Chemosaturation with percutaneous hepatic perfusion is effective in patients with ocular melanoma and cholangiocarcinoma.

BACKGROUND: Chemosaturation with percutaneous hepatic perfusion (CS-PHP; Hepatic CHEMOSAT® Delivery System; Delcath Systems Inc, USA) is a novel interventional procedure, which delivers high doses of melphalan directly to the liver in patients with liver tumors while limiting systemic toxicity through hemofiltration of the hepatic venous blood. We have previously shown promising efficacy for patients with ocular melanoma (OM) and cholangiocarcinoma (CCA) within our single-center and multi-center experiences. The aim of this study was to analyze the safety and efficacy of CS-PHP after 141 treatments at Hannover Medical School, Germany. METHODS: Overall response rates (ORR) were assessed according to Response Evaluation Criteria In Solid Tumors (RECIST1.1). Median Overall survival (mOS), median progression-free survival (mPFS), and median hepatic PFS (mhPFS) were analyzed using the Kaplan-Meier estimation. RESULTS: Overall, 60 patients were treated with CS-PHP in the salvage setting from October 2014 until January 2019 at Hannover Medical School with a total of 141 procedures. Half of the patients were patients with hepatic metastases of ocular melanoma (OM) (n = 30), 14 patients had CCA (23.3%), 6 patients had hepatocellular carcinoma (10%), and 10 patients were treated for other secondary liver malignancies (16.7%). In total, ORR and disease stabilization rate were 33.3% and 70.3% (n = 25), respectively. ORR was highest for patients with OM (42.3%), followed by patients with CCA (30.8%). Independent response-associated factors were normal levels of lactate dehydrogenase (odds ratio (OR) 13.7; p = 0.015) and diagnosis with OM (OR 9.3; p = 0.028). Overall, mOS was 9 months, mPFS was 4 months, and mhPFS was 5 months. Patients with OM had the longest mOS, mPFS, and mhPFS with 12, 6, and 6 months, respectively. Adverse events included most frequently significant, but transient, hematologic toxicities (80% of grade 3/4 thrombopenia), less frequently hepatic injury up to liver failure (3.3%) and cardiovascular events including two cases of ischemic insults (5%). CONCLUSION: Salvage treatment with CS-PHP is safe and effective particularly in patients OM and CCA. Careful attention should be paid to possible, serious hepatic, and cardiovascular complications.

Low anaesthetic waste gas concentrations in postanaesthesia care unit: A prospective observational study.

BACKGROUND: Volatile anaesthetics are a potential hazard during occupational exposure, pregnancy or in individuals with existing disposition to malignant hyperthermia. Anaesthetic waste gas concentration in postanaesthesia care units (PACU) has rarely been investigated. OBJECTIVE(S): The current study aims to assess concentrations of volatile anaesthetics in relation to room size, number of patients and ventilator settings in different PACUs. DESIGN: A prospective observational study. SETTING: Two different PACUs of the Hannover Medical School (Hannover, Germany) were evaluated in this study. The rooms differed in dimensions, patient numbers and room ventilation settings. PATIENTS: During the observation period, sevoflurane anaesthesia was performed in 65 of 140 patients monitored in postanaesthesia unit one and in 42 of 70 patients monitored in postanaesthesia unit two. MAIN OUTCOME MEASURES: Absolute trace gas room concentrations of sevoflurane measured with a compact, closed gas loop high-resolution ion mobility spectrometer. RESULTS: Traces of sevoflurane could be detected in 805 out of 970 samples. Maximum concentrations were 0.96 ±â€Š0.20 ppm in postanaesthesia unit one, 0.82 ±â€Š0.07 ppm in postanaesthesia unit two. Median concentration was 0.12 (0.34) ppm in postanaesthesia unit one and 0.11 (0.28) ppm in postanaesthesia unit two. CONCLUSION: Low trace amounts of sevoflurane were detected in both PACUs equipped with controlled air exchange systems. Occupational exposure limits were not exceeded.

Safety and efficacy of chemosaturation in patients with primary and secondary liver tumors.

BACKGROUND: Chemosaturation with percutaneous hepatic perfusion (CS-PHP; hepatic CHEMOSAT® delivery system; Delcath Systems Inc, USA) is a novel medical device, which delivers high doses of melphalan directly to the liver in patients with primary and secondary liver tumors while limiting systemic toxicity through hemofiltration of the hepatic venous blood. The aim of this study was to analyze the safety and efficacy of the second-generation CS-PHP after 54 treatments at Hannover Medical School, Germany. METHODS: Overall response rates (ORR) were assessed according to response evaluation criteria in solid tumors (RECIST1.1). Overall survival (OS), progression-free survival (PFS), and hepatic PFS (hPFS) were analyzed using the Kaplan-Meier estimation. RESULTS: 29 patients were treated with CS-PHP as last-line therapy up to five sessions. 19 patients had unresectable hepatic metastases from solid tumors [ocular melanoma (OM) n = 11; colorectal carcinoma n = 2; pancreatic adenocarcinoma n = 2; periampular carcinoma n = 2; breast and endometrial cancer each n = 1] and 10 patients were diagnosed with hepatocellular or cholangiocarcinoma (HCC/CCA). ORR was 19.2%. Patients with OM had the highest ORR (33.3%). Similar to patients with OM, patients with hepatobiliary tumors had durable disease stabilization (40%). Median OS, PFS, and hPFS were 261, 117, and 135 days, respectively. Tumor volume negatively correlated with OS. Complications and toxicities included thrombocytopenia, cardiovascular events, ulcerous bleeding, and edema. CONCLUSION: Second-generation CS-PHP seems to be effective and tolerable. Patient selection based on tumor volume and entity is of importance. Particularly, patients with OM and hepatobiliary tumors represent promising candidates for CS-PHP.

The molecular basis for species-specific activation of human TRPA1 protein by protons involves poorly conserved residues within transmembrane domains 5 and 6.

The surveillance of acid-base homeostasis is concerted by diverse mechanisms, including an activation of sensory afferents. Proton-evoked activation of rodent sensory neurons is mainly mediated by the capsaicin receptor TRPV1 and acid-sensing ion channels. In this study, we demonstrate that extracellular acidosis activates and sensitizes the human irritant receptor TRPA1 (hTRPA1). Proton-evoked membrane currents and calcium influx through hTRPA1 occurred at physiological acidic pH values, were concentration-dependent, and were blocked by the selective TRPA1 antagonist HC030031. Both rodent and rhesus monkey TRPA1 failed to respond to extracellular acidosis, and protons even inhibited rodent TRPA1. Accordingly, mouse dorsal root ganglion neurons lacking TRPV1 only responded to protons when hTRPA1 was expressed heterologously. This species-specific activation of hTRPA1 by protons was reversed in both mouse and rhesus monkey TRPA1 by exchange of distinct residues within transmembrane domains 5 and 6. Furthermore, protons seem to interact with an extracellular interaction site to gate TRPA1 and not via a modification of intracellular N-terminal cysteines known as important interaction sites for electrophilic TRPA1 agonists. Our data suggest that hTRPA1 acts as a sensor for extracellular acidosis in human sensory neurons and should thus be taken into account as a yet unrecognized transduction molecule for proton-evoked pain and inflammation. The species specificity of this property is unique among known endogenous TRPA1 agonists, possibly indicating that evolutionary pressure enforced TRPA1 to inherit the role as an acid sensor in human sensory neurons.

Platelet concentrates transfusion in cardiac surgery in relation to preoperative point-of-care assessment of platelet adhesion and aggregation.

Platelet dysfunction is an important cause of bleeding early after cardiac surgery. Whole-blood multiple electrode aggregometry (MEA), investigating the adhesion and aggregation of activated platelets onto metal electrodes, has shown correlations with platelet concentrates transfusion in this setting. Platelet activity in vivo is dependent on shear stress, an aspect that cannot be investigated with MEA, but with the cone and plate(let) analyzer (CPA) Impact-R that measures the interaction of platelets and von Willebrand factor (vWF) in whole blood under shear. We hypothesized that preoperative CPA may show better correlation with platelet concentrates transfusion post-cardiac surgery than MEA, since it is dependent on both platelet activity and platelet interaction with vWF multimers. Blood was obtained preoperatively from 30 patients undergoing aorto-coronary bypass (ACB) and 20 patients with aortic valve (AV) surgery. MEA was performed in hirudin-anticoagulated blood. The Impact-R analyses were performed in blood anticoagulated with hirudin, heparin or the standard anticoagulant citrate. For the light microscopy images obtained, the parameter surface coverage (SC) was calculated. Preoperative Impact-R results were abnormally decreased in AV patients and significantly lower than in ACB patients. For the Impact-R analysis performed in citrated blood, no correlation with platelet concentrates transfusion was observed. In contrast, MEA was comparable between the groups and correlated significantly with intraoperative platelet concentrates transfusion in both groups (rho between -0.47 and -0.62, p < 0.05). Multiple electrode aggregometry appeared more useful and easier to apply than CPA for preoperatively identifying patients with platelet concentrates transfusion in cardiac surgery.

Changes in acid-base, electrolyte and hemoglobin concentrations during infusion of hydroxyethyl starch 130/0.42/6 : 1 in normal saline or in balanced electrolyte solution in children.

INTRODUCTION: A balanced volume replacement strategy is a well established concept for correcting hypovolemia using plasma adapted isotonic crystalloid solutions with a physiological electrolyte pattern and acetate as bicarbonate precursor. Recently, third-generation hydroxyethyl starch (HES) has also become available in a balanced electrolyte solution instead of normal saline. Therefore, in this prospective non-interventional clinical study, the perioperative administration of HES 130/0.42/6 : 1 in normal saline (ns-HES) and in balanced electrolyte solution (bal-HES) was evaluated in children with a focus on acid-base, electrolyte and hemoglobin changes. METHODS: Following local ethics committee approval, pediatric patients aged up to 12 years with an ASA risk score of I-III undergoing perioperative administration of HES (ns-HES from May 2006 to December 2007, bal-HES from January 2008 to January 2009) were included. Patient demographics, the performed procedure, adverse drug reactions, hemodynamic data and the results of blood gas analysis were documented with a focus on changes in acid-base, electrolyte and hemoglobin concentrations. RESULTS: Of 396 enrolled patients (ASA I-III; age 2.3 +/- 3, range day of birth - 12 years; body weight 10.8 +/- 9, range 0.9-52 kg), 249 received ns-HES and 147 bal-HES (mean volume infused 9.9 +/- 4 and 9.4 +/- 6.9 ml x kg(-1), respectively). After HES infusion, hemoglobin decreased in both groups, whereas bicarbonate and base excess (BE) decreased only with ns-HES and remained stable with bal-HES (BE before infusion: ns-HES -1.8 +/- 2.8, bal-HES -1.7 +/- 2.7 mmol x l(-1); after infusion: ns-HES -2.6 +/- 2.4; bal-HES -1.6 +/- 2.6 mmol x l(-1), P < 0.05). Chloride (Cl) concentrations increased in both groups and were significantly higher with ns-HES (Cl before infusion: ns-HES 105.6 +/- 3.7, bal-HES 105.1 +/- 2.8 mmol x l(-1); after infusion: ns-HES 107.7 +/- 3.2, bal-HES 106.3 +/- 2.9 mmol x l(-1), P < 0.01). No serious adverse drug reactions were observed. CONCLUSION: Infusion related iatrogenic acid-base and electrolyte alterations can be minimized by using hydroxyethyl starch in a balanced electrolyte solution instead of normal saline.

The first scintigraphic detection of tumor necrosis factor-alpha in patients with complex regional pain syndrome type 1.

Tumor necrosis factor (TNF)-alpha has been identified as a pathogenic factor in many immunologically based diseases and complex regional pain syndrome (CRPS). In this case series, we used radiolabeled technetium anti-TNF-alpha antibody to scintigraphically image TNF-alpha in 3 patients with type 1 CRPS. The results show that TNF-alpha was localized only in affected hands of patients with early-stage CRPS. No uptake was seen in clinically unaffected hands and late-stage CRPS. Our findings support the growing evidence for neuroimmune disturbance in patients with CRPS and may have important further implications for specific anticytokine treatment in patients with CRPS.

Brain imaging of analgesic and antihyperalgesic effects of cyclooxygenase inhibition in an experimental human pain model: a functional MRI study.

One of the most distressing symptoms of many neuropathic pain syndromes is the enhanced pain sensation to tactile or thermal stimulation (hyperalgesia). In the present study we used functional magnetic resonance imaging (fMRI) and explored brain activation patterns during acute impact pain and mechanical hyperalgesia in the human ultraviolet (UV)-B model. To investigate pharmacological modulation, we examined potential differential fMRI correlates of analgesic and antihyperalgesic effects of two intravenous cyclooxygenase inhibitors, i.e. parecoxib and acetylsalicylic acid (ASA). Fourteen healthy volunteers participated in this double-blinded, randomized and placebo-controlled crossover study. Tactile stimuli and mechanical impact hyperalgesia were tested at the site of a UV-B irradiation and acute mechanical pain was tested at a site distant from the irradiated skin. These measurements were conducted before and 30 min after a 5-min intravenous infusion of either saline (placebo), parecoxib 40 mg or ASA 1000 mg. Acute mechanical pain and mechanical hyperalgesia led to widespread activations of brain areas known to comprise the human pain matrix. Analgesic effects were found in primary (S1) and secondary (S2) somatosensory cortices, parietal association cortex (PA), insula, anterior parts of the cingulate cortex and prefrontal cortices. These brain areas were also modulated under antihyperalgesic conditions. However, we observed a greater drug-induced modulation of mainly PA and inferior frontal cortex during mechanical hyperalgesia; during acute mechanical pain there was a greater modulation of mainly bilateral S2. Therefore, the results of the present study suggest that there is a difference in the brain areas modulated by analgesia and antihyperalgesia.

Involvement of intra-articular corticotropin-releasing hormone in postoperative pain modulation.

OBJECTIVES: Opioid receptors are expressed on peripheral nerve endings and opioid peptides (beta-endorphin, END) are produced in various immune cells of synovial tissue after knee trauma. Because corticotropin-releasing hormone (CRH) acts through its receptors on END-containing immune cells, this randomized controlled trial investigated whether the intra-articular (IA) injection of CRH reduces postoperative pain intensity and supplemental analgesic consumption in patients undergoing arthroscopic knee surgery. METHODS: Patients were randomly assigned to one of the following IA and IV treatments: group saline (SAL) (n=17) received isotonic SAL IA and 10 microg CRH IV; group CRH (n=16) received 10 microg CRH IA and SAL IV; group CNL (n=18) received 10 microg CRH plus 0.12 mg naloxone IA and SAL IV. Patients pain intensity at rest and during exercise, cortisol plasma concentrations as well as supplemental analgesics were documented. Immunohistochemistry analyzed colocalization of CRH receptors and END. RESULTS: IA but not IV CRH resulted in a significant but short lasting reduction of postoperative pain under both resting and exercise conditions without changes in cortisol plasma concentrations. Coadministration of naloxone reversed this pain reduction under resting but not exercise conditions. The majority of CRH receptor expressing cells contained END within synovial tissue. DISCUSSION: In conclusion, this first clinical trial provides preliminary evidence for a short but not robust analgesic effect of a single dose of IA CRH in patients undergoing arthroscopic knee surgery. Further clinical studies will have to examine different doses of IA CRH-induced analgesia and to support the involvement of opioid peptides.

The effects of paracetamol and parecoxib on kidney function in elderly patients undergoing orthopedic surgery.

The common adverse effects of traditional nonsteroidal antiinflammatory drugs on renal function include reductions in renal blood flow, glomerular filtration rate, and sodium and potassium excretion, mainly via inhibition of renal cyclooxygenase. We designed the present study to determine the effects of IV paracetamol or parecoxib on renal function in elderly patients undergoing orthopedic surgery. Seventy-five patients (76 +/- 8 yr, mean +/- sd) undergoing hip replacement or surgery of the femoral shaft completed this randomized and placebo-controlled study. After their arrival in the postanesthesia care unit, patients received an initial dose of the study medication, paracetamol 1000 mg IV (n = 25), parecoxib 40 mg IV (n = 25), or saline IV (n = 25); subsequent doses were administered for the next 3 days. Opioids were provided as rescue medication. Blood and urine samples were collected before and after surgery, and markers of renal function were determined. During the first 2 h after the initial dose of parecoxib, creatinine clearance was slightly diminished (125 +/- 83 to 86 +/- 45 mL/min, P < 0.05), whereas no significant decrease of creatinine clearance was observed in the placebo and paracetamol groups. After all treatments, sodium and potassium excretion as well as urine albumin and alpha-1-microglobulin were transiently increased (group differences: not signicifant). In conclusion, glomerular and tubular functions were transiently affected in all patients after orthopedic surgery; however, the differences between the treatment groups were small and not clinically relevant. Further studies are warranted to determine adverse renal effects of longer-lasting therapy with these drugs, especially in patients with renal impairment or concomitant diseases.

Intraoperative low-dose S-ketamine has no preventive effects on postoperative pain and morphine consumption after major urological surgery in children.

BACKGROUND: Clinical studies suggest low-dose ketamine may have preemptive effects on postoperative pain in adults. The objective of this study was to determine whether intraoperative low-dose S-ketamine reduces postoperative pain and morphine consumption in children undergoing major urological surgery. MATERIALS: Thirty children scheduled for major urological surgery were included in this prospective study. Anesthesia was performed as total intravenous anesthesia (TIVA) with alfentanil and propofol. Fifteen patients additionally received an intravenous bolus of S-ketamine (0.2 mg.kg-1) followed by a continuous infusion of 5 microg.kg-1.min-1, which was stopped immediately after skin closure (Ketamine Group). Another 15 patients received an infusion of saline (CONTROL group). After transfer to the PACU, pain intensity was evaluated using a numeric rating scale (NRS). First patient controlled analgesia (PCA) request, cumulative morphine consumption and pain intensities within the first 72 h were compared. RESULTS: Morphine consumption was not significantly different during the first 72 h ( CONTROL: 0.4 mg.kg-1, 0.24-0.51 mg.kg-1, Ketamine: 0.32 mg.kg-1, 0.19-0.61 mg.kg-1; median, 25-75% percentile; n.s.). However, differences were found in pain intensity during the first postoperative hour ( CONTROL: 4.0, 3.2-4.6, Ketamine: 2.5, 1.3-3.5; median, 25-75% percentile; P<0.05) and in the time to first PCA use ( CONTROL: 37, 28-46 min, Ketamine: 62, 38-68 min; median, 25-75% percentile; P<0.05). CONCLUSIONS: Intraoperative low-dose S-ketamine had no effect on morphine consumption during the first 72 h after surgery. The differences in pain intensity and time to first PCA use probably reflect additional sedation and antinociceptive effects of S-ketamine rather than a true 'prevention' of pain.

The effect of intravenous infusion of adenosine on electrically evoked hyperalgesia in a healthy volunteer model of central sensitization.

Human pain models invoking central sensitization, one of the key mechanisms of chronic pain, may be useful for characterizing new analgesics. A new model of electrical hyperalgesia can detect the efficacy of several analgesic mechanisms. Because IV adenosine can alleviate neuropathic pain, we investigated its effect on experimental sensitization. This was a double-blinded, randomized, two-period crossover study in 20 healthy volunteers. Current pulses (0.5 ms; 1 Hz) were applied intracutaneously to achieve pain rating of approximately 5 on a 0-10 numeric rating scale. Pain, areas of pinprick hyperalgesia, and tactile allodynia were assessed during the 2.5-h stimulation period. Adenosine (50 microg. kg(-1). min(-1)) and placebo were infused IV over 60 min. Additional testing was performed 24 h after each treatment. Adenosine reduced the area of pinprick hyperalgesia during the infusion compared with placebo; there was no significant effect on tactile allodynia or pain rating. The effect on hyperalgesia developed over 15 min and was significant (P < or = 0.05) for the rest of the infusion period. There was no difference between treatments at 24 h. Thus, in accordance with reports on neuropathic pain, adenosine reduced central sensitization in the human model of electrical hyperalgesia. However, adenosine did not have the long-term effects seen in patients. The model can investigate mechanisms of drugs for the treatment of chronic pain.

Mechanically induced axon reflex and hyperalgesia in human UV-B burn are reduced by systemic lidocaine.

The mechanisms for the induction of primary mechanical hyperalgesia are unclear. We analyzed the neurogenic axon reflex erythema (flare) following phasic mechanical stimulation in normal and in UV-B irradiated skin. In a cross-over double blind design (n = 10), low dose of systemic lidocaine suppressed mechanical hyperalgesia in sunburned skin and in the mechanically induced flare. Phasic mechanical stimulation, even at painful intensities, did not evoke a flare reaction in normal skin. However, stimulation within the UV-B burn dose-dependently provoked an immediate flare reaction. Systemic lidocaine suppressed the mechanically induced flare as well as the mechanical hyperalgesia in sunburned skin, while leaving the impact-induced ratings in normal skin unchanged. Systemic lidocaine reduced these effects of sensitization, but did not reduce ratings in normal skin. As mechanically insensitive ("sleeping") nociceptors have been shown to mediate the axon-reflex in human skin, sensitization of this class of nociceptors might contribute also to the UV-B-induced primary mechanical hyperalgesia.

Perioperative intravenous lidocaine has preventive effects on postoperative pain and morphine consumption after major abdominal surgery.

UNLABELLED: Sodium channel blockers are approved for IV administration in the treatment of neuropathic pain states. Preclinical studies have suggested antihyperalgesic effects on the peripheral and central nervous system. Our objective in this study was to determine the time course of the analgesic and antihyperalgesic mechanisms of perioperative lidocaine administration. Forty patients undergoing major abdominal surgery participated in this randomized and double-blinded study. Twenty patients received lidocaine 2% (bolus injection of 1.5 mg/kg in 10 min followed by an IV infusion of 1.5 mg. kg(-1). h(-1)), and 20 patients received saline placebo. The infusion started 30 min before skin incision and was stopped 1 h after the end of surgery. Lidocaine blood concentrations were measured. Postoperative pain ratings (numeric rating scale of 0-10) and morphine consumption (patient-controlled analgesia) were assessed up to 72 h after surgery. Mean lidocaine levels during surgery were 1.9 +/- 0.7 microg/mL. Patient-controlled analgesia with morphine produced good postoperative analgesia (numeric rating scale at rest,