ropivacaine in LC.
[10–12]
Until now, no pharmacokinetic data of wound infiltration with
ropivacaine has been described in LC, using different concen-
trations. Although local anesthetics are associated with few toxic
effects, the consequences of higher concentration of ropivacaine
could be lethal.
This study investigated the analgesic effects of different
concentrations of ropivacaine for laparoscopy-assisted infiltration
at port sites in patients undergoing laparoscopic cholecystectomy.
Furthermore, we analyzed the peak systemic plasma concen-
trations of ropivacaine to assess the safety profile of this drug.
2. Materials and methods
2.1. Patients
We recruited a total of 132 patients pre-operatively from Jan 2018 to
Feb 2019. This study was approved by the Institutional Ethics Board
of Sir Run Run Shaw Hospital, and written informed consent was
obtained from all patients. All patients scheduled for elective LC
were included. The inclusion criteria were: the American Society of
Anesthesiology physical status of I or II; patients aged 18 to 70 years;
a body mass index (BMI) not exceeding 30. The exclusion criteria
were: patients with known allergy to local anesthetics; patients with
history of chronic pain following use of current opioids; patients
with history of acute cholecystitis within 2 weeks prior to surgery; or
those who converted to open abdomen cholecystectomy. Before
surgery, all patients were trained to use a numerical rating scale
(NRS), in which 0 denoted no pain, while 10 represented the worst
imaginable pain. This trial was registered at chictr.org (ChiCTR-
TRC-14004193).
2.2. Randomization and blinding
After obtaining informed written consent, a randomization table
was generated by computer and was used to equally allocate the
patients to 4 separate groups: (Group H, Group M, Group L, and
Group C) in a 1:1:1:1 ratio by an independent anesthesiologist
before surgery. Prior to surgery, a nurse blinded to the grouping
prepared 20 ml of the experimental drug in the pre-anesthesia
room as follows; 0.75% ropivacaine in Group H, 0.5%
ropivacaine in Group M, 0.2% ropivacaine in Group L, and
0.9% normal saline in Group C. Results from the randomization
were kept in a sealed envelope and relayed to 1 of the nurses who
made preparations of the surgical procedure. The remaining
members of the clinical team, including the chief anesthesiologist,
were blinded to the group allocations.
2.3. Anesthesia protocol
A peripheral venous access was established prior to induction of
anesthesia, and none of the patients received pre-medication before
the induction. Standard monitoring included a five-lead electro-
cardiogram, non-invasive blood pressure, and pulse oxygen
saturation using a multi-functional monitor (GE DATEX-
OHMEDA S/5). All the patients who participated in the study
were anesthetized with propofol (2.0–3.0mg/kg), fentanyl (3mg/
kg), and cisatracurium (0.15mg/kg) according to standardized
general anesthesia guidelines set by the institute. General
anesthesia was maintained using sevoflurane, inspired at 1.5%
to 3.0%, and intravenous infusion of remifentanil, at a dose of
0.1mg/kg/hour. An additional dose of cisatracurium (0.03mg/kg)
was administrated every hour from induction up to 1 hour before
the end of the surgery. As anesthesia depth monitoring was not
available, sevoflurane concentration was adjusted according to the
anesthesiologists judgment for example, hemodynamic responseto
surgical stimulations, but narcotic doseswere not adjusted to avoid
impact on study results. After induction of general anesthesia,
patients in Group H, M,and L received wound infiltration 20ml of
0.75%, 0.5%, and 0.2% ropivacaine (Naropin; AstraZeneca,
London, UK), respectively while patients in Group C received 20
ml of 0.9% normal saline. The four-port technique was then used
to perform laparoscopic surgery. Briefly, the epigastric port site
was infiltrated using the blind method before CO
2
pneumo-
peritoneum was established. The remaining port site infiltrations
were implemented under the laparoscopy view to ensure good
distribution of local anesthesia to the subcutis, fascia and
peritoneum. The epigastric port and umbilical port toke 7ml
each, while the 2 smaller working ports toke 3ml each. Blood
samples were taken 30minutes after infiltration to analyze
ropivacaine concentration.
2.4. Surgery
All surgeries were performed by consultant surgeons proficient in
LC. The standard 4-trocar technique was used for all procedures,
with pneumoperitoneum pressure set to 12 mm Hg. After
removal of the gallbladder and completion of the surgery, we
carefully deflated the residual carbon dioxide.
2.5. Analgesia
Parecoxib 40 mg was administered at the end of the procedure
and all patients spent a night in the hospital. Pain intensity was
assessed using NRS. In cases where patients experienced
significant post-operative pain (NRS ≥4), we administered
rescue analgesics, either using intravenous 2.5 mg morphine for
PACU patients, or tramadol 100 mg P.O. for those in the ward.
Analgesics were administered repeatedly in cases where NRS
remained higher than 4.
2.6. Analysis of primary outcomes
Pain intensity at rest and coughing were recorded upon leaving
PACU and at 4 hours, 6 hours, 8hours, and 24 hours after
Liang et al. Medicine (2020) 99:46 Medicine
2

infiltration. This information was considered the primary
outcome and was conducted by a blinded investigator.
2.7. Analysis of secondary outcomes
Secondary outcomes comprised plasma concentration of ropi-
vacaine at 30 minutes after wound infiltration and was deter-
mined via high performance liquid chromatography-mass
spectrometry (HPLC-MS) performed at the Pharmacology
Laboratory of the Second Affiliated Hospital of Zhejiang
University School of Medicine. We recorded and compared
heart beats (HR) and mean arterial pressure (MAP) before
endotracheal intubation (T0), at endotracheal intubation (T1), at
skin incision (T2), at 5 minutes after skin incision (T3), at 10
minutes after skin incision (T4), at 15 minutes after skin
incision (T5) and 20 minutes after skin incision (T6). The
frequency at which rescue analgesics were used in the PACU and
ward were compared. In addition, we recorded and compared
incidences of sufentanil-associated adverse effects, including
PONV, pruritus, respiratory depression, and dizziness. Further-
more, any signs of local anesthetic toxicity such as prolonged Q-T
interval, arrhythmia, muscle tremors, or convulsions were
recorded.
2.8. Statistical analysis
Sample size was determined from a power calculation. The
calculation showed that 26 subjects per group were required to
achieve 80% power to detect a 20% difference in plasma
concentration of ropivacaine, assuming a significance level of
0.05. Taking into consideration of a possible dropout rate of
20%, we enrolled 33 subjects for each group. This allowed a final
data analysis to be performed. Therefore, 132 subjects were
recruited to ensure adequate data collection.
Distribution of variables was assessed using the Kolmogorov-
Smirnov test, while homogeneity of variance was evaluated using
Levenes tests. Quantitative data were expressed as mean ±
standard deviations, or medians and inter-quartile ranges. We
employed analysis of variance (ANOVA) to compare consistent
data, while SNK and LSD methods were used to compare groups.
A nonparametric test was used to compare inconsistent data,
Kruskal–Wallis H method for overall comparison, and Mann–
Whitney Umethod to compare groups. Categorical data were
expressed as frequencies and percentages, and were analyzed by
Chi-Squared or Fishers exact tests where appropriate. Value with
P<.05 were considered statistically significant. All statistical
analyses were carried out using SPSS for Windows version 17.0
(SPSS Inc. Chicago, IL, USA).
3. Results
3.1. Baseline characteristics
A summary of patient characteristics is shown in Figure 1. A total
of 132 subjects were recruited, 12 of which did not complete the
study due to either change of surgery method or surgical
cancelation. Consequently, only data from the remaining 120
subjects were analyzed in this study. There was no significant
difference in the demographic parameters among the 4 groups
(Table 1).
3.2. Port infiltration reduced pain intensity
NRS values for subjects in Group C were significantly higher at
rest (P=.000) and when coughing (P=.000) upon leaving PACU
and at 4hours, 6hours, 8hours, and 24hours after infiltration
compared to those in Group H, M, and L (Fig. 2). However, these
parameters were not significantly different among Groups H, M,
Figure 1. Aflow chart showing patients inclusion and exclusion procedure.
Liang et al. Medicine (2020) 99:46 www.md-journal.com
3

and L at rest or when coughing upon leaving PACU (P=.685,
P=.382) and at 4hours (P=.152,P=.957), 6 hours (P=.924,
P=.822), 8 hours (P=.150,P=.314), and 24hours (P=1.171,
P=.245) after infiltration (Fig. 2).
3.3. Anesthetic agents and intraoperative medications
Consumption of sevoflurane and remifentanil in Group C were
significantly higher (P=.002,P=.000) than in the other 3
groups, but no significant difference was observed among Groups
H, M and L (P=.634,P=.245). Similarly, no significant
differences were recorded in intra-operative medication among
the 4 groups (Table 2).
3.4. HR and MAP at T0 to T6
The HR at T2 in Group C was significantly higher (P=.000) than
in the other 3 groups (Fig. 3), while HR at T2 was not
significantly different among Groups H, M, and L (P=.61)
(Fig. 3). In addition, we found significantly higher (P=.000,
P=.000) MAP at T2 and T3 in Group C compared to the other 3
groups (Fig. 3), but no significant differences were obtained in
MAP at T2 and T3 among Groups H, M, and L (P=.376,
P=.766) (Fig. 3).
3.5. Plasma concentration of ropivacaine
The plasma concentration of ropivacaine at 30 minutes after
wound infiltration in Group H and M were significantly higher
(P <.05) than that in Group L (Fig. 4). On the other hand, the
difference in plasma concentrations of ropivacaine between
Groups H and M were not significant (P=.100) (Fig. 4).
3.6. Rescue analgesic requirements and side-effects
The frequency of analgesic use in Group C was significantly
higher (P=.016,P=.005) than the other 3 groups, while no
significant difference was recorded among Groups H, M, and L
(P=.866,P=.749) (Table 3). With regard to side-effects, there
was no significant difference in the incidence of post-operative
nausea and vomiting (P=.180,P=.644) (Table 4) at 24hours
among the 4 groups. A similar trend was observed for pruritus
(P=.288) (Table 4). In addition, none of the subjects experienced
respiratory depression or convulsions (Table 4), and there were
no signs of local anesthetic toxicity such as prolonged Q-T
interval, arrhythmia, muscle tremors, or convulsions.
4. Discussion
This study compared the analgesic effect, as well as the safety
profile of laparoscopy-assisted wound infiltration with different
concentrations of ropivacaine in patients undergoing LC. A key
finding of this trial is that infiltration with 0.75%, 0.5%, and
0.2% ropivacaine provides equally strong analgesic effects. This
is the first clinical study revealed that high concentration of
ropivacaine is not necessary for infiltration and dilution is
preferred when larger volume is needed.
Pain after LC emerge from:
Figure 2. Pain score (NRS) at rest (A), and accompanied with coughing (B)
upon leaving PACU and at 4 hours, 6 hours, 8 hours, and 24 hours after
infiltration in the 4 groups. ^P<.05 vs Group C,
∗
P<.05 vs Group C,
#
P<.05
vs Group C.
Table 1
Demographic and perioperative data.
Variable Group H (n =30) Group M (n =30) Group L (n =30) Group C (n =30) Pvalue
Age, yr 49.5 ±12.1 50.0 ±13.0 47.2±13.9 51.5±12.8 .638
Sex, (male/female) 10/20 13/17 12/18 8/22 .544
BMI, kg/m
2
23.6 ±2.7 23.4 ±3.0 22.6±2.8 23.5±2.8 .505
ASA, (I/II) 14/16 12/18 17/13 15/15 .629
Blood loss, ml 20.3 ±5.0 23.2 ±7.3 21.1 ±6.3 23.5 ±5.3 .122
Length of surgery, min 33.2 ±9.3 32.5 ±8.5 33.5 ±8.2 33.4 ±6.4 .969
Fluid infusion, ml 371.7 ±118.7 360.0 ±96.8 355.0±120.6 385.0±115.3 .741
Urine, ml 183.3 ±86.4 161.3 ±78.8 176.7±83.6 141.3±77.8 .202
Data are presented as mean ±standard deviation or number of patients (%).
ASA =American Society of Anesthesiology, BMI =body mass index.
Liang et al. Medicine (2020) 99:46 Medicine
4

1. incision sites;
2. referred pain attributed to pneumoperitoneum; and
3. wounds intrinsic to the liver after gallbladder removal.
[13,14]
The largest component (ranging between 50% and 70%) of
this pain is attributed to incision sites.
[15,16]
Mild to moderate
incisional pain exacerbates during episodes of coughing and
movement, although this gradually fades over time. However,
acute pain without effective control is likely to become chronic,
and negatively influence a patients quality of life.
[17]
Currently, given the recent advances in ultrasound, transversus
abdominis plane block (TAP) has been extensively applied in pain
management following LC.
[18–20]
However, only a handful of
studies have demonstrated that TAP provides comparable
analgesia effect with local anesthetic infiltration.
[21,22]
Wound
infiltration with local anesthetics, is a simple, feasible, and
financially considerate option, and is performed in multiple types
of surgery, generating satisfactory analgesia without major side
effects. Some studies have reported that local infiltration using
0.75%, 0.5%, or 0.25% ropivacaine effectively alleviates
postoperative pain.
[7,23–28]
Our findings are consistent with
these reports. Thierry et al demonstrated that 100 mg of
intraperitoneal ropivacaine (0.25%) provided similar analgesia
with 300mg of ropivacaine (0.75%).
[28]
However, the surgical
wound in this study had not been infiltrated with ropivacaine,
and the recommended does (100 mg of ropivacaine) in this study
is significantly higher than in our study. Meanwhile, other studies
have demonstrated that higher doses of ropivacaine yield better
and longer lasting analgesic effects compared to lower concen-
trations.
[29,30]
Explanations for these contradictory results
include: First, The pain intensity after LC is mild to moderate,
and the analgesic effect mainly depends on volume of local
anesthetics rather than the concentration since it is to block the
thin nerve endings. Second, traditional wound infiltration
approaches with blind methods may lead to incomplete
infiltration and thus suboptimal analgesia.
[24]
To ensure complete
infiltration, we used laparoscopy-assisted wound infiltration with
a large volume of ropivacaine. Third, our observation period was
24hours, which may not be adequate to fully reveal differences
between analgesic durations of ropivacaine with different
concentrations. Finally, local infiltration, prior to incision,
adopted in our study could have reduced central sensitization
Figure 4. Plasma concentration of ropivacaine at 30 minutes after wound
infiltration with different concentrations of ropivacaine in the 3 groups.
∗
P<.05
vs Group L.
Table 2
Anesthetic agents and intraoperative medication.
Variable Group H (n =30) Group M (n =30) Group L (n =30) Group C (n =30) Pvalue
Propofol, mg 127.2 ±20.8 124.2 ±20.5 119.0±19.4 124.2±21.3 .486
Fentanyl, mg 0.2 ±0.04 0.2 ±0.04 0.2 ±0.04 0.2 ±0.05 .978
Cisatracurium, mg 11.9 ±1.7 11.8 ±1.8 11.4 ±2.1 11.8 ±2.0 .762
Sevoflurane, n(%) 2.0±0.5
^^
2.1 ±0.5
∗∗
2.2 ±0.6
##
2.5 ±0.3 .002
Remifentanil, mg 0.18 ±0.04
^^
0.18 ±0.03
∗∗
0.20 ±0.02
##
0.22 ±0.03 .000
Atropine, n(%) 6 (20%) 5 (16.7%) 6 (20%) 7 (23.3%) .937
Ephedrine, n(%) 2 (6.7%) 4 (13.3%) 3 (10%) 6 (20%) .446
Data are presented as mean ±standard deviation or number of patients (%).
Figure 3. Heart rate (A), and mean arterial pressure (B) before endotracheal
intubation (T0), at endotracheal intubation (T1), at skin incision (T2), at 5 minutes
after skin incision (T3), at 10 minutes after skin incison (T4), at 15 minutes after
skin incision (T5) and 20 minutes after skin incision (T6) in the 4 groups.
∗∗
P<.01 vs Group C,
^^
P<.01 vs Group C,
##
P<.01 vs Group C.
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5

and pain intensity accordingly. Thus, the analgesic differences in
ropivacaine action, between different concentrations, might be
reduced. The reason why NRS remain different between Group C
and the other 3 groups at 24 hours was beyond the study.
The consumption of sevoflurane and remifentanil in Group C
were significantly more than in other 3 groups, while differences
among Groups H, M, and L were not significant. Meanwhile, the
HR at skin incision in Group C was significantly higher than in
the other 3 groups, while MAP at skin incision as well as 5
minutes after skin incision were significantly higher than in the
other 3 groups. In contrast, differences among the Groups H, M,
and L were not significant, confirming our conclusion that
laparoscopy-assisted wound infiltration with 0.2%, 0.5%, or
0.75% of ropivacaine decreased pain intensity to the same extent.
Local anesthetics used at the incision site trigger analgesia by
blocking peripheral afferents thereby inhibiting transmission of
noxious impulses to the spinal dorsal horn neurons.
[31,32]
Moreover, local anesthetics inhibit local inflammatory reaction
as well as hyperalgesia at the incision site.
[33]
Ropivacaine and
bupivacaine are long-acting local anesthetics that are widely used
worldwide as local anesthesia for postoperative pain manage-
ment. Ropivacaine has equal analgesic effects to bupivacaine but
results in fewer side effects, such as motor block, toxicity to
central nervous and cardiovascular system.
[34,35]
Thus, ropiva-
caine appears to be the most preferred local and postoperative
analgesic drug. Previously, ropivacaine at a concentration of
0.75% was found to be safe for infiltration, and its peak plasma
concentration was reported to be within safety limits. However,
the side effects of using high ropivacaine concentrations remain
unknown.
[36]
When compared to bupivacaine, ropivacaine is safer and has
higher systemic toxicity threshold. However, it is not risk-free.
For this reason, a single infiltration dose, not exceeding 200 mg is
recommended. Studies have found that blood concentration of
ropivacaine peaked 30 to 45minutes after infiltration, and the
threshold was 3.4 mg/ml when central toxic reactions oc-
curred.
[36,37]
Under general anesthesia, symptoms of systemic
toxicity of the central nervous system, such as dizziness, muscle
tremors, and convulsions may be concealed. However, higher
blood concentrations of ropivacaine may trigger cardiovascular
toxicity, causing circulatory collapse and even cardiac arrest.
In this study, plasma concentration of ropivacaine at 30
minutes after wound infiltration was significantly lower in Group
L compared to H and M. However, the difference between Group
H and Group M was not significant. The highest concentration of
ropivacaine (2.49 mg/ml) was detected in Group H, which may
have been caused by excessive absorption of ropivacaine.
Although none of the patients showed symptoms toxicity due
to local anesthesia, the necessity to use high concentration of
ropivacaine was not required. To ensure safety, we recommend
dilution of ropivacaine when a large volume is needed.
Nausea and vomiting are common complaints in patients
under anesthesia, which come from several factors.
[38]
Previous
studies show that wound infiltration can reduce consumption of
opioids as well as the associated side effects in traditional opioid-
based analgesia strategy. Notably, incidence of PONV, pruritus
and respiratory depression was not significantly different among
the 4 groups, although more morphine and tramadol were
consumed in Group C relative to other groups. This can be
attributed to the small sample size in the study.
The current study contains some limitations. First, the
observation period was too short to reveal potential differences
between analgesic durations under different ropivacaine doses.
Second, frequent blood samples collection after surgery will make
patients feel bored and increase complaints. Therefore, we only
observed the systematic blood concentration of ropivacaine at 1
time point, and could not assess the relationship between dosage
and blood concentration. Third, the depth of anesthesia
monitoring was not used in this study, which may affect the
results of the study. Finally, we did not consider other factors
affecting pain intensity, such as age, gender, and education status.
In conclusion, laparoscopy-assisted wound infiltration with
0.2%, 0.5%, or 0.75% ropivacaine provide equally effective pain
control in patients undergoing LC. Furthermore, higher peak
plasma concentration was recorded when ropivacaine was
infiltrated at high dose, and the peak levels did not exceed the
threshold of central toxicity. Future studies should explore the
optimal duration for different doses of ropivacaine wound
Table 3
Rescue analgesia.
Variable Group H (n =30) Group M (n =30) Group L (n =30) Group C (n =30) Pvalue
PACU, n(%) 11 (36.7%)
∗
12 (40%)
†
10 (33.3%)
‡
21 (70%) .016
WARD, n(%) 4 (13.3%)
∗
3 (10%)
†
5 (16.7%)
‡
13 (43.3%) .005
Data are presented as mean ±standard deviation or number of patients (%).
∗
P<.05 vs Group C.
†
P<.05 vs Group C.
‡
P<.05 vs Group C.
Table 4
Side effects.
Variable Group H (n =30) Group M (n =30) Group L (n =30) Group C (n =30) Pvalue
Nausea, n(%) 4 (13.3%) 9 (30%) 7 (23.3%) 3 (10%) .180
Vomiting, n(%) 1 (3.3%) 3 (10%) 1 (3.3%) 2 (6.7%) .644
Pruritus, n(%) 0 (0) 1 (3.3%) 0 (0) 2 (6.7%) .288
Respiratory depression, n(%) 0 (0) 0 (0) 0 (0) 0 (0) 1.000
Data are presented as number of patients (%).
Liang et al. Medicine (2020) 99:46 Medicine
6

infiltration in LC, as well as the relationship between dosage and
plasma concentration.
Author contributions
Min Liang, Dachun Zhou conceived and designed the trail. Yijiao
Chen, Wenchao Zhu collected the data. Min Liang analyzed the
data. Min Liang, Yijiao Chen and Wenchao Zhu wrote this
paper.
Conceptualization: Min Liang, Dachun Zhou.
Data curation: Min Liang, Yijiao Chen and Wenchao Zhu.
Methodology: Min Liang, Dachun Zhou.
Project administration: Dachun Zhou.
Software: Min Liang, Wenchao Zhu.
Writing –original draft: Min Liang, Yijiao Chen.
Writing –review & editing: Min Liang, Dachun Zhou.
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