
==== Front
Ann Med Surg (Lond)
Ann Med Surg (Lond)
MS9
Annals of Medicine and Surgery
2049-0801
Lippincott Williams & Wilkins Hagerstown, MD

AMSU-D-23-02671
10.1097/MS9.0000000000002354
00076
3
Reviews
The effect of intrathecal pethidine on post-spinal anesthesia shivering after cesarean section: a systematic review and meta-analysis
Afzal Muhammad MD amafzal@sgu.edu

Lee Amber DO bAlee@acheedu.org

Asad Muhammad MBBS eMmasad4525@gmail.com

Ali Alya MD calyaalimd@gmail.com

Farrukh Ameer Mustafa MD amf62888@gmail.com
h
Semakieh Bader DO bbsemakieh@achehealth.edu

Levin-Carrion Yaxel MD dYL1177@njms.rutgers.edu

Shah Shah Rukh MBBS gSonyshah13321@gmail.com

Khan Qaisar Ali MD fqaisarak62@gmail.com

a St. George’s University School of Medicine, True Blue, Grenada
b Arkansas College of Osteopathic Medicine, Fort Smith, AR
c Nassau University Medical Center Long Island, East Meadow, NY
d Rutgers New Jersey Medical School, Newark, NJ, USA
e Lady Reading Hospital
f Khyber Teaching Hospital MTI KTH, Peshawar
g Khyber Medical University Institute of Medical Sciences, Kohat, Pakistan
h University of Galway School of Medicine, Galway, Ireland
* Corresponding author. Address: St.George’s University School of Medicine, True Blue, Grenada. Tel.: +1347 279 8386. E-mail: mafzal@sgu.edu (M. Afzal).
9 2024
22 7 2024
86 9 54615470
15 12 2023
13 5 2024
Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.
2024
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0/

Background:

Spinal anesthesia is the most preferred method for cesarean section (C-section). This meta-analysis was performed to determine the effect of low and high intrathecal doses of pethidine on the maternal outcomes after C-section.

Methods:

A systematic search of PubMed, Scopus, Cochrane Library, and Google Scholar was performed. Random-effects meta-analysis was performed to derive odds ratios (ORs) from dichotomous data.

Results:

Seventeen randomized controlled trials with 1304 C-section patients were included. Patients who had received intrathecal pethidine experienced decreased shivering and intensity of shivering (OR 0.13; P<0.001) and (OR 0.21; P<0.001), respectively. Moreover, vomiting (OR 2.47; P=0.002) and pruritus (OR 5.92; P<0.001) were significantly higher in the pethidine group. There was no statistically significant difference in the incidence of nausea (OR 2.55; P=0.06) and hypotension (OR 0.91; P=0.67).

Conclusions:

Intrathecal pethidine can effectively decrease shivering, although it increases the risk of vomiting and pruritus. No significant difference was found both in the maternal hypotension and nausea.

Keywords:

pethidine
spinal anesthesia
cesarean section
surgical complications
SDCT
OPEN-ACCESSTRUE
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pmcIntroduction

Highlights

Pethidine is a synthetic phenylpiperidine derivative opioid that acts on μ and κ opioid receptors. Intravenous (IV) pethidine has long been used to treat and prevent shivering during surgery and the emergence from anesthesia. The anti-shivering mechanism is activated by IV pethidine acting on kappa-opioid receptors.

Unlike IV pethidine, the advantages and disadvantages of intrathecal pethidine are unclear.

Intrathecal pethidine effectively reduces the severity and incidence of post-spinal anesthesia shivering.

Low doses increase pruritus, nausea, and vomiting while showing no association with hypotension.

Surgeons could consider administering intrathecal pethidine at appropriate doses to subside PSAS effectively. However, continuous monitoring is needed to manage the side effects.

Spinal anesthesia is the most used anesthesia for elective and emergency cesarean section (CS) scenarios due to its simplicity and effective performance, low cost and quick application of anesthesia, providing sufficient analgesia and muscle relaxation for the procedure1,2. It is suggested by the Royal College of Obstetricians and Gynecologists that CS should be performed “with an urgency appropriate to the risk to the baby and the safety of the mother” as the target decision to delivery interval is achieved3. Anesthetic goals during CS include a specific anesthetic level to optimize surgical conditions and reduce maternal recall; adequate oxygenation of the mother and fetus; and minimal transfer of anesthesia to fetus4. CS is likely to have several adverse effects on the mother and the baby. For instance, mothers experience pain post- C-section likely due to spinal anesthesia wearing off without additional analgesia given5. Additionally, mothers experience hypotension, which is the most common minor postoperative complication of spinal anesthesia. Maternal hypotension is associated with bouts of nausea and vomiting with a risk of fetal acidosis. Shivering is another postoperative complication that can be troublesome as it interferes with the comfort and monitoring of the mother. Shivering results in increased oxygen consumption and carbon dioxide production, especially in mothers with low (thermoregulatory shivering) and high core temperatures (non-thermoregulatory shivering)6,7.

Pethidine or Meperidine is a synthetic phenylpiperidine derivative opioid that acts on μ and k opioid receptors. For a long period of time, intravenous (IV) pethidine has been used for the treatment and prevention of shivering during surgery and emergence. The anti-shivering mechanism is activated by IV pethidine acting on kappa-opioid receptors. Unlike IV pethidine, advantages and disadvantages of intrathecal pethidine are unclear8,9. For this purpose, we conducted this systematic review and meta-analysis to determine the efficacy of low-dose and high-dose intrathecal pethidine on CS patients with spinal anesthesia.

Methods

This systematic review and meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA, Supplemental Digital Content 1, http://links.lww.com/MS9/A563)10 and the framework laid out by the Cochrane Collaboration11.

Literature search and study selection

A comprehensive literature search of electronic databases, PubMed, Scopus, and Cochrane Library was performed from inception till September 2023. The following keywords were used in the search string: “meperidine”, “pethidine”, “intrathecal”, “spinal anesthesia”, and “cesarean section”. Detailed search strategy used in each database is shown in supplementary material Table S1, Supplemental Digital Content 2, http://links.lww.com/MS9/A564.

Articles initially shortlisted from each database were exported to Endnote Reference Library (Version X7.5; Clarivate Analytics, Philadelphia, Pennsylvania) software, where deduplication was performed. Two reviewers thoroughly reviewed the remaining articles first by title, then abstract, and finally a full-text evaluation was performed based on a preset eligibility criterion. Disagreements were resolved by consensus. The following inclusion criteria was employed to shortlist studies (1): randomized controlled trials (RCTs) (2), females undergoing cesarean section with spinal anesthesia (3), intrathecal meperidine (pethidine) administration between 5 and 50 mg (4), compared with bupivacaine or normal saline (5), studies involving the measurement of shivering or intensity of shivering. No language restrictions were placed when shortlisting articles. Exclusion criteria were the use of local anesthesia, non-elective surgery, combination of opioids in intervention or control, studies of observational nature, and studies whose full text was unavailable.

Data extraction and quality assessment

Two independent reviewers conducted the data extraction. Any disagreement was resolved by discussion. Additionally, a snowball searching method was applied where articles were found by going through the citations of relevant articles. Data extraction was performed of the following characteristics: study design, country of study, number of patients in each group, dosage of pethidine, and primary and secondary endpoints. In this study incidence and severity of shivering were the primary outcomes. Adverse events including pruritus, nausea, vomiting, and hypotension were the secondary outcomes. Quality assessment was performed using the Risk of Bias-2 (RoB-2) tool of the Cochrane Collaboration for randomized controlled trials12. Differences between the two independent reviewers in quality assessment were resolved by discussion. We performed an evaluation of our meta-analysis using the AMSTAR-2 checklist, Supplemental Digital Content 3, http://links.lww.com/MS9/A565 13. Our meta-analysis was found to be of high-quality.

Statistical analysis

Review Manager (version 5.4.1; Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2020) and Comprehensive Meta-Analysis were used for data analysis. A random-effects model was employed to derive odds ratios (ORs) and corresponding 95% CIs. Publication bias was assessed by generating funnel plots and Egger’s regression test (0.00001). A P value less than 0.05 was considered statistically significant for all outcomes. Heterogeneity was assessed with Higgin’s I2 test. A value of I2=25–50% was considered mild, 50–75% as moderate, and greater than 75% as significant heterogeneity. Sensitivity analysis was performed by to address moderate to high heterogeneity by excluding outliers.

Results

A total of 737 articles were shortlisted from the literature search. After removing duplicates and articles based on study design, patient population, and intervention, a total of 65 were given a full-text evaluation (Fig. 1). A total of 17 studies falling under our eligibility criteria were included in this systematic review and meta-analysis14–30. From these 17 studies, 13 had data on pethidine dose less than 20 mg and 11 included doses greater than 20 mg. This cut-off was used due to the greater and lesser effects of pethidine and approximately equal number of studies on both sides of the 20 mg mark. Seven hundred thirty-eight patients were included in the pethidine group and 566 in the control group. Study characteristics are shown in Table 1. Detailed characteristics of the included RCTs are shown in Table 2.

Figure 1 Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) flowchart.

Table 1 Characteristics of the included studies

Authors’ names	Year	Country	Dose, mg	Pethidine/control (number)	Shivering (%)	
Girma et al. 18	2022	Ethiopia	10	Pethidine (n=43)	9 (20.9)	
				Control (n=43)	23 (53.5)	
Azemati et al. 21	2022	Iran	10	Pethidine (n=30)	1 (3.33)	
				Control (n=30)	12 (40)	
Khezri et al. 17	2018	Iran	50	Pethidine (n=50)	33 (66)	
				Control (n=50)	41 (82)	
Shami et al. 19	2016	Iran	5	Pethidine (n=50)	11 (22)	
				Control (n=50)	25 (50)	
			10	Pethidine (n=50)	2 (4)	
				Control (n=50)	25 (50)	
Rastegarian et al. 16	2013	Iran	25	Pethidine (n=50)	4 (8)	
				Control (n=50)	15 (30)	
Yu et al. 15	2002	China	10	Pethidine (n=20)	3 (15)	
				Control (n=20)	8 (40)	
Hirmanpour et al. 14	2017	Iran	25	Pethidine (n=40)	2 (5)	
				Control (n=40)	26 (65)	
Zabetian et al. 29	2013	Iran	10	Pethidine (n=35)	5 (14.2)	
				Control (n=35)	33 (94.2)	
Mahmoud et al. 28	2016	Egypt	10	Pethidine (n=30)	8 (26.6)	
				Control (n=30)	20 (66.6)	
Nasseri et al. 20	2017	Iran	10	Pethidine (n=30)	2 (6.6)	
				Control (n=30)	18 (60)	
Hong et al. 27	2005	South Korea	10	Pethidine (n=30)	1 (3.3)	
				Control (n=30)	7 (23.3)	
Anaraki et al. 26	2012	Iran	15	Pethidine (n=39)	15 (38.4)	
				Control (n=39)	19 (48.7)	
			25	Pethidine (n=39)	11 (28.2)	
				Control (n=39)	19 (48.7)	
			30	Pethidine (n=39)	6 (15.3)	
				Control (n=39)	19 (48.7)	
Atalay et al. 23	2010	Turkey	25	Pethidine (n=20)	0 (0.0)	
				Control (n=20)	10 (50)	
			30	Pethidine (n=20)	0 (0.0)	
				Control (n=20)	10 (50)	
			35	Pethidine (n=20)	0 (0.0)	
				Control (n=20)	10 (50)	
Khan et al. 25	2011	Iran	10	Pethidine (n=24)	9 (37.5)	
				Control (n=24)	18 (75)	
			25	Pethidine (n=24)	2 (8.3)	
				Control (n=24)	18 (75)	
Shrestha et al. 22	2007	Nepal	10	Pethidine (n=30)	12 (40)	
				Control (n=30)	23 (76.6)	
Roy et al. 24	2004	Canada	15	Pethidine (n=20)	4 (20)	
				Control (n=20)	15 (75)	
Mohamed et al. 13	2018	Egypt	25	Pethidine (n=25)	6 (24)	
				Control (n=25)	22 (88)	

Table 2 Detailed trial characteristics

				Mean age		
Authors’ names	Centers	Randomized	Analyzed	Treatment	Control	Trial registration number	
Girma et al. 26	Single	86	86	25.9±3.7	27.2±3.5	PACTR202110617970132	
Azemati et al. 29	Single	60	60	29.3 ± 1.1	30.4 ± 1.1	IRCT2014100814372N4	
Khezri et al. 25	Single	100	100	27.9±6.1	28.3±7.8	IRCT201104073051N4	
Shami et al. 27	Single	150	150	31.3±5.5	31.8±4.7	IRCT2015090223869N1	
Rastegarian et al. 24	Single	100	100	27.0±6.1	26.3±3.7	—	
Yu et al. 23	Single	40	40	33.0±6.0	33.0±5.0	—	
Hirmanpour et al. 14	Multiple	80	80	30.9±5.9	31.1±4.9	—	
Zabetian et al. 22	Multiple	70	70	28.5±7.3	27.1±4.3	IRCT2012090410743N1	
Mahmoud et al. 21	Single	60	60	30.8±3.2	30.4±4.1	—	
Nasseri et al. 28	Single	63	60	29.4±6.0	29.8±5.3	IRCT2013091414656N1	
Hong et al. 20	Single	60	60	30.8±4.3	31.3±4.5	—	
Anaraki et al. 19	Multiple	156	156	28.7±5.0	28.7±5.0	IRCT138904101936N3	
Atalay et al. 16	Single	80	80	28.5±6.1	27.8±4.3	—	
Khan et al. 18	Single	72	72	28.0±6.3	27.1±8.3	—	
Shrestha et al. 15	Single	60	60	—	—	—	
Roy et al. 17	Single	40	40	31±5	32±6	—	
Mohamed et al. 13	Single	50	50	—	—	—	

Meta-analysis

Shivering

A total of 23 cohorts of pethidine and control were added to the incidence of shivering outcome. Overall, the pethidine group was associated with a decreased incidence of shivering [OR: 0.13 (0.08, 0.20) P<0.00001; I2=60%]. Pethidine was significantly associated with decreased shivering events post-spinal anesthesia in both, low-dose (<20 mg) and high-dose (>20 mg) pethidine subgroups [OR: 0.14 (0.08, 0.25) P<0.00001; I2=59%] and [OR: 0.10 (0.05, 0.23) P<0.00001; I2=64%], respectively (Fig. 2). A sensitivity analysis addressed heterogeneity by removing outliers, which decreased the overall heterogeneity to 48% (Figure S1, Supplemental Digital Content 4, http://links.lww.com/MS9/A566).

Figure 2 Forest plot of incidence of shivering.

Intensity of shivering

A random-effects meta-analysis was performed to evaluate the association between pethidine and intensity of shivering. Overall, pethidine was associated with a decreased incidence of severe shivering (Stage 3–4) [OR: 0.21 (0.11, 0.40) P<0.00001; I2=37%]. Low-dose [OR: 0.25 (0.09, 0.66) P<0.00001; I2=47%] and high-dose [OR: 0.18 (0.09, 0.34) P<0.00001; I2=0%] pethidine subgroups had similar findings as both were found to be associated with lesser intensity of shivering (Fig. 3).

Figure 3 Forest plot of intensity of shivering.

Adverse effects

Incidence of pruritus was evaluated in pethidine and control groups. Pethidine was significantly associated with increased events of pruritus in patients following spinal anesthesia [OR: 5.92 (2.69, 13.07) P<0.0001; I2=50%]. Both the low-dose [OR: 7.90 (1.77, 35.27) P=0.007; I2=61%] and high-dose groups [OR: 5.25 (1.94, 14.23) P=0.0001; I2=47%] had similar findings (Fig. 4).

Figure 4 Forest plot of incidence of pruritus.

A total of 11 cohorts of pethidine and control evaluated nausea events following spinal anesthesia. Pethidine was non-significantly associated with increased events of pruritus in patients following spinal anesthesia [OR: 2.55 (0.97, 6.69) P=0.06; I2=73%]. Low-dose pethidine was significantly associated with increased nausea events [OR: 3.36 (1.15, 9.85) P=0.03; I2=56%]. However, the high-dose group [OR: 1.86 (0.31, 11.13) P=0.49; I2=83%] had no significant association (Fig. 5).

Figure 5 Forest plot of incidence of nausea.

Pethidine was significantly associated with increased events of vomiting in patients following spinal anesthesia [OR: 2.47 (1.38, 4.41) P=0.002; I2=47%]. Low-dose pethidine was also significantly associated with increased vomiting in patients following C-section [OR: 3.04 (1.68, 5.51) P=0.0002; I2=1%]. However, the high-dose group [OR: 2.16 (0.84, 5.51) P=0.11; I2=63%] had no significant association (Fig. 6).

Figure 6 Forest plot of incidence of vomiting.

Hypotension was also evaluated in C-section patients following spinal anesthesia. Overall, no significant association was derived between pethidine and hypotension [OR: 0.91 (0.61, 1.38) P=0.67; I2=32%]. Both the low-dose [OR: 1.14 (0.73, 1.79) P=0.57; I2=0%] and high-dose groups [OR: 0.67 (0.30, 0.51) P=0.34; I2=61%] had similar findings (Fig. 7).

Figure 7 Forest plot of incidence of hypotension.

Quality assessment and publication bias

Quality assessment was performed using RoB-2 tool in which five domains are assessed for bias. All the included RCTs were found to be at a low risk of bias. Three studies showed some concerns in the randomization process whereas, two studies showed deviation from the intended interventions. Moreover, one study had a moderate risk of missing outcome data. Two articles had some concerns with the measurement of the outcome and three studies had some bias in the selection of results that were discussed. Detailed quality assessment is shown in supplementary figure S2, Supplemental Digital Content 5, http://links.lww.com/MS9/A567. Publication bias was assessed using funnel plot for the primary outcome shivering. Asymmetry was noted upon evaluating the funnel plot (Figure S3, Supplemental Digital Content 6, http://links.lww.com/MS9/A568). This was confirmed by Egger’s regression test showing a two-tailed p-value of 0.0001.

Discussion

In this meta-analysis we evaluated the impact of low (<20 mg) and high (>20 mg) dose of intrathecal pethidine on the incidence and severity of post-spinal shivering in women undergoing CS. Our study showed that intrathecal administration of pethidine in patients can significantly reduce post-spinal anesthesia shivering events. Additionally, pethidine was linked with lower severity of shivering. The intrathecal pethidine, however, increases the risk of pruritus and vomiting. No association was observed with nausea and hypotension events.

In the majority of the studies in our meta-analysis similar surgical procedures were followed when administering pethidine intrathecally. Firstly, patients received 5–7 ml/kg lactated Ringer’s solution before spinal anesthesia. Then, a 25-gauge Quincke needle was inserted intrathecally via a midline approach between L3/L4 and L4/L5, while the patient was in a sitting position with 2–2.5 ml bupivacaine 0.5% with the prespecified dosage of pethidine.

A meta-analysis conducted by Lin et al. 31 studied the effect of low-dose intrathecal pethidine in patients undergoing various surgical procedures. They found significantly lower incidence and severity of post-spinal anesthesia shivering; however, nausea and vomiting were increased. Similar findings were observed by Subramani et al. 32, who found intrathecal pethidine to lower severity and incidence of shivering in CS patients. The results of our meta-analysis are consistent with these findings. Recent randomized controlled trials by Girma et al. 19 and Azemati et al. 22. show similar findings as shivering incidence was significantly reduced and severity of shivering was also found to be decreased in patients in the pethidine group.

Spinal anesthesia impedes tonic vasoconstriction and causes readjustment of core heat from the trunk to the periphery thereby patients develop hypothermia and shivering. Post-spinal anesthesia shivering is an involuntary, repetitive activity of skeletal muscles as a reaction to core hypothermia to raise metabolic heat production9.

Intravenous pethidine reduces the incidence of post-spinal anesthesia shivering by the reduction of shivering threshold and binding to the kappa receptors9,33. Possible mechanisms for intrathecal pethidine to reduce shivering could be k-opioid receptor activity, anticholinergic action, biogenic monoamine reuptake inhibition, NMDA receptor antagonism, or stimulation of alpha 2–adrenoceptors, and possibly modulating the heat loss caused by vasodilatation after spinal anesthesia34–36.

In a recent RCT by Azemati et al. 22 there was no significant association between intrathecal pethidine and nausea and vomiting. Similar findings were observed by Nasseri et al. 21 These results are contrary to what Lin et al. 31 found as low-dose intrathecal pethidine increased the incidence of nausea and vomiting. This is consistent with our meta-analysis as the low-dose (<20 mg) subgroup showed increased nausea and vomiting events whereas the high dose (>20 mg) showed no significant association. Shami et al. 20 found 5, 10, 15 mg of intrathecal pethidine to be of no significance in causing vomiting and nausea. Since pethidine is an opiate, it inhibits the neurotransmission of pain by binding to the opioid receptors in the central nervous system37. Thus, pethidine could be attributed to nausea and vomiting caused by stimulation of the medullary chemoreceptor trigger zone38.

In our study, there was a significant association between both low- and high-dose intrathecal pethidine and pruritus. These findings are consistent with the study conducted by Jaafarpour et al. 39. Recent RCT by Azemati et al. 22 found that concomitant use of pethidine and bupivacaine increased the feeling of itching, which is also consistent with Bi et al. 40 as they compared the group that received hyperbaric bupivacaine with the groups treated by the pethidine in terms of side effects. They found that itching complications were more prevalent in the pethidine group.

Our meta-analysis is not without its limitations. Firstly, the included RCTs had a low sample size. Secondly, we decided on a low and high-dose cut-off of 20 mg on our own due to the equal statistical distribution of studies on either side and the low and high effects of pethidine observed on either side of the cut-off. Due to a low number of participants in some studies, it contributed to greater CIs in outcomes which resulted in increased heterogeneity. However, our meta-analysis has its strengths also. We included recent RCTs and conducted the meta-analysis with the greatest sample size as compared to previous meta-analysis on this topic. We found crucial dose-dependent associations that were not made previously. Since pethidine was statistically associated with decreasing severity and reduced post-spinal anesthesia shivering events, it could serve as a potent treatment in the clinical setting. However, caution is warranted with the dosing of pethidine as low dose (<20 mg) was associated with increased adverse events.

Conclusion

Intrathecal pethidine is effective in reducing the severity and incidence of post-spinal anesthesia shivering. However, it increases pruritus, nausea, and vomiting in low doses and it had no association with hypotension.

Provenance and peer review

Not commissioned, externally peer-reviewed.

Supplementary Material

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Supplemental Digital Content is available for this article. Direct URL citations are provided in the HTML and PDF versions of this article on the journal's website, www.lww.com/annals-of-medicine-and-surgery.
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