Antishivering Effect of Low Dose Meperidine in Caesarean Section under Spinal Anesthesia: A Randomized Double-blind Placebo-controlled Trial
Abdolreza Sotoodeh Jahromi,
Mohammad Yasin Karami
Mohamed Amin Ghobadifar
Shivering related to spinal anesthesia is a usual complication.
This study was designed to evaluate the anti-shivering effect of small intrathecal
dose of meperidine on the incidence and intensity of shivering in parturient
with caesarean section under spinal anesthesia. Seventy parturient, American
Society of Anesthesiologists (ASA) physical status I to II, scheduled for elective
caesarean section under spinal anesthesia were enrolled in two groups. The parturient
were randomized to receive 10 mg bupivacaine 0.5% and 10 mg meperidine (group
BM, n = 35) or placebo (10 mg bupivacaine 0.5% and normal saline, group B, n
= 35) 3 min after spinal puncture. Demographic values, surgery data, adverse
events and the mean intensity for each parturient were assessed during the whole
time of study period by a blinded observer. The incidence of shivering during
the whole time of the study period was significantly decreased in the group
of parturient who received intrathecal meperidine (p<0.001). There were no
significant differences in the other measured variables. These findings indicate
that using single-shot, mini-dose intrathecal Meperidine (10 mg) reduces the
severity and intensity of intra- and post-operative shivering in caesarean section
under spinal anesthesia without increasing adverse events.
to cite this article:
Hassan Zabetian, Abdolreza Sotoodeh Jahromi, Mohammad Yasin Karami and Mohamed Amin Ghobadifar, 2013. Antishivering Effect of Low Dose Meperidine in Caesarean Section under Spinal Anesthesia: A Randomized Double-blind Placebo-controlled Trial. International Journal of Pharmacology, 9: 305-311.
Received: July 29, 2013;
Accepted: January 02, 2014;
Published: February 04, 2014
Shivering occurs in response to sympatholysis, vasodilatation and increased
heat loss. Shivering related to spinal anesthesia is a usual complication and
reason of this unusual muscular activity is still unknown (Crowley
and Buggy, 2008). The incidence range of shivering was variable from 36-55%
in different studies (Chun et al., 2010; Locks,
2012; Khaw et al., 2006). Intraoperative
shivering is inhibited during general anesthesia; accordingly they are more
prone to hypothermia and post-operative shivering. Hence, there are two important
elements to regional anesthesia-induced shivering: (1) The desired effect of
shivering and (2) The unwanted effects of shivering (Bhukal
et al., 2011). Shivering increases cardiac output and causes tachycardia,
also hypothermia-induced shivering causes hypoxemia and increases total body
oxygen consumption. Those effects are bothersome in mothers and her fetus during
delivery (Locks, 2012). Due to the spinal anesthesia
advantages including rapid onset, minimal fetal and maternal drug exposure and
high success rate it is a popular technique for cesarean section (Khaw
et al., 2006). Shivering related to spinal and epidural anesthesia
is distressing for parturient that it may cause cardiovascular and metabolic
disturbance. There is little known about the best way of prevention of shivering
during spinal anesthesia (Crossley, 1992).
There are many drugs that have been used to treat per anesthetic shivering,
including meperidine, ketanserin, doxapram and clonidine and many studies have
showed that meperidine is extremely more effective in treating shivering than
others (Kranke et al., 2002, 2004).
Combined spinal-epidural block is more sufficient than epidural block because
its efficacy and fewer side effects (Karaman et al.,
2005). Meperidin is an opioid drug with known anti-shivering effect but
with their dose-dependant property adverse events such as hemodynamic effects,
nausea and vomiting. The antishivering effect of meperidine is referred to its
role in reducing the shivering threshold owing to its effect on kappa opioid
receptor and on α2b adrenoreceptor subtype (Khan
et al., 2011).
During last decade, some studies reported positive effects of different doses
of intrathecal meperidine during spinal anesthesia on reducing severity and
incidence of perioperative shivering (Fukuda, 2005; Casey
et al., 1988; Chen et al., 1993).
Intra venous meperidine widely is used for treatment shivering intraoperative
(during the caesarean section) and post operative (in recovery room) but it
could be associated with side effects. Alternatively, high dose using of intrathecal
meperidine may have similar side effects such as nausea, vomiting, respiratory
distress and pruritus. Adding meperidine to the intrathecal hyperbaric bupivacaine
fusion during spinal anesthesia reduces the incidence and severity of shivering
that was done on obstetrical populations undergoing caesarean delivery (Roy
et al., 2004; Hong and Lee, 2005).
Different doses of intrathecal meperidine have been used to prevent shivering
during spinal anesthesia (Khan et al., 2011;
Chen et al., 1993; Roy
et al., 2004; Hong and Lee, 2005; Kararmaz
et al., 2003). There is controversy between different studies in
concerning the best dose of meperidine for prevention of shivering. Using single-shot
intrathecal meperidine may be useful for reducing intra- and post-operative
shivering of parturient and it may be associated with fewer side effects. The
preventive effect of a low dose of intrathecal meperidine (10 mg) on shivering
has never been studied. The present study is performed to determine that single-shot,
mini-dose intrathecal meperidine is effective in reducing the incidence and
intensity of perioperative shivering in women with cesarean section.
MATERIALS AND METHODS
Patients: This was a randomized double-blind placebo-controlled trial study being performed in Peymaniyeh and Motahari Hospitals, two healthcare centers affiliated with Jahrom University of Medical Sciences between October 2012 and November 2012. One hundred parturients were considered for eligibility and after describing the study protocol, an informed consent was taken from the patients. Seventy parturients [American Society of Anesthesiologists (ASA) physical status I or II] scheduled for elective caesarean delivery under spinal anesthesia were enrolled (Fig. 1). Parturients with history of sever preeclampsia, contraindication to spinal anesthesia and caesarean section surgery excluded from study. Diabetes, preoperative body temperature >38°C, allergy to the study medications (meperidine and bupivacaine), ASA III and IV, drug addiction, a height <152 cm, Reynauds syndrome and hypo or hyperthyroidism are other exclusion criteria. Parturients with BMI >25 or <19 were excluded.
Intervention: Parturients were randomly divided into 2 groups by random drawing of sealed envelopes (computer-based table of randomization). No parturient was excluded after randomization. Medication was prepared by an assistant not involved in the study. When the medications were prepared, the assistant gave them to anesthesiology resident who was not involved into the study and was responsible for performing spinal anesthesia. Before performance of spinal anesthesia, parturients were monitored and received intravenous warmed (37°C) lactated Ringers solution 15 mL kg-1. Oxygen 5 L min-1 was administered through a Hudson mask during anesthesia and parturient were covered with blankets but not actively warmed. All prepared solutions were warmed to 37°C. Parturients were randomly assigned to receive hyperbaric bupivacaine (0.5%; 10 mg) and meperidine (Actavis, Zug, Switzerland) in a dosage of 10 mg (35 patients; BM group) or matched hyperbaric bupivacaine dosage with equivalent volume of sterile saline (35 patients; B group). By using a midline approach within a 25-gauge Whitacre needle, spinal anesthesia was performed in the sitting position at the inter space of L3-L4. After spinal injection, patients were placed supine with a left lateral tilt.
Study design and assays: The time at the end of injection was determined
as T0. By using pinprick, sensory block was evaluated at 1 min intervals for
ten min, 5 min intervals for 35 min, then at 10 min intervals until regression
to L3. The level of segment blocked during operation and in the Post-anesthesia
Care Unit (PACU) was assessed. Shivering intensity was graded with a scale which
is described by Crossley and Mahajan (Crossley and Mahajan,
1994). The incidence and intensity of shivering were measured before operation
and every 5 min during intraoperative and postoperative period (whole time of
the study period). The blood pressure, heart rate, diastolic and systolic blood
pressure, core and peripheral temperature, peripheral oxygen saturation and
intrathecal opioid-related side-effects were recorded simultaneously with sensory
levels and shivering intensity by a blinded observer. Shivering was stopped
with IV clonidine (0.5 μg kg-1) after evaluation and grading
of shivering intensity in groups for unwanted complication on fetus and mother.
Arterial hypotension was defined as a decrease in systolic blood pressure <80
mm Hg or less than 30% of the baseline value. It was treated with 5-10 mg of
ephedrine IV. Metoclopramide 10 mg IV and diphenhydramine 25 mg IV were used
for treating nausea and pruritus, respectively. Core and skin temperature were
measured by tympanic probes and skin thermometers in axillaries region, respectively,
every 15 min during operation and in the PACU.
|| Participation flow diagram through requirement
The temperature of operating room was maintained at 21-23°C. If nausea,
vomiting and pruritus had occurred during operation and in the PACU, they were
noted. Apgar scores at 1 and 5 min were reported. Surgery duration was also
recorded. All data was collected by a blinded observer. Ethical approval for
this study (References number: D/A/3755) was provided by the Ethical Committee
of Jahrom University of Medical Sciences, Jahrom, Iran (Chairperson M. Poorahmad;
M.D.) on 30 July 2012. This trial was registered at www.irct.ir
(Trial Number:IRCT2012090410743N1) and http://www.who.int/ictrp/en/.
Statistical analysis: Based on the preliminary study, a power anaylsis
was done to find a sufficient sample size in determining a significant difference
in intensity and incidence of shivering by using an alpha value of 0.05 and
a power of 80%. The incidence of shivering was 65% in group B (P1) and 25% in
group BP (P2) in this preliminary study. This established that a sample size
of twenty four patients was adequate per group. Thirty five parturients enrolled
in each group to compensate for possible none valuable data. The Statistical
Package for Social Science (SPSS) for Windows, version 16 (SPSS Inc., Chicago,
IL) was used for data analysis. The quantitative variables (age, weight, height,
Body Mass Index (BMI), Heart Rate (HR), Systolic Blood Pressure (SBP), Dyastolic
Blood Pressure (DBP), Apgar score, Core and skin temperature, Surgery duration
and time to reach highest block, incidence of shivering between groups analysed
by Independent t-tests. The highest segment blocked, shivering intensity and
incidence and other proportions between groups Compared by chi-square test.
Mann-Whitney U-test was used between two-group comparisons by Bonferroni correction
if needed. X2 tests or Fishers exact test as appropriate were used to
compare dichotomous nominal variables such as vomiting, nausea, respiratory
distress and pruritus. Data are reported as means-standard deviation for 95%
confidence interval. A 2-sided p value<0.05 was considered statistically
There were no significant differences between the 2 groups regarding demographic and surgical data, except the time to reach the highest sensory level block, shorter in the group receiving meperidine (Table 1).
|| Demographic and surgery data during the whole time of the
study period. Values are Mean±SD or median (range)
|aB: Control group. BM: Case group, bBMI:
Body mass index. SBP: Systemic blood pressure. DBP: Diastolic blood pressure
||Frequency of adverse effects due to use of meperidine and
placebo in the two study groups during the whole time of the study period
|aB: Control group. BM: Case group, bFrequency
(percentage) is reported
||Incidence of shivering during the whole time of the study
period in the meperidine group was significantly lower than the controls:*p<0.05
There were no differences in adverse effects between the two study groups (Table 2).
The incidence of shivering during the whole time of the study period was significantly
decreased in the group of parturients who received intrathecal meperidine (p<0.001)
(Fig. 2). Shivering was less intense in the BM group compare
to B group during the whole time of the study period (p<0.05) (Fig.
3). None of the parturients receiving meperidine experienced grade 3 or
4 shivering, whereas it concerns 8 ( 22.86%) parturients in the group B (Table
||Shivering intensity for each patient, (0): No shivering, (1):
Pillow erection or peripheral vasoconstriction but no visible shivering,
(2): Mmuscular activity in only one muscle group, (3): Muscular activity
in more than one muscle group but not generalized shivering; (4): Shivering
involving the whole body. Shivering was less intense in the BM group (p<0.05).
B group = Control group; BM group = Case group
Clonidine was used as a rescue for shivering treatment over 2 parturients
of BM group and thirty of controls. Need for analgesic drugs was more in the
controls (p<0.001). Apgar scores were similar for the two study groups (p>0.05).
No patient had to be excluded due to the need for supplementary sedation or
inadequate spinal anesthesia.
According to reported data, adding small dose of intrathecal meperidine (10 mg) reduces the incidence and intensity of intra- and post-operative shivering of obstetric population in caesarean section under spinal anesthesia without increasing adverse events.
|| Incidence and intensity of shivering in B and BP groups
|B: Control group. BM: Case group, Frequency (percentage) is
reported. x2 test or Fishers exact test was used
In the present study, shivering was significantly less intense in experimental
group compare to controls. The Authors study are in agreement with the recent
studies that showed less intensity of shivering in meperidine used group (Khan
et al., 2011; Chen et al., 1993;
Roy et al., 2004; Hong
and Lee, 2005). In the recent literature, a complete discussion of antishivering
mechanism of meperidine can be found (Fukuda, 2005).
Meperidine is a synthetic opioid binds to both mu and kappa receptors which
are useful for treating moderate to severe pains. Anti shivering effect is due
to binding to both alpha and beta-two receptors (Locks,
2012; Bryant et al., 2011). In a Meta-analysis
study demonstrated that just 1.3 patients need to be treated stop shivering
in one single patient after administration of IV meperidine. (Kranke
et al., 2004) Prevention of shivering has not been fully understood,
as compared with treatment. The alfentanil, morphine and fentanyl are not as
effective as meperidine in treating shivering (Pang
et al., 1998; Nishikawa et al., 2000;
Karakaya et al., 2001). In present study, the
author used intrathecal form of meperidine for its antishivering effect. Recent
data showed that intrathecal meperidine is more useful than IV and IM forms
of meperidine in reducing severity and incidence of shivering (Hu
et al., 1992; Nordberg et al., 1988)
it may because of types of receptors that they may involve. The authors study
data suggested the preliminary findings.
This dose of meperidine doesnt have specific side effects. In the present
study, there is not any significant incidence of postoperative side effects
including nausea, vomiting and respiratory distress. In contrast, other studies
reported nausea and vomiting as side-effects of meperidine during spinal anesthesia
for caesarean section. Meperidine is metabolized to norpethidine which has CNS
toxic effects. Doses of 25 mg are associated with supratoxic levels of norpethidine
(Nordberg et al., 1988). High dosage of meperidine
is along with side effects such as vomiting, nausea, drowsiness, bronchospasm,
respiratory depression, pruritus, hypotension, bradycardia and central nervous
system excitatory (Freye, 1974; Morisy
and Platt,1986; Kaiko et al., 1983). In
the recent study, the use of intrathecal meperidine (12.5 or 25 mg and 0.2 mg
kg-1) for caesarean section during spinal anesthesia for the prevention
of shivering was not recommended as its use is associated with increased incidence
of nausea and vomiting (Khan et al., 2011; Chen
et al., 1993; Roy et al., 2004).
Nausea and vomiting are troublesome side effects which are encountered during
spinal anesthesia for caesarean section. On the basis of these findings, single-shot,
mini-dose intrathecal meperidine is not associated with side effects. It seems
that meperidine induced nausea and vomiting was decreased may due to low sympatholysis
effect of single-shot intrathecal meperidine, relatively. In the study of English
literature, Roy et al. (2004), showed that using
low dose (0.2 mg kg-1) intrathecal meperidine reduces the incidence
and intensity of shivering but side effects related to meperidine, such as vomiting
and nausea were not noted in their study (Roy et al.,
2004). As, these finding are in controversy with previous studies, the idea
seems intriguing and could be pursued in future studies in different literatures.
As same as with the previous studies (Khan et al.,
2011; Hong and Lee, 2005), in this study, data
showed no significant differences in core and peripheral temperatures between
groups. The effect of meperidine on core temperature is species-dependent and
complex. In animal models large doses of meperidine can cause hypothermia. Moreover,
the hypothermic effect is intensified by the low environmental temperatures.
The role of warming fluids in decreasing hypothermia has been attributed to
in other studies (Hong and Lee, 2005). Although, parturient
have not been actively warmed in this study but the fluids infusion were warmed.
As it is shown in Table 1, parturient were failed to prevent
parurient from becoming hypothermic.
The present study finding showed the time to maximal block was significantly
shorter in the experimental group: This effect was directly commensurate to
low level of meperidine dose. These results offered that meperidine added to
hyperbaric bupivacaine does not prolong total anesthesia time. Furthermore,
sensory block was at the desired level of T4 in both groups and with regard
to level of sensorial block, no significant differences between groups were
observed. The same level of sensorial block in both groups indicated that firstly,
the development of hypothermic is related to the equal potential effects of
block height and secondly, sensory block height was not influenced by intrathecal
meperidine. These data were similar to the results found by Roy
et al. (2004).
In the present study the mean Apgar score of the newborns in 1 and 5 min were
8 and 9, respectively and no significant differences were observed among experimental
group. The studies of intrathecal meperidine effects on neonates and fetus of
mothers who were under spinal anesthesia for caesarean section demonstrated
no significant side effects (The umbilical cord blood base/acid status, blood
gas and Apgar scores of such infants were measured) (Nordberg
et al., 1988; Freye, 1974; Morisy
and Platt, 1986).
The present study had some advantages and limitations. The advantage of this study is that authors do not dichotomize continuous variables data which gives an additional impact on exactness. The authors acknowledge that the only one dose was studied and this doesnt allow drawing any definitive conclusions. Therefore, a dose-effects study is required for confirming the data.
The authors concluded that using single-shot, mini-dose intrathecal meperidine (10 mg) reduces the severity and intensity of intra- and post-operative shivering in caesarean section under spinal anesthesia without increasing adverse events. Other studies should be designed and compare with the present study. It is suggested that small dose of intrathecal meperidine should be used to prevent shivering in parturients schedulded for elective caesarean section under spinal anaesthesia.
This project was supported by the Student Research Committee of Jahrom University of Medical Sciences. The authors are grateful to in the staff members of Gynecology and Obstetrics operating room in Peymaniyeh and Motahari Hospitals, Jahrom University of Medical Sciences.
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