Meta-Analysis of Open-Heart Surgery Pain Relief Using Transversus Thoracic Plane Blocks

,


Introduction
Patients undergoing open-heart surgery with midsternotomy incision often experience severe pain after surgery.Early postoperative pain exacerbates stress response; increases the incidence of pulmonary atelectasis, pneumonia, and cardiovascular adverse events; prolongs hospitalization; and increases mortality [1].Poor control of acute pain in the early postoperative period may develop into chronic pain, significantly afecting patients' quality of life in the long term [2].Terefore, pain management in patients after cardiac surgery is of paramount importance.High-dose opioid is the primary perioperative analgesic for open-heart surgery.However, opioids have been associated with ventilator-associated pneumonia, prolonged time on tubes, and prolonged intensive care unit (ICU) stays and hospitalizations [3].At present, with the promotion of ultrasound technology in the feld of anesthesia, multimodal analgesia based on the regional nerve block has been widely used and achieved promising results [4].
Te sources of pain in open-heart surgery are complex; they include pain from superfcial, deep somatic sources and postoperative visceral components.Midsternotomy incision is considered the primary source of pain, with the most severe pain occurring within the frst 24 h.Te sternal region is mainly sensed by the intercostal nerves [5].Sensation in this region was mainly innervated by the anterior cutaneous branch of the intercostal nerve, which migrated from the intercostal nerve in the paraspinal region [6].Transverse thoracic muscle plane (TTMP) block is a blocking technique developed in recent years.It involves injecting local anesthetic between the intercostal muscles and the transverse pectoral muscles, efectively blocking the anterior cutaneous branch of the intercostal nerve [7].Several studies reported the use of TTMP in diferent types of surgeries, including mastectomy, sternal fractures, open pectus carinatum, pericardiocentesis, and cardiac implantable electronic device insertions involving the anterior chest wall [8][9][10][11][12].In 2019, a pilot feasibility study explored the efcacy and safety of TTMP for analgesia in open-heart surgery [13].Subsequently, several studies reported the application of TTMP in cardiac surgery, but the sample size of individual studies is small and their clinical efects are still controversial.Te advantages of TTMP after open-cardiac surgery have not yet been fully and efectively demonstrated.
Terefore, this study aimed to evaluate the analgesic efect of TTMP on recovery after midsternotomy cardiac surgery by meta-analysis to provide reference for postoperative analgesia and accelerated recovery of cardiac surgery patients.

Literature Review and Search
Strategy.Tis study followed the Preferred Reporting Items for Systematic Evaluation and Meta-Analysis, and it was registered on the PROSPERO website.Computerized searches, without language restriction, were performed by two independent investigators on PubMed, Cochrane, Embase, CNKI, and Wanfang databases.Te time period was from database construction to March 2023.Te search terms were "transverse thoracic muscle plane block, cardiac surgery, postoperative."Trial registries were searched in accordance with prepublished protocols to identify ongoing trials.Manual searches were performed through the reference lists of relevant primary and review articles to ensure completeness.Te supplementary fles provide records of specifc searches (Supplementary Table 1).

Inclusion and Exclusion Criteria. Te inclusion criteria
for this meta-analysis were as follows: (1) study design: randomized controlled trials (RCTs); (2) study population: adult patients undergoing midsternotomy cardiac surgery; (3) intervention: receiving TTMP guided by ultrasound for the experimental group and a blank control or placebo for the control group; and (4) outcome measures: at least one outcome parameter, including postoperative opioid consumption, early postoperative pain scores, duration of endotracheal intubation, length of ICU stay, and incidence of nausea and vomiting.Te exclusion criteria were as follows: (1) reviews or case reports and retrospective studies, (2) pediatric patients, (3) conference abstracts, (4) duplicate publications, and (5) incomplete data in literature.

Data Retraction.
EndNote 20 was used to select trials from duplicates that matched the study.Two researchers (RPZ and XLY) examined the titles and abstracts for eligibility and carefully assessed the full texts to ensure they met the inclusion criteria.Tey independently performed documentation and data extraction and resolved any disagreements by mutual discussion or consultation with a third party (YZ).Attempts were made to contact corresponding authors with incomplete data or studies in progress for further information.Te general data extracted were as follows: name of the frst author, time of publication, sample size, intervention, analgesic regimen, and so on.Te primary outcome extracted was 24-hour postoperative opioid consumption.Te secondary outcomes included pain scores at rest and during exercise at 12 h and 24 h postoperatively, time of frst analgesia demand, extubation time, length of stays in ICU, time of frst feces, incidence of nausea and vomiting, and length of hospitalization.Postoperative opioid consumption was converted to oral morphine equivalents (morphine iv 10 mg = morphine oral 30 mg = hyd romorphone iv 1.7 mg = tramadol oral 150 mg = pethidine iv 75 mg = sufentanil iv 15 μg = fentanyl iv 150 μg) [14].All postoperative pain scores were converted to equivalent scores on a 0-10 cm visual analog scale (VAS).

Quality Assessment.
For the included RCTs, the recommended criteria of Cochrane Systematic Evaluation Manual 5.1.0were strictly followed, and a third evaluator was asked to judge any inconsistent results [15].Te following criteria were mentioned in the evaluation of the quality of literature: (1) generation of randomized sequences; (2) whether the allocation was hidden; (3) blinding of investigators and subjects; (4) blinding of study results; (5) completeness of the outcome data; (6) selective reporting of study results; and (7) other biases.Each included literature was evaluated in accordance with the abovementioned criteria and judged as "high risk of bias," "low risk of bias," or "unclear risk of bias."2.5.Statistical Analysis.Statistical analysis was performed using RevMan 5.3 software.Continuous data were expressed as the mean diference (MD), and its 95% confdence interval (CI) and statistical transformations were used to estimate the mean and SD when the mean and 95% CI were reported or if the median (IQR) and median (min and max) were reported [16].If data could not be transformed and contacting the authors was unsuccessful, the data were not included in the analysis.Te heterogeneity of the literature was assessed by calculating the I 2 coefcients.I 2 > 50% was considered signifcant heterogeneity and a random-efects model was applied, whereas I 2 < 50% was considered small heterogeneity and a fxed-efects model was applied.Subgroup and sensitivity analyses were performed to explore the sources of heterogeneity for the main surgical outcomes, focusing on the surgical type, use of cardiopulmonary bypass, and timing of blockade.A p value <0.05 was considered statistically signifcant.Te funnel plot of the main outcome indicators was used to assess the publication bias of the included studies.were searched.Among them, 215 studies were obtained after eliminating duplicates.Ten, 37 studies were included after reading the titles and abstracts and excluding articles that did not meet the inclusion criteria.Finally, 13 studies were included after reading the full text, including seven studies in English [13,[17][18][19][20][21][22] and six non-English [23][24][25][26][27][28] studies.Zhao et al. [26] performed TTMP with diferent local anesthetic concentrations for comparison, and we selected the higher concentration group for inclusion in the analysis.Te total number of patients was 805, of which 404 were categorized into the TTMP group and 401 into the control group.Te studies were published between 2019 and 2023, which indirectly indicates that TTMP is a new technique.Te fowchart of literature screening is shown in Figure 1.

Search
Te basic characteristics of the included studies are shown in Table 1.Te patients included in the study were above 18 years of age, and they underwent diferent types of surgeries, such as coronary artery bypass grafting, aortic valve replacement, mitral valve replacement, or multiple valve replacement.TTMP was performed before induction of anesthesia in four studies, after induction of anesthesia in seven studies, and at the end of surgery in two studies.Seven studies involved placebo injections of saline, and six studies had blank control.Patient-controlled intravenous analgesia was chosen as the postoperative analgesic modality in 10 studies.

Quality Assessment.
In accordance with the Cochrane risk-of-bias tool, most of the included articles were assessed to have low risk of bias.All included studies showed a low risk of randomization.Eight of the 13 studies did not describe allocation concealment in detail, and fve of these were from non-English literature.Te specifc risk assessments are shown in Figure 2.
Te evidence was formally graded using GRADEpro software to provide an overall level of evidence for the effectiveness of ultrasound-guided TTMP for analgesia in open-heart surgery.Te quality levels for each secondary outcome ranged from low to high, as shown in Table 2. Detailed information was provided in the supplementary material (Supplementary Table 2).First 24 H.Among the included literature, 11 compared the 24hour postoperative opioid consumption [13,[17][18][19][20][21][22][24][25][26][27].Te results of the heterogeneity test showed signifcant heterogeneity (I 2 � 98%).Tus, the studies were analyzed using a random-efects model, and the results showed that the 24-hour postoperative opioid consumption in the TTMP group (MD � −41.88 mg; 95% CI −51.99, −31.77; p < 0.001; and I 2 � 98%) was signifcantly less than that in the control (Figure 3).According to the GRADE system, the quality of evidence for our primary outcome was moderate.

Postoperative Opioid Consumption during the
To explore the high heterogeneity observed in the study, we frst performed sensitivity analyses for each exclusion of results, and the heterogeneity did not change signifcantly.Subsequently, we performed subgroup analyses in accordance with the type of surgery, timing of block, and postoperative analgesia modality.Similarly, no source of heterogeneity was identifed (Supplementary Figure 1).

Time of First Analgesic Demand.
Of the studies included, four studies [13,17,18,20] reported the time of frst analgesic demand.Te TTMP group showed a statistically signifcant prolongation of the time of frst analgesic demand compared with the control group.Te quality of evidence was downgraded to low due to heterogeneity and imprecision (Table 2).

Time of First Feces.
Tree studies [19,21,25] compared the time of frst feces.Te TTMP group had a signifcantly shorter time of frst faces than the control group.Te quality of evidence was downgraded to low due to heterogeneity and imprecision (Table 2).

Incidence of PONV.
Of the included studies, seven studies [13,17,21,22,[24][25][26] reported the incidence of nausea and vomiting in patients, and it was lower in the Journal of Cardiac Surgery TTMP group than in the control group.Te quality of evidence was downgraded to low due to heterogeneity and imprecision (Table 2).

Length of Hospital
Stay.Among the studies included, fve studies [19-21, 24, 25] reported the length of hospitalization of the patients, and it was shorter in the TTMP group than in the control group.Te quality of evidence was downgraded to low due to heterogeneity and imprecision (Table 2).Forest plots for secondary endpoints are shown in the Supplementary fle (Supplementary Figure 2).

Publication Bias.
A funnel plot based on comparisons of postoperative opioid use for the primary outcome showed that the included studies were generally symmetrical, suggesting no signifcant publication bias (Figure 5).

Discussion
Te results of this study showed that the perioperative ultrasound-guided TTMP block was efective in reducing opioid consumption during the frst 24 h and lowering the pain scores postoperatively in patients undergoing open-heart surgery compared with those in the blank or placebo groups.Moreover, it showed advantages in prolonging the time of frst analgesia demand, shortening the time of extubation, shortening ICU stay and hospitalization, and decreasing nausea and vomiting in the postoperative period.
Pain management after sternotomy cardiac surgery has always been a concern for anesthesiologists.A large number of opioids are used in the perioperative period of cardiac surgery to suppress surgical stress [29].Te use of large doses of opioids may cause postoperative respiratory depression, prolong the duration of mechanical ventilation, and increase the incidence of nausea and vomiting [3,30].In addition, the use of perioperative opioids is being reexamined due to societal concerns about opioid abuse [31].Multimodal analgesic regimens combining regional nerve blocks with nonopioid medications have been extensively studied to promote rapid recovery of patients who underwent cardiac surgery [4].Previous studies showed that epidural anesthesia and paravertebral nerve blocks provide excellent analgesia after cardiac surgery, reduce myocardial oxygen consumption, and decrease cardiac surgery mortality.However, perioperative heparinization and anticoagulation for cardiac surgery may increase the risk of intrathecal hematoma [32][33][34][35].Te anterior serratus plane block and pectoralis plane (PECS) block   [39].Tis fnding suggested that the anterior serratus plane block or PECS for median open-heart surgery may have the risk of incomplete analgesia [40].Ultrasound-guided TTMP is a method of targeting the anterior cutaneous branch of the intercostal nerve.Local anesthetic injected between the transversus pectoralis and intercostal muscles blocks the anterior cutaneous branches of the intercostal nerves 2-6, thus producing analgesia in the medial mammary region and the anterior sternal region [7].Cadaveric studies showed that the injection of local anesthetic into the T4-5 intercostal space is more preferable than injection into the T3-4 intercostal space because it has a wider difusion range [41].Te results of the present study showed that patients who underwent TTMP during the perioperative period of median sternotomy for cardiac surgery showed a decrease in opioid use at 24 h postoperatively and a decrease in pain scores at 12 h and 24 h postoperatively.Tese fndings were related to the fact that TTMP blocked the anterior cutaneous branch of the intercostal nerve and produced analgesia in the anterior region of the sternum.Te good analgesic efect of TTMP may also be refected in the recovery benefts for patients, including prolonging the time of frst postoperative analgesia demand; shortening postoperative endotracheal tube exposure, ICU stay, and hospitalization; and decreasing the incidence of postoperative nausea and vomiting.In two studies of TTMP in pediatric cardiac surgery, TTMP was shown to be efective in providing analgesia and accelerating recovery [42,43].In addition, a study comparing the analgesic efects of TTMP with the pectointercostal fascial block in open-heart surgery showed that TTMP and pectointercostal fascial block had similar efects on morphine consumption and pain scores in cardiac surgery patients at 24 h after surgery [44].Tis fnding is not difcult to understand because although the pectointercostal fascial block is injecting local anesthetic between pectoralis major and intercostal muscles, the nerves acted on are the anterior cutaneous branch of intercostal nerves.Even some scholars suggested that it is a diferent name for the same type of nerve block [45].
Similar to other chest wall nerve blocks, TTMP is a simple and safe procedure and no block-related adverse events were described in the included studies.Sepolvere et al. noted that the TTMP injection site is adjacent to the internal mammary artery, which may have an efect on the need to access the internal mammary artery for coronary artery bypass grafting.In patients with a history of sternotomy, the tissue scarring may interfere with the difusion of the drug, thus afecting the block's efectiveness [46].Some studies attempted continuous TTMP block using catheter placement [47], but similar to continuous parasternal block, the risk of infection must be considered [48].
A recent meta-analysis study evaluated the analgesic efect of TTMP for thoracic surgery [49].However, the studies included cardiac surgery, cardiac implantable electronic device surgery, and mastectomy; moreover, the intervention was combined with other fascial blocks in some of the included studies, which showed greater heterogeneity.Te results showed a large degree of heterogeneity.In comparison, the present study has the following advantages: (1)   Journal of Cardiac Surgery to cause severe postoperative pain [50] and may provide a more accurate evaluation of the clinical efects of TTMP.
(2) Necessary sensitivity analyses and separate subgroup analyses were performed on the basis of type of surgery, timing of block, and postoperative analgesia to obtain the sources of high heterogeneity.Although the issue of high heterogeneity could not be resolved, it may be related to the fact that open-heart surgery involves complex sources of pain due to the involvement of body surface tissues, sternum, thoracic cavity, and intracardiac manipulation.Most of the studies did not mention drain placement, and the location of the drain may be a place that could not be covered by TTMP, thereby suggesting the need for more analgesic modalities to alleviate pain after cardiac surgery.In addition, each institution has its own unique pain management strategies, which were converted statistically in this study, and such diference may also be a source of heterogeneity.
(3) Tis study found that TTMP reduced patients' pain scores 24 hours after surgery.However, this result is consistent with previous studies.Local anesthetics are generally not efective for more than 24 h.We speculate that it may be related to the timing of the block.( 4) Recently added studies and non-English published studies were included, which increased the sample size of the study.Journal of Cardiac Surgery

Conclusions
Tis meta-analysis of moderate evidence confrmed that ultrasound-guided TTMP reduces opioid consumption after open-heart surgery, lowers patients' early postoperative pain scores, prolongs the time of frst analgesic demand, shortens extubation time and ICU stay, reduces the incidence of nausea and vomiting, and accelerates patients' recovery for discharge.However, a notable detail is that the complexity of cardiac surgery requires a large-scale randomized controlled trial or a multicenter study to confrm the fndings of this study.

Figure 1 :
Figure 1: Flowchart of the search strategy to identify the eligible randomized controlled trials.

Figure 2 :
Figure 2: A summary of bias for each included study.

Table 1 :
Characteristics of the included studies.
[38]k was efective on the long thoracic nerve, thoracic dorsal nerve, and lateral cutaneous branch of the intercostal nerve but less efective on the anterior cutaneous branch of the intercostal nerve[38].Song et al. applied PECS combined with paraspinal nerve block to breast cancer resection, and the postoperative pain in the combined paraspinal nerve block group was reduced compared with that in the PECS-alone group it only included open-heart surgeries, which are known