Emergency liver resection for non-traumatic lesions. A systematic review.

AIM: Primary liver tumors have an incidence of 20% regarding benign tumors respectively 5.7% of the overall incident cases of cancer. In any major hepatic injury, the surgical treatment has two main goals: hemostasis and excision of the affected liver segments. We aimed to systematic review the non-traumatic emergency liver resections, in order to raise concern about a rather rare, but difficult to treat hepatic pathology, which implies divergent therapeutical approach, and emergency liver surgery remains the first or backup option. METHODS: A literature survey was performed guided by the words "liver resections", "major liver resections", "emergency liver resection". "hepatocellular carcinoma" using four databases: Pubmed, Scopus, Web of Science and Embase. All titles referred in English, published from 2000 until 2021, were checked for eligibility. RESULTS: Six publications were considered relevant for major liver resections in emergency, from a total of 331 articles that were reviewed. Large hepatocellular carcinomas and adenomas were the most common types of tumors found at risk for spontaneous rupture. The patients with hemodynamic instability, reduced liver function and large tumors had lower long-term survival and disease-free survival. Major hepatectomy was indicated as a viable solution for prolonging survival rate, whenever the patient's general status permits it per primam. CONCLUSIONS: Emergency major liver resection for tumoral causes prolongs survival even if the cause is usually malignant. The tumor can be resected with negative resection margins, respecting the correct oncological requirements, both per primam or staged approach according to each case specifically. KEY WORDS: Adenoma, Emergency, Hemorrhage, Hepatocellular Carcinoma, Liver Resection, Liver Tumors.

Analgesic Modalities in Patients Undergoing Open Pancreatoduodenectomy-A Systematic Review and Meta-Analysis.

BACKGROUND: This systematic review explored the efficacy of different analgesic modalities and the impact on perioperative outcome in patients undergoing pancreatoduodenectomy. METHODS: A systematic literature search was performed on PubMed, Embase, Web of Science, Scopus, and Cochrane Library Database using the PRISMA framework. The primary outcome was pain scores on postoperative day one (POD1) and postoperative day two (POD2). The secondary outcomes included length of hospital stay (LOS) and specific procedure-related complications. RESULTS: Five randomized controlled trials and ten retrospective cohort studies were included in the systematic review. Studies compared epidural analgesia (EA), patient-controlled analgesia (PCA), continuous wound infiltration (CWI), continuous bilateral thoracic paravertebral infusion (CTPVI), intrathecal morphine (ITM), and sublingual sufentanil. The pain scores on POD1 (p < 0.001) and POD2 (p = 0.05) were higher in the PCA group compared with the EA group. Pain scores were comparable between EA and CWI plus PCA or CTPVI on POD1 and POD2. Pain scores were comparable between EA and ITM on POD1. The procedure-related complications and length of hospital stay were not significantly different according to the type of analgesia. CONCLUSIONS: EA provided lower pain scores compared with PCA on the first postoperative day after pancreatoduodenectomy; the length of hospital stay and procedure-related complications were similar between EA and PCA. CWI and CTPVI provided similar pain relief to EA.

Postoperative Analgesia after Laparoscopic Cholecystectomy - Prospective, Randomized, Double Blind, Control Trial.

In this prospective, randomized, double blind control trial we aim to investigate which of the most used analgesic techniques after laparoscopic cholecystectomy is the most efficient. Methods: This study included 81 patients that were randomly distributed into 3 groups using a computer-generated random number which was enclosed in a sealed envelope: group A (control) received classic multimodal iv opioid analgesia, group B received Tap block in oblique subcostal approach (OSTAP) and group C received local anesthetic infiltration of the trocar insertion sites (LAI). The primary outcome of this trial was to evaluate the efficacy of each analgetic technique by measuring VAS pain scores. Secondary outcome included intraoperative opioid requirement and the opioid consumption in the first 24h postoperatively. Intraoperative parameters and outcome data were recorded by an anesthesiologist who was blinded to the study groups. Results: We analyzed a total of 75 patients. For the primary outcome variable, VAS pain scores at rest were significantly reduced in OSTAP group at each time point assessed in the first 24 hours after surgery compared with LAI group and IV opioid analgesia group (p 0.001). Intraoperative fentanyl consumption and 24h pethidine consumption were also significantly reduced in TAP block group compared with LAI group and IV opioid analgesia group (p 0.001). Conclusions: Our study showed that OSTAP block is a more efficient analgesia technique compared with IV opioid analgesia and with local anesthetic infiltration of trocar sites after laparoscopic cholecystectomy surgery. This trial was registered at www.clinicaltrials.gov (NCT02707250).

Laparoscopic Pancreatoduodenectomy in Elderly Patients: A Systematic Review and Meta-Analysis.

Background and Aims: Recent single-center retrospective studies have focused on laparoscopic pancreatoduodenectomy (LPD) in elderly patients, and compared the outcomes between the laparoscopic and open approaches. Our study aimed to determine the outcomes of LPD in the elderly patients, by performing a systematic review and a meta-analysis of relevant studies. Methods: A comprehensive literature review was conducted utilizing the Embase, Medline, PubMed, Scopus and Cochrane databases to identify all studies that compared laparoscopic vs. open approach for pancreatoduodenectomy (PD). Results: Five retrospective studies were included in the final analysis. Overall, 90-day mortality rates were significantly decreased after LPD in elderly patients compared with open approaches (RR = 0.56; 95%CI: 0.32−0.96; p = 0.037, I2 = 0%). The laparoscopic approach had similar mortality rate at 30-day, readmission rate in hospital, Clavien−Dindo complications, pancreatic fistula grade B/C, complete resection rate, reoperation for complications and blood loss as the open approach. Additionally, comparing with younger patients (<70 years old), no significant differences were seen in elderly cohort patients regarding mortality rate at 90 days, readmission rate to hospital, and complication rate. Conclusions: Based on our meta-analysis, we identify that LPD in elderly is a safe procedure, with significantly lower 90-day mortality rates when compared with the open approach. Our results should be considered with caution, considering the retrospective analyses of the included studies; larger prospective studies are required.

Mechanistic Insights in Hemophagocytic Lymphohistiocytosis: Subsequent Acute Hepatic Failure in a Multiple Myeloma Patient Following Therapy with Ixazomib-Lenalidomide-Dexamethasone.

Hemophagocytic lymphohistiocytosis (HLH) is a rare, elusive, and life-threatening condition that is characterized by the pathologic and uncontrolled secondary activation of the cytotoxic T-cells, natural killer cells (NK-cells), and macrophages of the innate immune system. This condition can develop in sporadic or familial contexts associated with hematological malignancies, as a paraneoplastic syndrome, or linked to an infection related to immune system deficiency. This leads to the systemic inflammation responsible for the overall clinical manifestations. Diagnosis should be thorough, and treatment should be initiated as soon as possible. In the current manuscript, we focus on classifying the HLH spectrum, describing the pathophysiology and the tools needed to search for and correctly identify HLH, and the current therapeutic opportunities. We also present the first case of a multiple myeloma patient that developed HLH following therapy with the ixazomib-lenalidomide-dexamethasone protocol.

The Role of miR-155 in Nutrition: Modulating Cancer-Associated Inflammation.

Nutrition plays an important role in overall human health. Although there is no direct evidence supporting the direct involvement of nutrition in curing disease, for some diseases, good nutrition contributes to disease prevention and our overall well-being, including energy level, optimum internal function, and strength of the immune system. Lately, other major, but more silent players are reported to participate in the body's response to ingested nutrients, as they are involved in different physiological and pathological processes. Furthermore, the genetic profile of an individual is highly critical in regulating these processes and their interactions. In particular, miR-155, a non-coding microRNA, is reported to be highly correlated with such nutritional processes. In fact, miR-155 is involved in the orchestration of various biological processes such as cellular signaling, immune regulation, metabolism, nutritional responses, inflammation, and carcinogenesis. Thus, this review aims to highlight those critical aspects of the influence of dietary components on gene expression, primarily on miR-155 and its role in modulating cancer-associated processes.

Are presepsin and resistin better markers for bacterial infection in patients with decompensated liver cirrhosis?

BACKGROUND: Bacterial infections impair prognosis in patients with cirrhosis. Presepsin and, more recently, resistin are promising markers of infection and sepsis in patients without cirrhosis. AIMS: The aim of our study was to assess the performance of presepsin and resistin as early markers of infection compared with C reactive protein (CRP) and procalcitonin (PCT), and their prognostic relevance in patients with decompensated cirrhosis. METHODS: One hundred and fourteen consecutive patients with decompensated cirrhosis were enrolled and followed-up for 28 days. Diagnostic performances of CRP, PCT, presepsin and resistin were assessed. RESULTS: Fifty-three (46.5%) patients had bacterial infections of which 30 (56%) had sepsis. Presepsin and resistin had similar performance as CRP and PCT for the diagnosis of infection (best cut-off of 1444 pg/ml and 20 ng/ml, respectively) and sepsis. Presepsin (HR = 5.5; 95%CI: 2.36-13.21, p < 0.0001) and the ≥500 pg/ml increase of presepsin at 48 h (HR = 9.24; 95%CI: 3.66-23.27, p < 0.008) were independently associated with 28-day mortality. CONCLUSIONS: Presepsin and resistin have similar diagnostic performances to CRP and PCT for bacterial infection in decompensated cirrhosis. Presepsin and Δ presepsin ≥500 pg/ml have also a prognostic relevance for 28-day mortality.

Gallbladder carcinoma. Surgical management of gallblad-der carcinoma. An analysis of 37 cases.

BACKGROUND & AIMS: Gallbladder carcinoma is a rare yet very aggressive cancer. In this study we evaluate the presentation, staging, procedures, complications and survival of patients with gallbladder carcinoma. MATERIAL AND METHODS: Data at presentation, operative findings, postoperative evolution, complications and survival data were analyzed for 37 patients with gallbladder carcinoma (as cohort study) confirmed at histopathology between January 2005 and December 2011 in Surgical Department of Regional Institute of Gastroenterology And Hepatology "Octavian Fodor" Cluj-Napoca, Romania. RESULTS: In 12 cases we had the suspicion of GBC (gallbladder carcinoma) before surgery, in 6 cases GBC was suspected intraoperatory and in 19 cases only after the histopathology exam. Radical cholecystectomy was considered in 9 cases (24.32%): 4 cases with cholecystectomy alone (patients with Tis-T1) and in 5 cases liver resection was associated. CONCLUSION: The GBC has a low incidence (0.35% out of all cholecystectomies), the females being more affected (F:B=4.3:1). GBC was associated with low resecability rate (24.32%) and having a bad prognosis (survival under a year in stages T3 and T4). In most cases the diagnosis was hidden by an acute inflammatory process (acute cholecystitis) and the diagnosis was made after surgical intervention, therefore, the histopathology is crucial in these situations. KEY WORDS: Gallbladder carcinoma, Jaundice, Palliative treatment, Resection, Survival.

Anaesthesia and Intensive Care Residents' Perception of Simulation Training in Four Romanian Centres.

INTRODUCTION: Simulation training offers an opportunity to educate anaesthesia and intensive care (AIC) residents safely. At present, it is not yet a mandatory part of residency curriculum.The aim of the study was to evaluate the residents' perception of the inclusion of simulation-based training in the Romanian AIC residency program. MATERIAL AND METHODS: Romanian AlCs in anaesthesia and intensive care from four training centres completed a twenty-question survey regarding their views on simulation during their residency training. Residents were divided into junior, in the first three years, or senior groups, in the last two years of residency training. The questionnaire included Likert-scale multiple-choice, open-ended, and "yes" or "no"questions regarding simulator learning, the frequency of simulation sessions, and the value of the simulation sessions in improving practice, skills or teamwork. The open-ended questions, asked which were the respondents' preferred topics to be included in simulation sessions. RESULTS: Fifty-six percent of residents completed and returned the questionnaire. Ninety-eight percent of them considered simulation-learning useful once a month or every three months especially in the first two years of training. All residents thought simulation sessions would improve their skills, communication abilities, and teamwork. Senior residents paid more attention to clinical scenarios (p=0.007), haemodynamic monitoring (p=0.017) and mechanical ventilation (p=0.004) as compared to juniors. All residents considered difficult airway management, and cardiac life support to be very important issues to be included in simulation sessions. CONCLUSION: The survey demonstrated that simulation-based training should play a greater role and eventually became compulsory in training program in AIC academic centres.

Esophagojejunal anastomosis fistula, distal esophageal stenosis, and metalic stent migration after total gastrectomy.

Esophagojejunal anastomosis fistula is the main complication after a total gastrectomy. To avoid a complex procedure on friable inflamed perianastomotic tissues, a coated self-expandable stent is mounted at the site of the anastomotic leak. A complication of stenting procedure is that it might lead to distal esophageal stenosis. However, another frequently encountered complication of stenting is stent migration, which is treated nonsurgically. When the migrated stent creates life threatening complications, surgical removal is indicated. We present a case of a 67-year-old male patient who was treated at our facility for a gastric adenocarcinoma which developed, postoperatively, an esophagojejunostomy fistula, a distal esophageal stenosis, and a metallic coated self-expandable stent migration. To our knowledge, this is the first reported case of an esophagojejunostomy fistula combined with a distal esophageal stenosis as well as with a metallic coated self-expandable stent migration.

The influence of total intravenous anaesthesia and isoflurane anaesthesia on plasma interleukin-6 and interleukin-10 concentrations after colorectal surgery for cancer: a randomised controlled trial.

BACKGROUND: Although it has been demonstrated that both surgery and anaesthesia induce immune suppression, it remains unclear whether there are differences between anaesthetic techniques in inducing immune suppression in cancer patients. OBJECTIVE: The aim of this present study was to compare the effects of total intravenous anaesthesia (TIVA) and isoflurane anaesthesia on plasma concentrations of interleukins IL-6 and IL-10 in patients undergoing surgery for colorectal cancer. DESIGN: A randomised, controlled, open-label study. SETTING: University hospital. PATIENTS: Seventy patients undergoing open colorectal surgery with tumour resection were randomised prospectively into one of two groups; 60 patients completed the study. INTERVENTIONS: Group 1 (n = 30) received TIVA and group 2 (n = 30) received isoflurane. Propofol infusion rate and inspired concentration of isoflurane were titrated to achieve bispectral index values of 40 to 55. MAIN OUTCOME MEASURES: Plasma concentrations of IL-6 and IL-10 were measured preoperatively, before surgical incision and at 2 and 24 h postoperatively. The area under the curve (AUC) for IL-6 and IL-10 over 24 h and plasma interleukin concentrations at each time point were compared between the groups. RESULTS: Median (range) AUC for IL-6 was 4657 (1219 to 8427) pg h ml in the TIVA group and 5349 (839 to 8126) pg h ml in the isoflurane group. For IL-10, AUC was 1165 (344 to 5258) pg h ml in the TIVA group and 1405 (463 to 8161) pg h ml in the isoflurane group. When comparing interleukin concentrations between study groups at different time intervals, there were no significant differences in plasma concentrations of IL-6 or IL-10. Intragroup comparisons revealed that IL-6 and IL-10 concentrations were significantly increased 2 and 24 h postoperatively in both groups when compared with their baseline values (P < 0.01 and P < 0.01 at 2 and 24 h for the TIVA group and isoflurane group, respectively). CONCLUSION: We found no significant differences between the effects of TIVA and isoflurane anaesthesia on plasma concentrations of IL-6 and IL-10 after colorectal cancer surgery during the first 24 h postoperatively. Further studies are needed to determine differences in long-term outcome of these patients. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01902849. The study was registered retrospectively.

The influence of a prophylactic dose of dexamethasone for postoperative nausea and vomiting on plasma interleukin concentrations after laparoscopic cholecystectomy: a randomised trial.

BACKGROUND: Little is known about the effects of small doses of dexamethasone used for the prophylaxis of postoperative nausea and vomiting on the innate host response. OBJECTIVES: We studied the influence of dexamethasone 4 mg on the perioperative plasma concentrations of interleukins after laparoscopic cholecystectomy. We hypothesised that there would be differences in pro-inflammatory interleukin concentrations in patients who received dexamethasone. DESIGN: A randomised controlled study. SETTING: University hospital. PATIENTS: Forty-six patients undergoing laparoscopic cholecystectomy under total intravenous anaesthesia were allocated randomly into one of two study groups; 42 patients completed the study. INTERVENTIONS: Patients in group 1 (dexamethasone, n = 22) received dexamethasone 4 mg and group 2 (n = 20) acted as controls. MAIN OUTCOME MEASURES: Plasma levels of tumour necrosis factor alpha and interleukins 1ß, 6, 8, 10 and 13 were measured before anaesthesia, before surgery and 2 and 24 h after surgery. The frequency and number of episodes of postoperative nausea and vomiting were recorded. RESULTS: Areas under the curve of the percentage variation of interleukins 6 and 8 were significantly lower in the dexamethasone group. There were no significant differences between groups in the areas under the curve for tumour necrosis factor alpha and interleukins 1ß, 10 and 13. The greatest variation in interleukin concentrations was 2 h postoperatively, when the concentration of interleukin 6 was greater in the control group, whereas the concentration of interleukin 10 was higher in the dexamethasone group. Twenty-four hours after surgery, only the concentration of interleukin 6 remained significantly increased in both groups (P = 0.001 and P = 0.002, respectively). There were no significant differences between groups in respect of postoperative nausea and vomiting. CONCLUSION: Prophylactic dexamethasone given before laparoscopic cholecystectomy produced a significant decrease in concentrations of interleukins 6 and 8. Further studies are needed to investigate the clinical implications of these findings.

Total Intravenous Anesthesia-Target Controlled Infusion for colorectal surgery. Remifentanil TCI vs sufentanil TCI.

The aim of the study was to compare the effect of remifentanil and sufentanil administered for total intravenous anaesthesia (TIVA) using target-controlled infusion (TCI) on intraoperative hemodynamic response, tracheal intubation and extubation times in patients undergoing colorectal surgery. METHODS: Sixty patients undergoing open colorectal surgery for colorectal tumors or inflammatory diseases were randomized prospectively into one of two groups: remifentanil group R (n = 30) received TIVA-TCI with propofol and remifentanil and sufentanil group S (n = 30) received TIVA-TCI with propofol and sufentanil. Changes of mean arterial pressure (MAP) and heart rate (HR) were compared during induction and maintenance of anaesthesia. Response to tracheal intubation was assessed as episodes of hypertension, increased HR and bispectral index values, sweating, lacrimation, and coughing. The numbers of target plasma concentration (Cp) adjustments of opioids and propofol due to painful stimulation were recorded during surgery. Recovery time expressed as extubation time was also evaluated. RESULTS: MAP and HR, expressed as area under the curve (AUC), were not significantly different between groups during anesthesia and surgery. During induction of anesthesia, MAP values decrease from baseline, in both groups (p < 0.001). Intergroup comparison revealed that MAP decreased more in the remifentanil than sufentanil group (p = 0.027). HR decreased from baseline values only in the remifentanil group (p = 0.05). The number of target concentration adjustments for propofol and opioid was higher in the remifentanil group as compared with sufentanil group (p = 0.02 and p = 0.04). Hemodynamic responses to tracheal intubation and extubation times were not significantly different between the groups. CONCLUSION: Both remifentanil and sufentanil TCI produced stable hemodynamic conditions during open colorectal surgery but sufentanil TCI was associated with less decrease in blood pressure and heart rate, and required fewer dose adjustments during anesthesia induction.

Choice of anesthetic technique on plasma concentrations of interleukins and cell adhesion molecules.

BACKGROUND: Whether inflammatory responses to surgery are comparably activated during total intravenous anesthesia (TIVA) and during volatile anesthesia remains unclear. We thus compared the perioperative effects of TIVA and isoflurane anesthesia on plasma concentrations of proinflammatory and anti-inflammatory interleukins and cell adhesion molecules. METHODS: Patients having laparoscopic cholecystectomies were randomly allocated to two groups: 44 were assigned to TIVA and 44 to isoflurane anesthesia. IL-1ß, IL-6, IL-8, IL-10, IL-13, and the cellular adhesion molecules intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 were determined preoperatively, before incision, and at 2 and 24 hours postoperatively. Our primary outcomes were area-under-the-curve cytokine and adhesion molecule concentrations over 24 postoperative hours. RESULTS: The only statistically significant difference in area-under-the-curve concentrations was for IL-6, which was greater in patients given isoflurane:78 (95% confidence interval (CI): 52 to 109) pg/ml versus 33 (22 to 50) pg/ml, P= 0.006. Two hours after surgery, IL-6 was significantly greater than baseline in patients assigned to isoflurane: 47 (95% CI: 4 to 216, P<0.001) pg/ml versus 18 (95%CI: 4 to 374, P<0.001) pg/ml in the TIVA group. In contrast, IL-10 was significantly greater in patients assigned to TIVA: 20 (95% CI: 2 to 140, P<0.001) pg/ml versus 12 (95% CI: 3 to 126, P<0.001) pg/ml. By 24 hours after surgery, concentrations were generally similar between study groups and similar to baseline values. CONCLUSION: The only biomarker whose postoperative area-under-the-curve concentrations differed significantly as a function of anesthetic management was IL-6. Two hours after surgery, IL-6 concentrations were significantly greater in patients given isoflurane than TIVA. However, the differences were modest and seem unlikely to prove clinically important. Further studies are needed.

The effects of a small dose of dexamethasone on cell adhesion molecules during laparoscopic cholecystectomy.

BACKGROUND AND OBJECTIVE: There are only a few publications on the effects of dexamethasone on the plasma levels of cell adhesion molecules (CAMs). The goal of this study was to investigate the effects of dexamethasone 4 mg on the perioperative plasma levels of CAMs (soluble intercellular adhesion molecules [sICAM-1] and soluble vascular cell adhesion molecules [sVCAM-1]) during laparoscopic cholecystectomy. METHODS: Forty-two patients undergoing laparoscopic cholecystectomy under total intravenous anesthesia were enrolled and randomly divided into two groups: the first group received dexamethasone 4 mg (DEX group, n = 21) and the second group were controls (C group, n = 21). Plasma levels of sICAM-1 and sVCAM-1 were assessed before anesthesia, after induction (before surgery), and at 2 and 24 hours after surgery, respectively. Comparisons were performed for area under the plasma concentration-time curve (AUC) and within-group values. RESULTS: AUC comparison for sICAM-1 showed significantly increased levels in the C group (p = 0.036), while there was no significant difference for sVCAM-1 (p = 0.052). Within-group analysis showed increased levels for both sICAM-1 and sVCAM-1 in the C group at 24 hours postoperatively (p = 0.35 and p = 0.025, respectively). CONCLUSIONS: In our study, dexamethasone 4 mg given before laparoscopic cholecystectomy determined a significant decrease in plasma levels of sICAM-1. Both sICAM-1 and sVCAM-1 remained increased compared with baseline at 24 hours in the C group. This may partially explain the postoperative anti-inflammatory effects of dexamethasone. Further studies are needed.

Implementing fast-track protocol for colorectal surgery: a prospective randomized clinical trial.

BACKGROUND: Fast-track protocols are followed by an enhanced recovery, early return to bowel function and to complete nutrition, and a reduced hospital stay. Our study was designed to implement fast-track protocol in our university hospital. METHODS: The 96 consecutive patients with colorectal neoplasm included in the study were randomized in two equal groups: group 1 (FT) included patients undergoing colorectal surgery in a fast-track protocol, and group 2 (C) included patients undergoing colorectal surgery with a conventional care protocol. As with other fast-track protocols, our protocol included carbohydrate fluids load before operation, early mobilization and oral feeding, regular prokinetics, and multimodal postoperative analgesia. Time to restoration of bowel function, to complete mobilization and feeding, length of hospital stay, and incidence of complications and readmissions were monitored. RESULTS: Time to mobilization, restoring of bowel function, and complete oral feeding were significantly shorter with fast-track protocol (p = 0.001, p = 0.042, and p = 0.01, respectively). Hospital stay also was shorter in the fast-track group (p = 0.001). The incidence of complications did not significantly differ with the study groups. CONCLUSIONS: In our study, fast-track protocol resulted in a shorter time to mobilization, complete feeding, and discharge from hospital. Fast-track protocol did not increase the incidence of complications. However, we consider that our data require further confirmation with powered multicenter national studies.

Potentiation of nociceptive responses to low pH injections in humans by prostaglandin E2.

UNLABELLED: Inflammation and trauma lead to tissue acidification and release of inflammatory mediators, including prostaglandin E2 (PGE2). Protons can evoke pain through acid-sensing ion channels (ASICs) and TRPV1 receptors. In this study, we examined whether PGE2 can potentiate proton-induced nociception in humans on injection into skin and muscle. Psychophysical and vascular responses to microinjections of protons (pH 6.0 and 6.5), PGE2 (10-6 and 10-7 M) and their combinations into forearm skin (30 microL) or anterior tibial muscle (50 microL) were assessed in 16 male subjects. Pain intensity, axon reflex erythema, and heat pain thresholds were recorded after skin challenge; pain intensity and thresholds for pressure-evoked pain were recorded after intramuscular injections. Intradermal or intramuscular injections of PGE2 induced very low levels of pain similar to saline. Administration of low pH caused moderate pain within 5 seconds that declined rapidly over 15 to 20 seconds. In comparison, coinjection of low pH with PGE2 led to a biphasic profile of the pain response. Combined pH + PGE2 stimulation provoked significantly increased pain in the second phase after injections (20 to 100 seconds) both in skin and muscle, whereas the initial injection pain was not enhanced. Heat pain thresholds were reduced after PGE2 and combined pH + PGE2, whereas flare responses were rather attenuated on coadministration of low pH with PGE2. Intriguingly, when compared with skin, muscle pain was significantly lower in the initial phase (0 to 15 seconds) but significantly higher in the second phase (20 to 100 seconds after injection). PERSPECTIVE: PGE2 can potentiate nociceptor activation by protons in human skin and muscle, indicated by increased sustained pain ratings. This can be best explained by TRPV1 sensitization in the presence of PGE2, a mechanism potentially relevant for inflammatory and injury-induced pain.