A single-blind randomized controlled trial of celiac plexus block for analgesia after whipple surgery

Abstract

Background

Effective management of both incisional and visceral postoperative pain during open abdominal surgery is crucial for patient recovery. This study evaluated the effect of celiac plexus block on postoperative pain and recovery.

Methods

This single-center, patient-assessor-blinded, blank-controlled randomized clinical trial was conducted from March 9, 2022, to November 12, 2023. A total of 78 patients scheduled for open Whipple surgery were randomized. The intervention involved either receiving a celiac plexus block (Group NB) with 20 ml of 0.5% ropivacaine during surgery or not receiving the block (Group GC). Both groups received traditional postoperative analgesia. The primary outcome was opioid consumption within 72 h post-surgery. Secondary outcomes included the frequency of analgesic pump presses, pain scores, hemodynamic parameters before and after nerve block as well as postoperatively, levels of postoperative inflammatory markers, time to first flatus, length of postoperative hospital stay, and perioperative complications.

Results

Among the 78 patients enrolled, 37 were randomized to receive intraoperative celiac plexus block and 41 were not. In total, 12 patients (8 in group GC and 4 in group NB) were excluded because of protocol deviations, and 66 patients (33 in each group) were included in the per-protocol analysis. Group NB demonstrated significantly lower total opioid consumption within the first 72 h post-surgery than group GC (mean (SD), 66 (18.8) mg vs. 88.9 (21.2) mg, respectively; P < 0.01). Pain scores assessed using the Visual Analog Scale were consistently lower in group NB at all postoperative time points (all P < 0.05). The first press of the patient-controlled analgesia (PCA) pump occurred significantly later, and the daily frequency of PCA pump presses was lower in group NB. The time to first flatus and length of postoperative stay were shorter in group NB but not statistically significant. Only inflammatory markers showed significantly lower C-reactive protein (CRP) levels in group NB at 24 h postoperatively. Hemodynamic monitoring results indicated that it had a minor impact.

Conclusion

We confirmed that the direct-vision intraoperative celiac plexus block is a safe and effective procedure that significantly reduces postoperative opioid consumption and pain scores. Further studies with larger sample sizes are warranted to confirm these findings and explore long-term outcomes.

Trial registration

Clinical Trial Registry Identifier: NCT05205720. Registered on January 25, 2022.

Introduction

Currently, complex surgeries still require open procedures, resulting in significant postoperative pain and delayed gastrointestinal recovery [1]. Postoperative pain from abdominal surgery is primarily due to incisional and visceral sources [2]. Despite numerous abdominal wall nerve blocks effectively manage incisional pain [3, 4], visceral pain also significantly impedes recovery [5, 6]. However, research on postoperative analgesia following visceral nerve blockade is limited.

According to anatomical studies, the visceral branches of the autonomic nervous system emit preganglionic fibers into the celiac ganglia. After converging with fibers from the sympathetic nervous system, they emit postganglionic fibers, which branch along the blood vessels to innervate the upper abdominal organs. The celiac plexus is located anterior to the T₁₂-L₁ vertebral bodies within the tissues on either side of the abdominal aorta [7, 8] (Fig. 1).

In treating chronic upper abdominal pain, especially in pancreatic cancer, metastases affecting pancreas [9], celiac plexus block (CPB) [10, 11] via anterior and posterior approaches has been effective and safe. Some studies have used intraoperative CPB as a part of multimodal analgesia, but their quality is limited and conclusions vary [12,13,14]. Animal studies have indicated that CPB can significantly reduce stress responses and enhance gastrointestinal motility, potentially improving postoperative recovery [15, 16]. Although CPB has been proposed for abdominal surgery anesthesia since 1927, its use in postoperative pain control remains under-researched. A recent study suggested that combining CPB with wound infiltration reduces opioid consumption and shortens gastrointestinal post-anesthesia recovery time [13].

Based on these insights, we designed a prospective study to evaluate the efficacy, feasibility, and safety of CPB in patients undergoing Whipple surgery, which usually results in severe postoperative pain. We compared traditional analgesia with or without CPB to assess its impact on postoperative outcomes.

Materials and methods

Study design and settings

This single-center, patient-assessor-blinded, blank-controlled randomized clinical trial enrolled the first patient on March 9, 2022, and ended on November 12, 2023, in China. The study adhered to the Consolidated Standards of Reporting Trials (CONSORT) guidelines and was approved by the Ethics Committee of the Second Affiliated Hospital of Zhejiang University (Study 2021 − 1022). All participants signed informed consent to participate in this study prior to enrollment to ensure compliance with the Declaration of Helsinki’s standards for human research.

Patient selection criteria

During the study period, patients scheduled to undergo open Whipple surgery were screened. The inclusion criteria were as follows: (1) age ≥ 18years; (2) received open Whipple surgery. The exclusion criteria were as follows: (1) patients unable to cooperate with evaluations; (2) patients with history of drug abuse, non-standard surgical procedures, planned postoperative ICU admission, local anesthetic allergy, anatomical variation of the celiac ganglia indicated by abdominal CT, abdominal aortic diseases, or an American Society of Anesthesiologists (ASA) classification of 4 or 5. Withdrawal criteria: Patients who underwent unplanned surgeries, required reintubation or a second surgery, received ICU care within three days post-surgery, died within two weeks post-surgery, or experienced any unexpected events were withdrawn from the study.

Randomization and blinding

Randomization was conducted using a computer-generated table of random numbers, with allocation concealment achieved using the sealed envelope technique. Eligible participants were randomized in a 1:1 ratio to receive either a celiac plexus block (group NB, nerve block) or no block (group GC, blank control) during surgery based on the number in the envelopes. Only the patients and the postoperative follow-up staff of the Acute Pain Service (APS) team (anesthetic nurses trained in postoperative pain management) were blinded. For patient safety, surgeons, anesthesiologists, and other healthcare personnel were not blinded to the treatment group. The study statisticians were not involved in patient recruitment or surgical procedures.

General anesthesia protocol

All enrolled patients followed our hospital’s standard general anesthesia protocol for such surgeries. Upon entering the operating room, patients were routinely monitored with ECG, HR, NIBP, SpO₂, and BIS. Radial artery cannulation and central venous catheterization were performed under ultrasonographic guidance. Invasive arterial pressure and pulse contour cardiac output monitoring (PulsioFlex, ProAQT) were obtained via radial artery access.

Anesthesia induction drugs included midazolam (3–5 mg), etomidate (0.2 mg/kg), sufentanil (0.5–0.8 µg/kg), and rocuronium (0.6 mg/kg). Anesthesia maintenance consisted of propofol and remifentanil infusion pumps, supplemented with sevoflurane. Cisatracurium (5 mg) was administered every 40–60 min as needed, along with intermittent supplementation of sufentanil. Fluid infusion includes crystalloids, colloids, and blood products. At the end of the surgery, dexamethasone (5 mg) and palonosetron (0.25 mg) were administered to prevent postoperative nausea and vomiting.

After the incision was sutured, ultrasound-guided abdominal wall nerve block was performed with 0.3% ropivacaine (Naropin^®, AstraZeneca) diluted to 50 ml. The type of nerve block was determined based on the surgical incision. For rooftop incisions, a subcostal transversus abdominis plane block was used, while for midline incisions, a combination of rectus sheath block and transversus abdominis plane block was selected.

After surgery, patients were transferred to the Post-Anesthesia Care Unit (PACU). Once the patient recovered naturally and was assessed for safety, endotracheal extubation was performed. The patients were then transferred back to the ward after being observed for no abnormalities.

All patients received intravenous PCA pumps with local area network data transmission capabilities. The pump contained 250 mL normal saline, including weight-adjusted hydromorphone (12 mg for patients weighing < 50 kg, 14 mg for patients weighing 50–60 kg, 16 mg for patients weighing 60–70 kg, 18 mg for patients weighing 70–80 kg, and 20 mg for patients weighing > 80 kg). The background infusion rate was set at 2 ml/hour, with a single bolus of 5 ml available every 15 min, if needed. If patients experienced inadequate pain relief after using the analgesia pump, ward physicians administered dezocine (5–10 mg per dose) or other opioid medications as needed until satisfactory pain control was achieved.

CPB technique

In group NB, additional vision-guided transabdominal CPB was performed intraoperatively by the surgeon. Before closing the abdomen, the celiac artery and celiac trunk were re-exposed. The target blockade site was at the level of the root of the celiac trunk within the tissues on both sides of the abdominal aorta (Fig. 1). A 25-gauge, 6 cm puncture needle connected to an extension tube and a syringe was used. The surgeon stabilized the celiac artery and celiac trunk with the left hand, while inserting the needle with the right hand. The assistant created negative pressure. If no blood or fluid was aspirated, 10 ml of 0.5% ropivacaine diluted in saline (Naropin^®, AstraZeneca) was slowly injected per side with several aspirations. After needle withdrawal, if necessary, hemostasis was achieved using low-energy electrocoagulation or vascular suturing.

Fig. 1

Anatomy of the celiac plexus. This image is taken from the 3Dbody APP and has been used with permission

Outcome measures

The primary study outcome was equivalent morphine consumption within 72 h post-surgery, including the consumption of PCA pumps and rescue analgesic medication.

The secondary study outcomes included mean arterial pressure (MAP), heart rate (HR), cardiac index (CI), and systemic vascular resistance index (SVRI) before and 5, 10, and 20 min after CPB. Laboratory tests including white blood cell count (WBC), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), interleukin-6 (IL-6), and procalcitonin (PCT) were measured at the end of surgery and 24 h post-surgery. Postoperative VAS scores during both rest and cough were assessed after extubation and at 6, 12, 24, 48, and 72 h post-surgery. MAP, HR and SpO₂ were monitored and recorded every 12 h post-surgery for 72 h. Additional outcomes included the time to first pump press, daily frequency of pump presses, time to first flatus, length of postoperative hospitalization, and incidence of adverse events and complications during the perioperative period.

Sample size

Using data from a previous study [13], the calculated effect size (d) was approximately 0.69. Assuming an equal allocation ratio (1:1) between the two groups, with α = 0.05 and β = 0.2, the corresponding values are Z_1α/2 = 1.96 and Z_1−β ≈ 0.84. Using the formula: n=$\:2\times\:{\left(\frac{{z}_{1-\frac{\alpha\:}{2}}+{z}_{1-\beta\:}}{d}\right)}^{2}$, the required sample size per group is calculated as n = 33. Considering an anticipated dropout rate of 10–20% during the study, the total sample size is estimated to be approximately 74–82 participants.

Statistical analysis

For continuous variables, the mean or median was used depending on the distribution. Categorical variables are expressed as percentages. Differences between groups were assessed using independent-sample t-tests, Mann-Whitney U tests and χ² tests. Statistical analysis was conducted using IBM SPSS version 20 software (IBM, Armonk, New York, USA), with significance set at P < 0.05 (two-tailed).

Results

General characteristics of patients

From March 2022 to November 2023, 141 patients received Whipple surgery in our institution and 78 were enrolled in the study. 12 patients were excluded, leaving 66 patients for analysis. Among the excluded patients, 5 were transferred to the ICU unexpectedly, 4 had intraoperative procedure changes, 2 experienced severe vomiting resulting in minimal use of the PCA pump, and 1 encountered PCA pump malfunction (Fig. 2). The baseline characteristics of the two groups were comparable, with no statistically significant differences observed (Table 1).

Fig. 2

CONSORT flow diagram. Patients in group NB received celiac plexus block (CPB) during the surgery, while those in group GC did not

Table 1 Patient characteristics and intraoperative data

Primary outcome

The data analysis of 66 patients revealed that within 72 h after surgery, the consumption of opioid medications on day 1 (0–24 h), day 2 (24–48 h), and day 3 (48–72 h) was consistently lower in group NB than in group GC (P < 0.05) after conversion to morphine equivalent doses. Further calculation of the effect size for total morphine consumption yielded a Cohen’s d value of 1.14, indicating a large difference between the two groups (Table 2; Fig. 3).

Secondary outcomes

In group NB, the first press of the PCA pump occurred later than that in group GC. The daily frequency of presses within 72 h was consistently lower in group NB, with significant differences except on the third day. Group NB showed earlier time to first flatus and shorter postoperative stay than group GC, though these differences were not statistically significant.

Regarding blood inflammatory indices, group NB had significantly lower CRP levels than group GC at 24 h postoperatively, while other differences were not statistically significant (Table 2). Postoperative VAS scores, both at rest and during cough, were significantly lower in group NB than in group GC at all assessment time points (Fig. 4).

Within group NB, hemodynamic changes during the CPB procedure. Among the measured parameters, only SVRI exhibited statistically significant changes at 10 and 20 min post-CPB initiation compared with pre-CPB values (Table 3). Considering the possibility of circulatory instability following CPB, MAP, HR and SpO₂ were recorded every 12 h postoperatively. All these values remained within the safe ranges. Statistically significant differences between the two groups were observed only at 12 h and 24 h postoperatively for HR and at 72 h postoperatively for MAP (Fig. 5).

Fig. 3

Opioid consumption in 72 h post-surgery. D1 (0–24 h), D2 (24–48 h), and D3 (48–72 h). Pink dots represent individual patient consumption in group GC, while green dots represent consumption in group NB

Table 2 Primary and selected secondary outcomes

Fig. 4

Postoperative pain assessment assessed by Visual Analog Scale (VAS). The pain scores at different time points in the rest (left) and cough (right) state were presented and compared in group NB and group GC. The pain scores in group NB were significantly lower than those in group GC at all time points (all P <0.05)

Table 3 Hemodynamic changes during CPB procedure

Fig. 5

Basic vital signs within 72 h postoperatively. The HR (left) and MAP (right) at each time after surgery were presented and compared in group NB and group GC. T0 denotes the time of discharge from the recovery room, while T12 to T72 represent consecutive 12-hour intervals from 12 to 72 hours postoperatively. ** P < 0.05

Adverse events

All patients successfully underwent surgical procedures. No signs of local anesthetic toxicity such as arrhythmias or depression of respiration were observed during the perioperative period. In group NB, two patients experienced localized bleeding following puncture, which was effectively managed with electrocautery. Additionally, there were no cases of severe diarrhea or postoperative hypotension in group NB. Severe nausea and vomiting occurred in 2 patients in group NB and 4 patients in group GC. In group GC, two patients had to stop using the analgesic pump due to severe vomiting and were subsequently excluded. Moreover, severe postoperative bloating or secondary gastroparesis was observed in three patients in group GC but not in group NB.

There were two fatalities in group NB. One case was a patient over 80 years old who developed postoperative renal failure leading to multiple organ dysfunction. The patient was transferred to the ICU on the fourth postoperative day and died approximately one month later. Another one was a patient over 70 years old who was discharged after 28 days but required emergency surgery for severe wound bleeding a week post-discharge and then died.

Discussion

Postoperative pain following open abdominal surgery remains severe and greatly affects recovery outcomes. This study explored the role of a single celiac plexus block (CPB) in early pain management after Whipple surgery. The results demonstrated that an additional intraoperative CPB, compared to performing only abdominal wall nerve block, significantly reduced opioid consumption within the first 72 h postoperatively. Similarly, patients who received CPB exhibited significantly lower pain scores within 72 h postoperatively, both at rest and during cough. Regarding safety, hemodynamic monitoring before and after the CPB procedure only revealed a significant decrease in SVRI, but all parameters remained within the normal ranges. Despite the risks for postoperative circulatory instability and significant systemic effects of ropivacaine, recordings of vital signs indicated that the CPB procedure had only a minimal impact. These findings suggest that CPB is both effective and safe.

Additionally, opioid-sparing effects and comprehensive analgesia may accelerate postoperative recovery. Our results indicated that patients who received CPB had faster gastrointestinal recovery and shorter hospital stay, although these differences did not reach statistical significance. Lastly, considering the sympathetic-endocrine system’s role in inflammatory activity post-surgery, we compared the postoperative inflammation levels. Among the common inflammatory markers, the CPB procedure only reduced the CRP levels. The specific mechanisms and potential clinical implications of these findings warrant further investigation.

Our study closely references the retrospective study by Teo [13] and reaches largely consistent conclusions. In Teo’s study, 38 patients who underwent open abdominal surgeries were included. One group received intraoperative CPB and bilateral continuous preperitoneal local anesthetic infusion, while the other group received only preperitoneal infusion (PPI). The CPB procedure was in line with ours. A total of 10–20 ml of 0.25% bupivacaine was administered. All patients had bilateral pre-peritoneal catheters inserted for continuous nerve block and a PCA pump for intravenous analgesia. The results showed that within the first 48 h postoperatively, the total morphine consumption in the combined block group decreased by approximately 50% (36.1 mg vs. 78 mg). Our patients’ morphine consumption was slightly higher, possibly due to Teo’s use of continuous abdominal wall nerve block. Regarding postoperative recovery, Teo evaluated the proportion of patients ambulating daily and found no significant differences between the groups. Considering the numerous factors influencing ambulation, we chose to measure the time to the first flatus, but similarly did not observe a significant improvement.

CPB is already a very mature clinical operation. There are not only different approaches but also different guided methods such as ultrasound, CT, and X-ray. However, these methods all have uncertainties for successful blocks. Therefore, we believe that intraoperative direct vision guidance based on anatomical positioning is better when CPB is applied to postoperative analgesia. But in laparoscopic surgery, visceral pain often exceeds abdominal wall pain, suggesting a broader application potential for the CPB technique. Several small studies have delved into this topic and concluded that it can significantly improve postoperative pain [12, 14]. However, more rigorously designed clinical trials are required to validate these findings.

In addition, we did not elaborate on the postoperative use of non-opioid drugs. We usually use NSAIDs to participate in postoperative pain control. However, during the entire study period, the actual use of NSAIDs in our institution was changed several times due to policy changes in medical insurance and pharmacy management. As a result, patients in different periods used different drugs, such as flurbiprofen, ketorolac, indomethacin, etc. But considering the situation of two groups in the same period is basically similar. We still believe that the main research conclusion is reliable.

Our study appears to have a relatively high exclusion rate (12/78 ≈ 15%). The main reason for exclusion is that the treatments of these patients did not follow the original research protocol, resulting in inaccurate primary outcome and inability to collect secondary outcomes. Therefore, we believe that these data cannot be statistically analyzed according to the intention-to-treat principle. In retrospect, Whipple surgery is difficult, although radiological approach could provide important clinical features [17], there are still many intraoperative changes, making it difficult to accurately predict the surgical outcome. Some dropout patients should indeed not have been considered for inclusion in the initial evaluation stage. If these patients are removed, our dropout rate will be greatly reduced.

Focusing on the nerve block itself, issues such as indicators of a successful block and the duration of a single block are also worthy of attention. Unlike stellate ganglion blocks causing facial vasodilation and lumbar sympathetic blocks leading to increased skin temperature [18, 19], early changes induced by CPB may lack clear indicators. However, in our study, the changes in SVRI before and after CPB caught our attention. Anesthesiologists have reported that blood pressure commonly dropped 3–5 min after the CPB procedure, small doses of norepinephrine are often needed to stabilize blood pressure until it returns to normal after approximately 10 min. This phenomenon aligns with the mechanism of CPB, in which sympathetic nerve blockade leads to decreased local vascular SVRI and blood pressure. Owing to the compensatory response of the systemic blood pressure regulation system, these changes are temporary. Therefore, we suggest that invasive blood pressure or more precise SVRI changes could serve as indicators of successful CPB. Nonetheless, further detailed research is required to validate this hypothesis. The duration of a nerve block is typically determined by the time until the block effect disappears; however, the block effect of CPB is difficult to measure directly. We hypothesized that the time of the patient’s first press of the analgesic pump would roughly reflect the duration of CPB. Based on this, we concluded that CPB at the given concentration could last for approximately 20 h, which is sufficient to cover early postoperative pain.

In our study, we used 20 ml of 0.5% ropivacaine for CPB and 50 ml of 0.3% ropivacaine for abdominal wall block, aiming to use slightly higher concentrations to avoid uncertain block failures. In fact, injecting near blood vessels has always carried systemic effects due to drug absorption, which may lead to earlier onset of analgesia but also increases the risk of ropivacaine toxicity. But these are also considered part of the nerve block effect. The total dose of ropivacaine used was 250 mg, which exceeded the generally accepted safe dose of 200 mg. However, since ropivacaine was administered at different sites and times, we believe that the risk of drug toxicity was low. Continuous vital signs monitoring supports this assessment.

Advantages

This research zeroed in on the issue of visceral pain following Whipple surgery, a concern that is frequently overlooked in clinical practice and leads to heightened patient suffering. Our study is a randomized controlled trial aiming to demonstrate the potential of CPB. Additionally, the detailed description of the CPB procedure provided can serve as a valuable reference for other researchers.

Limitations

First, the main limitation of this study was its small sample size. Some observed indicators showed differences that lacked significant clinical significance, which might become more pronounced with a larger sample size. Second, only the time to first flatus is used to reflect the recovery of gastrointestinal function, without evaluating sleep quality and anxiety for comprehensive recovery. Third, for patient safety, neither the surgeons nor the anesthesiologists were blinded. This may have introduced bias. Fourth, we didn’t set a placebo control group which would have been better for trial principles because the ethics committee thought it was only risky without benefit for control group patients. Another limitation of this study is the use of two different abdominal wall block techniques, which may introduce variability in postoperative pain management outcomes. While existing literature and our clinical experience suggest comparable analgesic effects, individual responses to these techniques could vary.

Conclusion

Our study confirmed that direct-vision intraoperative celiac plexus block is a safe and effective procedure. This can be a crucial component of multimodal analgesia for postoperative pain management in open abdominal surgery like Whipple. Future studies with larger sample sizes are essential to validate its findings.