Gastrointestinal Complications After Pancreatoduodenectomy With Epidural vs Patient-Controlled Intravenous Analgesia: A Randomized Clinical Trial | Anesthesiology | JAMA Surgery | JAMA Network
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Figure.  CONSORT Flow Diagram
CONSORT Flow Diagram

EDA indicates perioperative thoracic epidural analgesia; and PCIA, patient-controlled intravenous analgesia.

aVisit 7 was performed 30 days after the index operation. In 4 patients, the telephone visit could not be performed at the exact date and was performed either more than 7 days before or 7 days after the planned date. This was assessed as protocol violation and these patients were not included in the per-protocol analysis.

Table 1.  Baseline and Clinical Characteristics of the Modified Intention-to-Treat Population
Baseline and Clinical Characteristics of the Modified Intention-to-Treat Population
Table 2.  Intraoperative Characteristics of the Modified Intention-to-Treat Population
Intraoperative Characteristics of the Modified Intention-to-Treat Population
Table 3.  Secondary Outcomes Including Postoperative Complications of the Modified Intention-to-Treat Population
Secondary Outcomes Including Postoperative Complications of the Modified Intention-to-Treat Population
Table 4.  Pain Level on Numeric Rating Scale, Transfusion of Blood Products, Fluid Management, and Administration of Vasopressors of the Modified Intention-to-Treat Population
Pain Level on Numeric Rating Scale, Transfusion of Blood Products, Fluid Management, and Administration of Vasopressors of the Modified Intention-to-Treat Population
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    Original Investigation
    May 27, 2020

    Gastrointestinal Complications After Pancreatoduodenectomy With Epidural vs Patient-Controlled Intravenous Analgesia: A Randomized Clinical Trial

    Author Affiliations
    • 1Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany
    • 2The Study Centre of the German Surgical Society, Heidelberg University Hospital, Heidelberg, Germany
    • 3Department of Anaesthesiology, Heidelberg University Hospital, Heidelberg, Germany
    • 4Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany
    • 5Department of General, Visceral, Transplant, Vascular and Paediatric Surgery, University Hospital of Würzburg, Würzburg, Germany
    • 6Department of Anaesthesiology and Critical Care, University Hospital of Würzburg, Würzburg, Germany
    • 7Surgical and Oncological Department, Pancreas Institute, University Hospital Trust, Verona, Italy
    • 8Department of Anaesthesiology and Intensive Care, Verona University Hospital, Verona, Italy
    • 9Department of General, Visceral, Thorax and Transplantation Surgery, Klinikum Stuttgart, Katharinenhospital, Stuttgart, Germany
    • 10Department of Anaesthesiology and Operative Intensive Care, Klinikum Stuttgart, Katharinenhospital, Stuttgart, Germany
    • 11Department of Anesthesiology and Intensive Care, Philipps-University Marburg, Marburg, Germany
    • 12Department of General and Visceral Surgery, Medical Centre, University of Freiburg, Freiburg, Germany
    • 13Department of Anaesthesiology and Critical Care, Medical Centre, University of Freiburg, Freiburg, Germany
    • 14Department of Surgery, University Medical Centre Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
    • 15Department of Anaesthesiology and Intensive Care, University Medical Centre Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
    • 16Department of Visceral, Thoracic, Transplant and Paediatric Surgery, Justus Liebig University of Giessen, Giessen, Germany
    • 17Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy, Justus Liebig University of Giessen, Giessen, Germany
    • 18Department of Surgery, General Public Hospital of the Brothers of St John of God, St Veit/Glan, Austria
    • 19Department of Anaesthesiology and Intensive Care Medicine, General Public Hospital of the Brothers of St John of God, St Veit/Glan, Austria
    • 20Department of Abdominal Surgery, University Medical Centre Ljubljana, Ljubljana, Slovenia
    • 21Clinical Department of Anaesthesiology and Intensive Therapy, University Medical Centre Ljubljana, Ljubljana, Slovenia
    JAMA Surg. 2020;155(7):e200794. doi:10.1001/jamasurg.2020.0794
    Key Points

    Question  Does postoperative patient-controlled intravenous analgesia decrease the occurrence of gastrointestinal complications after pancreatic surgery compared with perioperative thoracic epidural analgesia?

    Findings  In this randomized clinical trial of 248 patients, the primary end point of gastrointestinal complications after pancreatic surgery did not differ between patients receiving postoperative patient-controlled intravenous analgesia and those receiving perioperative thoracic epidural analgesia.

    Meaning  The choice between patient-controlled intravenous analgesia and thoracic epidural analgesia after pancreatic surgery should not be based on concerns regarding gastrointestinal complications; the 2 methods are comparable with regard to effectiveness and safety.

    Abstract

    Importance  Morbidity is still high in pancreatic surgery, driven mainly by gastrointestinal complications such as pancreatic fistula. Perioperative thoracic epidural analgesia (EDA) and patient-controlled intravenous analgesia (PCIA) are frequently used for pain control after pancreatic surgery. Evidence from a post hoc analysis suggests that PCIA is associated with fewer gastrointestinal complications.

    Objective  To determine whether postoperative PCIA decreases the occurrence of gastrointestinal complications after pancreatic surgery compared with EDA.

    Design, Setting, and Participants  In this adaptive, pragmatic, international, multicenter, superiority randomized clinical trial conducted from June 30, 2015, to October 1, 2017, 371 patients at 9 European pancreatic surgery centers who were scheduled for elective pancreatoduodenectomy were randomized to receive PCIA (n = 185) or EDA (n = 186); 248 patients (124 in each group) were analyzed. Data were analyzed from February 22 to April 25, 2019, using modified intention to treat and per protocol.

    Interventions  Patients in the PCIA group received general anesthesia and postoperative PCIA with intravenous opioids with the help of a patient-controlled analgesia device. In the EDA group, patients received general anesthesia and intraoperative and postoperative EDA.

    Main Outcomes and Measures  The primary end point was a composite of pancreatic fistula, bile leakage, delayed gastric emptying, gastrointestinal bleeding, or postoperative ileus within 30 days after surgery. Secondary end points included 30-day mortality, other complications, postoperative pain levels, intraoperative or postoperative use of vasopressor therapy, and fluid substitution.

    Results  Among the 248 patients analyzed (147 men; mean [SD] age, 64.9 [10.7] years), the primary composite end point did not differ between the PCIA group (61 [49.2%]) and EDA group (57 [46.0%]) (odds ratio, 1.17; 95% CI, 0.71-1.95 P = .54). Neither individual components of the primary end point nor 30-day mortality, postoperative pain levels, or intraoperative and postoperative substitution of fluids differed significantly between groups. Patients receiving EDA gained more weight by postoperative day 4 than patients receiving PCIA (mean [SD], 4.6 [3.8] vs 3.4 [3.6] kg; P = .03) and received more vasopressors (46 [37.1%] vs 31 [25.0%]; P = .04). Failure of EDA occurred in 23 patients (18.5%).

    Conclusions and Relevance  This study found that the choice between PCIA and EDA for pain control after pancreatic surgery should not be based on concerns regarding gastrointestinal complications because the 2 procedures are comparable with regard to effectiveness and safety. However, EDA was associated with several shortcomings.

    Trial Registration  German Clinical Trials Register: DRKS00007784

    Introduction

    Although the mortality rate of pancreatic surgery has decreased to less than 5% at high-volume centers, morbidity is still high, driven mainly by surgical complications.1 Adequate perioperative analgesia is a key component of the Enhanced Recovery After Surgery (ERAS) Society principles2 and reduces complications.3

    Perioperative thoracic epidural analgesia (EDA) is advocated by current guidelines as first-line therapy after major abdominal surgery2,4 but carries a low risk of epidural hematoma5 and has high failure rates.6 Perioperative thoracic epidural analgesia is achieved by injection of local anesthetics with or without concomitant opioids into the epidural space. Epidural injections attenuate the endocrine-metabolic responses and lower stress-induced organ dysfunctions.3 In addition, the sympathetic block promotes vasodilation.7 Thus, EDA can provoke undesirable hypotension,8 which is a risk factor for surgical complications.9 Subsequent immoderate fluid administration and vasopressor treatment are also thought to contribute to postoperative morbidity, including anastomotic insufficiency.10,11 Patient-controlled intravenous analgesia (PCIA) is a reasonable alternative to EDA that is presumably associated with less fluid administration and vasopressor treatment.

    Most previous trials comparing PCIA with EDA focused predominantly on the effectiveness of analgesia. Some studies demonstrated a statistically significant but not clinically relevant superiority of EDA,12 while others reported noninferiority of PCIA.13 The evidence for the effects of EDA on morbidity and mortality in abdominal surgery is controversial14-16; the evidence on the cardiovascular and respiratory effects also remains inconclusive.14,17,18

    Even if EDA is said to promote surgical complications, reporting of clearly defined surgical complications is rare in previous trials. To date, no randomized clinical trial has independently examined surgical outcomes of EDA after pancreatic surgery. In a retrospective study, Pratt et al19 reported that pain management after elective partial pancreatoduodenectomy with PCIA vs EDA was associated with a 15% lower occurrence of postoperative gastrointestinal complications, including pancreatic fistula, bile leakage, delayed gastric emptying, postoperative gastrointestinal bleeding, and postoperative ileus. Reduction of clinically relevant complications after pancreatic surgery would be important, with the potential to change daily practice. Thus, the aim of this trial was to investigate whether the frequency of gastrointestinal complications after partial pancreatoduodenectomy could be reduced by 15% with the use of postoperative PCIA compared with EDA in a multicenter randomized controlled setting. We postulated that healing of anastomoses may be compromised by increased intraoperative administration of vasopressors and intravenous fluids due to the antisympathetic, vasodilatory effects of EDA.

    Methods
    Trial Design and Participants

    The PAKMAN trial was an adaptive, pragmatic, multicenter, superiority randomized clinical trial with 2 parallel study groups. The trial was conducted from June 30, 2015, to October 1, 2017, in 9 centers for pancreatic surgery located in Germany (n = 6), Austria (n = 1), Slovenia (n = 1), and Italy (n = 1). Detailed information about inclusion and exclusion criteria as well as trial visits is provided in the trial protocol.20 After providing written informed consent, adult patients scheduled to undergo elective partial pancreatoduodenectomy were included unless they had known chronic pancreatitis, chronic pain syndrome, severe chronic obstructive pulmonary disease (Global Initiative for Chronic Obstructive Lung Disease stage≥III),21 American Society of Anesthesiologists status IV or more, or any contraindication to the use of PCIA or EDA.22 The PAKMAN trial protocol20 and other relevant documents were approved by the independent ethics committee of all participating institutions (Ethikkommission der Medizinischen Fakultät Heidelberg, Comitato Etico delle Province di Verona e Rovigo, Ethikkommission der Landesärztekammer Baden-Württemberg, Ethikkommission der Albert-Ludwigs-Universität Freiburg, Ethikkommission der Universität zu Lübeck, Ethikkommission am Fachbereich Medizin der Justus-Liebig Universität Gießen, Ethikkommission des Landes Kärnten, Komisija za medicinsko etiko [KME], rebublika slovenija, ministrstvo za sdravje) (trial protocol in Supplement 1). The trial was conducted in accordance with the ethical principles of the Declaration of Helsinki23 and the principles of Good Clinical Practice.24 Reporting of the trial complied with the recommendations of the Consolidated Standards of Reporting Trials (CONSORT) guideline.25 The PAKMAN trial was registered with the German Clinical Trials Register (DRKS00007784) on March 23, 2015. PAKMAN was designed, managed, and analyzed by the Study Center of the German Surgical Society.

    Randomization and Masking

    Patients were randomized to receive either PCIA or EDA prior to surgery using a central web-based randomization tool (http://www.randomizer.at). Randomization was stratified by each center and performed with a block size of 4. Trial personnel not involved in the treatment of participants conducted randomization. Masking of patients and physicians involved in treatment was not possible.

    Interventions

    Detailed information about surgical procedures and trial interventions are provided in the published protocol.20 Owing to the nature of a pragmatic trial, the applied interventions were performed according to local practice. In the PCIA group, intravenous opioids for postoperative analgesia were administered via a patient-controlled analgesia device. In the EDA group, prior to induction of general anesthesia, a thoracic epidural catheter was inserted and used intraoperatively and postoperatively according to local standards to achieve anesthesia. Local anesthetics with or without opioid analgesics were infiltrated continuously into the epidural space for at least 2 postoperative days. Type of medication, dosage, and use of additional pain medication were left to the discretion of the trial sites. Most patients received an epidural catheter at level Th 6 to 8. After exclusion of intrathecal catheter placement, most patients received a bolus injection of 10 mL (5 mg/mL) of ropivacaine hydrochloride supplemented by 20 μg of sufentanil citrate prior to surgery. Intraoperative administration of repetitive doses was left to the discretion of the treating anesthetist. In the postoperative period, most patients received a continuous epidural infusion of 6 to 8 mL (2 mg/mL) of ropivacaine hydrochloride supplemented with sufentanil. The rate of infusion was adapted to patients’ needs, with the aim to remove the epidural catheter on postoperative day 4.

    Outcomes

    Detailed information about the end points of the PAKMAN trial can be found in the published trial protocol.20 The primary end point was defined according to the retrospective study by Pratt et al19 as manifestation of 1 of the following complications within 30 days after the index operation: pancreatic fistula,26 bile leakage,27 delayed gastric emptying,28 gastrointestinal bleeding,20 or postoperative ileus.20

    The secondary end points were single items of the primary end point, 30-day mortality, neuraxial hematoma, any neurologic complication, pneumonia, urinary tract infection, wound infection, intra-abdominal abscess, intra-abdominal bleeding, pain, duration of surgery, administered blood products, intraoperative and postoperative rates of vasopressor therapy and amount of the primary vasopressor norepinephrine, intraoperative and postoperative fluid substitution, postoperative weight change, number of days in the intensive care unit, length of hospital stay, revision surgery, and readmission rate.

    Serious adverse events (SAEs) were assessed in all patients. The intensity, outcome, and causal relationship to the trial intervention of each SAE had to be classified at the individual trial sites and reported to the coordinating investigator.

    Statistical Analysis

    Data were analyzed from February 22 to April 25, 2019. The confirmatory analysis of the trial was primarily based on the full analysis set according to the intention-to-treat principle, taking into account all patients randomized to 1 of the study groups who received partial pancreatoduodenectomy and underwent at least 1 postoperative trial visit. In addition to the full analysis set, a per-protocol analysis was performed as a sensitivity analysis. For the safety analysis, an additional as-treated analysis set was used. A logistic regression model incorporating the covariates intervention (PCIA or EDA), age (years), body mass index (calculated as weight in kilograms divided by height in meters squared), sex (male or female), and surgeon’s experience (≤25, 26-50, 51-75, or >75 operations performed) was applied to analyze the primary end point.

    For the secondary end points, means and SDs or absolute and relative frequencies are reported and descriptive analyses were performed. For categorical variables, absolute numbers and frequencies are presented and the χ2 test was used; for continuous variables, means and SDs are reported and the Mann-Whitney test was used. As a measure of treatment effect, odds ratios were computed for binary outcome parameters and mean differences for continuous end points, each together with their 95% CIs. All P values were from 2-sided tests and results were deemed statistically significant at P < .05.

    All statistical analyses were performed with SAS, version 9.4 (SAS Institute Inc). The trial was overseen by a data safety monitoring board.

    Sample Size Calculation

    The sample size calculation was based on an expected difference of 15% (19% vs 34%) in the frequency of gastrointestinal complications between postoperative PCIA and EDA up to postoperative day 30, as reported by Pratt et al.19 To account for uncertain transferability of these rates to our cohort, we chose a 2-stage group sequential design according to O’Brien and Fleming.29 This design allowed adjustment of the sample size or termination of the trial for reasons of either futility or efficacy after the primary end point was available for two-thirds of the total patient cohort. The study was planned to be stopped prematurely if the first-stage P value for the difference between PCIA and EDA was below 0.0146 or above 0.40. With a level of significance α = 5% and a power of 1−β = 80%, a total sample size of 278 patients (139 per group) would have been required to confirm a difference of 15%. To account for perioperative dropouts, an additional 92 patients were planned to be recruited, resulting in a total of 370 patients.

    Results
    Trial Flow

    Between June 30, 2015, and October 1, 2017, 371 patients were randomly assigned to receive PCIA (n = 185) or EDA (n = 186), of whom 248 patients (124 in each group) were analyzed (Figure). Sixty patients in the PCIA group and 59 patients in the EDA group were excluded from the primary analysis because they did not undergo partial pancreatoduodenectomy, but rather underwent total pancreatectomy (n = 38), exploratory laparotomy (n = 32), palliative bypass procedure (n = 21), local resection (n = 16), pancreatic left resection (n = 7), or another type of surgery (n = 5). Three patients were excluded because of the lack or withdrawal of consent early after randomization (PCIA, 1; and EDA, 2).

    The planned interim analysis was performed in January 2018. On the basis of the results of the interim analysis, the data safety monitoring board recommended that the null hypothesis should be accepted. However, it was not planned to stop recruiting during the interim analysis, and all 370 patients had already been randomized when the data safety monitoring board recommended termination of the trial.

    Patients’ Baseline Characteristics and Intraoperative Data

    The baseline characteristics of the trial participants are presented in Table 1. Sex, age, body weight, body mass index, and comorbidities were well balanced between the groups. The characteristics of the surgical procedure were also comparable between the groups (Table 2).

    Primary and Secondary End Points

    The primary composite end point, postoperative gastrointestinal complications, did not differ between the PCIA group (61 [49.2%]) and EDA group (57 [46.0%]; odds ratio, 1.17; 95% CI, 0.71-1.95; P = .54). Moreover, sex, age, body mass index, and surgeon’s experience showed no significant association with occurrence of the primary composite end point. None of the sensitivity analyses (per-protocol set and as-treated set) affected the results for the primary end point.

    The secondary end point of 30-day mortality was similar between the groups (PCIA, 4 [3.2%] vs EDA, 3 [2.4%]; P = .70). The causes of death were cholangiosepsis (n = 1), insufficiency of biliodigestive anastomosis (n = 1), insufficiency of the pancreatojejunostomy (n = 3), ischemia of the small intestine (n = 1), and thrombosis of the hepatic artery with subsequent liver failure (n = 1).

    Individual gastrointestinal complications also showed no major differences between the groups (Table 3). Clinically relevant pancreatic fistula occurred equally frequently (PCIA, 26 [21.0%]; and EDA, 23 [18.5%]; P = .63). Bile leakage was also seen equally frequently (PCIA, 13 of 121 [10.7%]; and EDA, 13 of 122 [10.7%]; P = .98). Rates of other complications, duration of surgery, length of hospital stay, duration of intensive care treatment, rate of revision surgery, and rate of readmissions did not differ between the 2 groups.

    Pain levels were equivalent between the 2 groups (Table 4). Eight patients assigned to the PCIA group did not receive PCIA. Instead, 6 patients actually received EDA on organizational grounds (n = 4) or at the patient’s request (n = 2).

    In 13 patients (10.5%) assigned to receive EDA, no EDA was performed because of technical difficulties (n = 7) or comorbidities (n = 6). In 10 patients (8.1%) in the EDA group, secondary postoperative failure of EDA due to malfunction or pain (n = 5) or paresthesia (n = 5) was seen. Accordingly, EDA was associated with more neurologic adverse effects such as paresthesia, hypesthesia, and limitation of peripheral motor function (EDA, 5 [4.0%] vs PCIA, 0 [0%]; P = .02). All events were transient and rated as minor complications. Overall, failure of EDA occurred in 23 patients (18.5%). Of all 23 patients with failure of EDA, 20 (87.0%) received PCIA instead.

    Furthermore, transfusion of blood products was comparable between the groups, as was intraoperative and postoperative administration of crystalloid and colloid fluids. However, the amount of intraoperatively administered vasopressors was significantly lower for the PCIA group than for EDA group (mean [SD], 1.397 [3.656] vs 1.611 [2.032] mg norepinephrine; P = .001; Table 4). Significantly fewer patients in the PCIA group than in the EDA group needed vasopressors postoperatively (31 of 123 [25.2%] vs 46 of 123 [37.4%]; P = .04). In addition, patients in the PCIA group gained less weight up to postoperative day 4 than patients in the EDA group (mean [SD], 3.4 [3.6] vs 4.6 [3.8 kg]; P = .03).

    The safety analysis in the as-treated population yielded similar rates of patients with at least 1 SAE for the 2 groups (PCIA, 55 of 128 [43.0%] vs EDA, 42 of 115 [36.5%]; P = .31) and similar overall numbers of SAEs per group (PCIA, 81 vs EDA, 70). There were no obvious differences in the frequency, severity, and outcome of SAEs or regarding their causal relationship to the trial intervention.

    Discussion

    To our knowledge, PAKMAN is the first multicenter randomized clinical trial comparing PCIA-based and EDA-based analgesia after pancreatic surgery with a composite of gastrointestinal complications as the primary end point. We could not verify the 15% reduction in gastrointestinal complications for PCIA vs EDA that we expected based on a retrospective study.19 No significant differences were found for any other postoperative complication. Low pain scores in both groups demonstrated the effectiveness of both procedures. However, PCIA was associated with a significantly lower dose of intraoperatively administered vasopressors, a smaller proportion of patients in need of vasopressors after surgery, and less weight gain by postoperative day 4. Moreover, EDA was associated with an 18.5% failure rate.

    Perioperative thoracic epidural analgesia–mediated sympathetic block, consecutive hypotension,19 and subsequent immoderate fluid administration and vasopressor treatment are thought to contribute to intestinal edema, resulting in anastomotic insufficiency and other gastrointestinal complications.7,30 In recent years, most centers have implemented fluid-restrictive anesthetic regimens for patients undergoing pancreatic surgery to prevent fluid overload.10,31 Consequently, predominantly vasopressor-based concepts were implemented to prevent hypotension and subsequent organ dysfunction.32 Consistent with these developments in treatment concepts, the rate of patients given vasopressors is higher in our trial compared with previous studies. Patients in both groups received similar amounts of fluids and patients in the EDA group were given higher doses of vasopressors. However, these differences did not show any clinical effect regarding the outcomes of this trial. As the 2 groups received similar amounts of fluids, the observed weight gain by postoperative day 4 may have resulted from reduced kidney function in patients receiving EDA. Also, our trial was not designed to determine a potential causal relationship between vasopressor use or fluid administration and outcomes.

    The rates of gastrointestinal complications expected from the retrospective analysis by Pratt et al19 were clearly exceeded by our trial, which might be explained by detection and selection bias caused by the retrospective design compared with our prospective data collection. Complication rates in our trial were in line with previous randomized clinical trials.33-37 Also, the reported failure rate of EDA is in line with the previously published failure rates of 13% to 47% even when EDA is performed by experienced personnel.6

    Subgroup analysis evaluating the experience of the surgeon showed no association with the primary end point. However, most of the surgeons were very experienced (90% had performed >75 operations); accordingly, the subgroup of beginners may be too small to represent significant differences. Also, it is plausible that experienced surgeons were assigned to more complex cases that were prone to complications. Therefore, this finding needs to be interpreted with caution.

    To date, more than 35 randomized clinical trials comparing EDA with PCIA after abdominal surgery have been published. However, many of them were conducted more than 10 years ago, when surgical techniques were less sophisticated and fewer concepts for enhanced recovery were implemented. Frequently, either the cohorts comprised patients undergoing various surgical procedures or less complex operations38-40 were investigated that are performed without EDA today. Therefore, we decided to compare surgical complications as the primary outcome after EDA vs PCIA in patients undergoing pancreatic surgery. Partial pancreatoduodenectomy can be considered a meaningful surrogate for major abdominal surgery in general owing to the complexity of resection and the elaborate reconstruction phase with 3 gastrointestinal anastomoses.

    Previous trials demonstrated controversial results regarding better pain control,6,7,13,14,39 earlier bowel movement,40 or fewer pulmonary15,38 and cardiovascular complications18,41 with EDA. Moreover, in the ERAS Society guidelines for perioperative care for pancreatic surgery, a high evidence level for superior pain control with EDA, a moderate evidence level for reduced respiratory complications, and a low evidence level for recommendation of epidural analgesia to reduce overall morbidity are described.42 The results of our trial do not support any of the preference of EDA given in ERAS Society protocols.

    In our trial, pain levels did not differ significantly between groups. In both groups, pain scores were low, probably owing to a structured pain management plan with the support of an acute pain service, which is implemented in many hospitals today. Cardiac and pulmonary complications are relevant end points associated with mortality. Although only patients with complex abdominal surgery were included, the incidence rates of pneumonia and cardiovascular complications were very low and no patient died due to a cardiac, vascular, or pulmonary event. Furthermore, surgical complications were more frequent than pulmonary or cardiovascular adverse events, and morbidity and mortality after complex abdominal surgery43 were mainly related to a limited number of gastrointestinal complications. Such surgery-related complications are of high relevance for patients, clinicians, and administrators because they prolong intensive care unit and hospital stay and increase treatment costs. Neither the rates of postoperative complications nor analgesic effectiveness support favoring either EDA or PCIA compared with the other.

    The external validity of our results is assured by the pragmatic design of the trial and the results of the sensitivity analyses. Broad inclusion criteria were chosen to test interventions under conditions resembling routine practice and to yield results that could be generalized. The key steps of EDA and PCIA were predefined and techniques were otherwise performed according to centers’ standard procedures. Several confounding factors such as surgeon’s experience, underlying disease, method of pancreatic anastomosis, and type of general anesthesia were not predetermined in the protocol but are available for subgroup analysis.

    Perioperative thoracic epidural analgesia is associated with high procedure costs (3 times higher than with PCIA), is time consuming, and requires additional staff resources with specific training.44 However, economic aspects were not investigated in the present study.

    Limitations

    Some limitations should be considered when interpreting our results. Blinding of patients and treating physicians was not done because all components of the primary end point were well defined and objectively measurable without being prone to subjective interpretation.45 It seems unlikely that end points such as pancreatic fistula would differ significantly if the observer were blinded.45 The only subjective end point was pain; hence, the conclusions regarding pain must be judged with the possibility of performance bias in mind.

    Conclusions

    The question of what analgesic strategy is best for patients undergoing pancreatic surgery is frequently assessed in an emotional manner. Analgesia is a sensitive issue for patients; some are reluctant to accept EDA because of the fear of serious neurologic complications such as paraplegia. The results of this trial will aid a more objective and less emotional decision-making process between PCIA and EDA in individual cases, taking into account the patient’s wishes, as stipulated by current guidelines46 and the principles of evidence-based medicine.

    Similar rates for the combined primary end point of gastrointestinal complications were observed for both PCIA and EDA. Consequently, the choice between PCIA and EDA for pain control after pancreatic surgery should not be based on concerns regarding such complications. In light of the comparable morbidity and similar effectiveness of PCIA and EDA, together with the various shortcomings of EDA, a critical appraisal of guideline recommendations and ERAS Society protocols for EDA as the criterion standard of postoperative analgesia for pancreatic surgery is warranted.2,4,42 Based on the results of the PAKMAN trial, decision-makers should consider PCIA as an at least equivalent recommendation.

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    Article Information

    Accepted for Publication: March 1, 2020.

    Corresponding Author: Markus W. Büchler, MD, Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany (markus.buechler@med.uni-heidelberg.de)

    Published Online: May 27, 2020. doi:10.1001/jamasurg.2020.0794

    Author Contributions: Dr Knebel had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Klotz, Larmann, Bruckner, Hofer, Diener, Büchler, Knebel.

    Acquisition, analysis, or interpretation of data: Klotz, Larmann, Klose, Bruckner, Benner, Doerr-Harim, Tenckhoff, Lock, Brede, Salvia, Polati, Köninger, Schiff, Wittel, Höetzel, Keck, Nau, Amati, Koch, Eberl, Zink, Tomazic, Novak-Jankovic, Hofer, Diener, Weigand, Knebel.

    Drafting of the manuscript: Klotz, Hofer, Diener, Knebel.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: Klose, Bruckner, Benner, Diener, Knebel.

    Obtained funding: Klotz, Doerr-Harim, Tenckhoff, Knebel.

    Administrative, technical, or material support: Klotz, Klose, Bruckner, Doerr-Harim, Tenckhoff, Brede, Salvia, Polati, Köninger, Wittel, Keck, Nau, Amati, Zink, Tomazic, Novak-Jankovic, Hofer, Knebel.

    Supervision: Salvia, Schiff, Hoetzel, Keck, Diener, Weigand, Büchler, Knebel.

    Conflict of Interest Disclosures: Dr Larmann reported receiving grants from B. Braun-Stiftung; and personal fees from Philips, Measurements and Monitors and Mitsubishi Chemical Europe outside the submitted work. No other disclosures were reported.

    Funding/Support: The PAKMAN trial was an investigator-initiated trial financed by the Dietmar Hopp Foundation.

    Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Group Information: The PAKMAN Trial Group members are as follows: PAKMAN trial coordination: Writing Committee: Rosa Klotz, Phillip Knebel, and Markus K. Diener (Study Centre of the German Surgical Society [SDGC], Heidelberg, Germany; Jan Larmann (Department of Anaesthesiology, Heidelberg University Hospital, Heidelberg, Germany); Markus W. Büchler (Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany); Trial design: Rosa Klotz, Phillip Knebel, Colette Doerr-Harim (SDGC), and Alexander Schellhaass (Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy, BG Trauma Centre Ludwigshafen, Ludwigshafen, Germany); Stefan Hofer (Department of Anaesthesiology, University Hospital, Heidelberg, Germany); Thomas Bruckner (Institute of Medical Biometry and Informatics [IMBI], Heidelberg, Germany); Markus W. Büchler and Markus A. Weigand (Department of Anaesthesiology, Heidelberg University Hospital, Heidelberg, Germany); Trial management: Inga Rossion, Colette Doerr-Harim, Marta Kluczynski, Solveig Tenckhoff, and Ann-Valerie Keller (SDGC); Serious adverse event management: Rosa Klotz and Colette Doerr-Harim; Data management: Christina Klose (IMBI); Analysis: Thomas Bruckner, Laura Benner (IMBI), and Stella Preussler (IMBI); Steering committee: Jürgen Weitz (Department of General, Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, TU Dresden, Germany); Thomas Bruckner, Stefan Hofer, Alexander Schellhaass, and Phillip Knebel; Data safety and monitoring board: Gabriele Ihorst (Clinical Trials Unit of the Medical Centre, University of Freiburg, Freiburg, Germany); Volker Fendrich (Department of Endocrine Surgery, Schön Klinik Hamburg Eilbek, Hamburg, Germany); Marco Gruss (Department of Anaesthesiology, Klinikum Hanau, Hanau, Germany); Quality assurance: Steffen Luntz and Karsten Thelen (Coordination Centre for Clinial Trials, KKS, University of Heidelberg, Heidelberg, Germany).

    PAKMAN trial investigators and participating centers (in alphabetical order of location, including patient recruitment numbers): Sophia Chikhladze, Andrea Klock, and Olivia Sick (Department of General and Visceral Surgery, Department of Anaesthesiology and Critical Care, Medical Centre–University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; 17 patients); Fabian Edinger, and Sophie Ruhrmann (Department of Visceral, Thoracic, Transplant and Paediatric Surgery, Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy, Justus Liebig University of Giessen, Giessen, Germany; 22 patients); Barbara Maichle, Dagmar Anders, and Jörg Kaiser (Department of General, Visceral and Transplantation Surgery, Department of Anaesthesiology, Heidelberg University Hospital, Heidelberg, Germany; 227 patients); Alenka Spindler Vesel (Department of Abdominal Surgery, Clinical Department of Anaesthesiology and Intensive Therapy, University Medical Centre Ljubljana, Ljubljana, Slovenia; 3 patients); Ursula Holler, and Hryhoriy Lapshyn (Department of Surgery, Department of Anaesthesiology and Intensive Care, University Medical Centre Schleswig-Holstein—Campus Lübeck, Lübeck, Germany; 15 patients); Nadine Fuchs, Gilbert Hainzl, and Jörg Tschmelitsch (Department of Surgery, Department of Anaesthesiology and Intensive Care Medicine, General Public Hospital of the Brothers of St. John of God St. Veit/Glan, S. Veit an der Glan, Austria; 7 patients); Anika Brückner, Sandra Cseledes, Katharina Feilhauer, and Andreas Köstlin (General, Visceral and Transplantation Surgery, Department of Anaesthesiology and Operative Intensive Care, Klinikum Stuttgart—Katharinenhospital, Stuttgart; 24 patients); Debora Ciprani, Matteo De Pastena, Alvise Martini, Erica Secchettin, and Elisabetta Sereni (Surgical & Oncological Department, Pancreas Institute, Department of Anaesthesiology and Intensive Care, Verona University Hospital, Verona, Italy; 24 patients); Katrin Bischof, Christoph-Thomas Germer, Ingo Klein, Gudrun Kindl, Stefan Löb, Christian Markus, Daniel Röder, Norbert Roewer, Armin Wiegering, and Thomas Wobbe (Department of General, Visceral, Transplant, Vascular and Paediatric Surgery, Department of Anaesthesiology and Critical Care, University Hospital of Würzburg, Würzburg, Germany; 30 patients).

    Data Sharing Statement: See Supplement 2.

    Additional Contributions: We thank the staff of all participating centers of the PAKMAN trial group for their outstanding commitment and support of the trial. Furthermore, we would like to thank the nursing staff and the clinical partners who were not directly involved in the conduct of this trial but without whom successful completion of the trial would not have been possible.

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