Opioid-induced bowel dysfunction: suggestions from a multidisciplinary expert Board.

Constipation, one of the adverse effects of opioid therapy with a major impact on quality of life, is still an unmet need for cancer patients, particularly those with an advanced and progressive disease, and for non-cancer patients chronically treated with opioids. The awareness of this condition is poor among healthcare providers, despite the recent publication of guidelines and consensus conferences. An early multidisciplinary approach of opioid-induced bowel dysfunction (OIBD), based on available therapies of proven effectiveness, could support clinicians in managing this condition, thus increasing patients' adherence to pain therapy. Several Italian experts involved in the management of patients suffering from pain (anaesthesia pain therapy, oncology, haematology, palliative care, gastroenterology) joined in a Board in order to draw up an expert opinion on OIBD. The most frequent and still unsolved issues in this field were examined, including a more comprehensive definition of OIBD, the benefits of early intervention to prevent its occurrence and the most appropriate use of peripherally acting mu-opioid receptor antagonists (PAMORAs). The use of the recently introduced PAMORA naloxegol was analysed, in light of the current literature. The Board proposed a solution for each open issue in the form of recommendations, integrated with the contribution of representatives from different disciplines and often accompanied by procedural algorithms immediately usable and applicable in daily clinical practice. Safety and quality of life of the patient suffering from pain and from the adverse effects of pain therapies have been the mainstays of this expert opinion, in cooperation with general practitioners and caregivers.

Low-dose buprenorphine infusion to prevent postoperative hyperalgesia in patients undergoing major lung surgery and remifentanil infusion: a double-blind, randomized, active-controlled trial.

BACKGROUND: Postoperative secondary hyperalgesia arises from central sensitization due to pain pathways facilitation and/or acute opioid exposure. The latter is also known as opioid-induced hyperalgesia (OIH). Remifentanil, a potent µ-opioid agonist, reportedly induces postoperative hyperalgesia and increases postoperative pain scores and opioid consumption. The pathophysiology underlying secondary hyperalgesia involves N-methyl-D-aspartate (NMDA)-mediated pain pathways. In this study, we investigated whether perioperatively infusing low-dose buprenorphine, an opioid with anti-NMDA activity, in patients receiving remifentanil infusion prevents postoperative secondary hyperalgesia. METHODS: Sixty-four patients, undergoing remifentanil infusion during general anaesthesia and major lung surgery, were randomly assigned to receive either buprenorphine i.v. infusion (25 µg h-1 for 24 h) or morphine (equianalgesic dose) perioperatively. The presence and extent of punctuate hyperalgesia were assessed one day postoperatively. Secondary outcome variables included postoperative pain scores, opioid consumption and postoperative neuropathic pain assessed one and three months postoperatively. RESULTS: A distinct area of hyperalgesia or allodynia around the surgical incision was found in more patients in the control group than in the treated group. Mean time from extubation to first morphine rescue dose was twice as long in the buprenorphine-treated group than in the morphine-treated group: 18 vs 9 min (P=0.002). At 30 min postoperatively, patients receiving morphine had a higher hazard ratio for the first analgesic rescue dose than those treated with buprenorphine (P=0.009). At three months, no differences between groups were noted. CONCLUSIONS: Low-dose buprenorphine infusion prevents the development of secondary hyperalgesia around the surgical incision but shows no long-term efficacy at three months follow-up.

Effects of passive leg raising on microvascular venous compartment in critically ill patients.

BACKGROUND: Even though fluid loading is thought to improve organ perfusion, the way in which it does so remains unclear. We assessed how the microvascular bed in skeletal muscle reacts to passive leg raising in patients with and without sepsis or septic shock. METHODS: We studied 40 critically ill patients (group A) and 30 healthy controls (group B). The forearm microvascular bed was assessed using near-infrared spectroscopy before and after passive leg raising. We measured stressed and unstressed volumes, inside pressures, blood flow, microvascular compliance and tone. RESULTS: In group A, passive leg raising induced a microvascular bed increase from 4.9 (3.2-6.5) mL/100 mL tissue to 5.7 (3.9-8.1) mL/100 mL tissue (P=0.005), leaving inside pressures unchanged, whereas in group B neither volumes nor pressures changed. Patients without sepsis showed an increase in the stressed volume from 0.22 (0.10-0.28) mL/100 mL tissue to 0.34 (0.23-0.66) mL/100 mL tissue (P=0.039) and a decrease in compliance (P=0.004), whereas, in septic shock, the unstressed volume increased from 4.20 (3.01-5.82) mL/100 mL tissue to 5.32 (4.01-11.50) mL/100 mL tissue (P=0.036). In critically ill patients near-infrared spectroscopy showed no difference in microvascular variables between responders and non-responders to passive leg raising, but responders showed a cardiovascular response shorter than healthy subjects. CONCLUSIONS: Our study provides evidence that macrocirculatory parameters are unreliable to derive measurements of stressed and unstressed volumes. Our results indicate that in septic shock, the enlargement of the unstressed volume associated with passive leg raising induces loss of fluids to the interstitium, thus leaving organ perfusion unchanged or worse.

Assessing skeletal muscle variations in microvascular pressure and unstressed blood volume at the bedside.

OBJECTIVE: Quantitative NIRS measurements for MBV partitioning inside microvessels are of current physiologic and clinical interest. In this study, in healthy subjects, we sought new bedside NIRS variables for noninvasively measuring Vu and Pi changes. METHODS: Fifteen healthy subjects underwent graded venous congestion for MBV measurements with NIRS and the reference technique strain-gauge plethysmography. From ΔMBV we calculated vascular compliance, blood flow, and new NIRS variables including V(u) and P(it) and P(crit). RESULTS: Extrapolating MBV changes to 0 yielded Pit 4.19 ± 0.5 mmHg corresponding to a Vu of 2.53 ± 0.43 mL/100 mL T. The slope for MBV began steeper at values below 18 mmHg (P(crit)). Microvascular compliance measured with NIRS or with strain gauge gave matching results. The change in MBV depended on the oxyhemoglobin increase. No correlation was found between Vu and microvascular compliance or the overall ΔMBV. Cumulative pressure steps showed higher linearity in ΔMBV than that induced by discontinuous steps. CONCLUSIONS: The new NIRS variables we report could be a practical bench-to-bedside tool to assess venous driving pressure for systemic perfusion and measure changes in Vu within the microvascular bed.

Neuromodulation of chronic headaches: position statement from the European Headache Federation.

The medical treatment of patients with chronic primary headache syndromes (chronic migraine, chronic tension-type headache, chronic cluster headache, hemicrania continua) is challenging as serious side effects frequently complicate the course of medical treatment and some patients may be even medically intractable. When a definitive lack of responsiveness to conservative treatments is ascertained and medication overuse headache is excluded, neuromodulation options can be considered in selected cases. Here, the various invasive and non-invasive approaches, such as hypothalamic deep brain stimulation, occipital nerve stimulation, stimulation of sphenopalatine ganglion, cervical spinal cord stimulation, vagus nerve stimulation, transcranial direct current stimulation, repetitive transcranial magnetic stimulation, and transcutaneous electrical nerve stimulation are extensively published although proper RCT-based evidence is limited. The European Headache Federation herewith provides a consensus statement on the clinical use of neuromodulation in headache, based on theoretical background, clinical data, and side effect of each method. This international consensus further gives recommendations for future studies on these new approaches. In spite of a growing field of stimulation devices in headaches treatment, further controlled studies to validate, strengthen and disseminate the use of neurostimulation are clearly warranted. Consequently, until these data are available any neurostimulation device should only be used in patients with medically intractable syndromes from tertiary headache centers either as part of a valid study or have shown to be effective in such controlled studies with an acceptable side effect profile.

A six year retrospective review of occipital nerve stimulation practice--controversies and challenges of an emerging technique for treating refractory headache syndromes.

BACKGROUND: A retrospective review of patients treated with Occipital Nerve Stimulation (ONS) at two large tertiary referral centres has been audited in order to optimise future treatment pathways. METHODS: Patient's medical records were retrospectively reviewed, and each patient was contacted by a trained headache expert to confirm clinical diagnosis and system efficacy. Results were compared to reported outcomes in current literature on ONS for primary headaches. RESULTS: Twenty-five patients underwent a trial of ONS between January 2007 and December 2012, and 23 patients went on to have permanent implantation of ONS. All 23 patients reached one-year follow/up, and 14 of them (61%) exceeded two years of follow-up. Seventeen of the 23 had refractory chronic migraine (rCM), and 3 refractory occipital neuralgia (ON). 11 of the 19 rCM patients had been referred with an incorrect headache diagnosis. Nine of the rCM patients (53%) reported 50% or more reduction in headache pain intensity and or frequency at long term follow-up (11-77 months). All 3 ON patients reported more than 50% reduction in pain intensity and/or frequency at 28-31 months. Ten (43%) subjects underwent surgical revision after an average of 11 ± 7 months from permanent implantation - in 90% of cases due to lead problems. Seven patients attended a specifically designed, multi-disciplinary, two-week pre-implant programme and showed improved scores across all measured psychological and functional parameters independent of response to subsequent ONS. CONCLUSIONS: Our retrospective review: 1) confirms the long-term ONS success rate in refractory chronic headaches, consistent with previously published studies; 2) suggests that some headaches types may respond better to ONS than others (ON vs CM); 3) calls into question the role of trial stimulation in ONS; 4) confirms the high rate of complications related to the equipment not originally designed for ONS; 5) emphasises the need for specialist multidisciplinary care in these patients.

Immature platelet fraction in predicting sepsis in critically ill patients.

PURPOSE: To establish whether in critically ill patients without sepsis at intensive care unit (ICU) admission the percentage immature platelet fraction (IPF%) is a cellular marker predicting sepsis to verify a possible correlation between IPF% changes and manifest sepsis and describe the IPF% time course after ICU admission. METHODS: Prospective, observational 7-day study of 64 adult patients admitted to a general ICU at a University Hospital with no sepsis criteria. We measured daily IPF%, procalcitonin (PCT), C-reactive protein, platelets, white blood cell count and coagulation variables. Thirty-one patients with sepsis at ICU admission were studied as controls. RESULTS: The only variable we tested at ICU admission that predicted sepsis was plasma IPF% (p < 0.001; >4.7 %: sensitivity 56.2 % IC 37.7-73.6; specificity 90.0 % IC 73.4-97.8). IPF% and PCT values were higher for the patients who had sepsis at admission and during the study than in patients in whom sepsis never developed (IPF%: p = 0.017; PCT: p = 0.030). Among the outcome variables, logistic regression was identified as the only variable related to the development of sepsis, IPF% (r = 0.51; p = 0.004). In patients who developed sepsis IPF% was inversely correlated with platelet count (r = -0.60; p < 0.001) and had high values before sepsis became manifest, decreasing significantly on the 2nd day thereafter. CONCLUSIONS: In patients without sepsis at ICU admission IPF% increases before sepsis becomes manifest. Measuring IPF% through an easily available technology can therefore provide an early cellular marker predicting the development of sepsis.

Emerging treatment for chronic migraine and refractory chronic migraine.

INTRODUCTION: Chronic migraine (CM), the suffering of 15 or more headache days with at least 8 of these migraine days, afflicts 1.3% - 5.1% of the global population. CM is the most common disorder faced by experts in tertiary headache centers. When resistant to conventional medical treatment and prophylactic medication this condition is known as refractory chronic migraine (RCM). RCM is one of the greatest challenges in headache medicine. AREAS COVERED: State-of-the-art and future medical treatments of chronic migraine include: OnabotulinumtoxinA, antiepileptic drugs (Levetiracetam, Magnesium valproate hydrate, Lacosamide, BGG-492), 5-HT agonists (Lasmiditan, NXN-188, novel delivery systems of Sumatriptan, a well-established drug treatment for acute migraine), CGRP receptor antagonists (BMS-927711), ML-1 agonists (Ramelteon), orexin receptor antagonist (MK-6096), plant-derived compound (LLL-2011) and other multitarget drugs such as Tezampanel, Tonabersat, intranasal carbon dioxide and BOL-148. The role for neuromodulation, the application of targeted electrical stimulation, will be examined. EXPERT OPINION: Medication overuse headache (MOH) is now recognized to be a major factor in many cases of both chronic and refractory chronic migraine. MOH must be addressed prior to evaluating the effectiveness of new preventative and prophylactic treatment approaches. Innovative new drugs and electrical neuromodulation are promising CM treatments. Future studies must carefully screen patients and acquire data that can lead to personalized, tailored treatment strategies.

Critical pneumonia complicating early-stage pregnancy.

We present a case of community-acquired methicillin-resistant Staphylococcus aureus necrotizing pneumonia, Panton-Valentine leukocidin positive, in a woman at 14 weeks of pregnancy. To our knowledge, this is the first case reporting this critical lung infection occurring during an early phase of pregnancy. This case study alerts physicians to the increasing worldwide spread of these uncommon yet virulent and potentially lethal infections. In our patient, antibiotic therapy with linezolid plus rifampin started at 14 weeks of pregnancy had a successful outcome without inducing toxicity or teratogenesis in the fetus.

Microcirculatory changes and skeletal muscle oxygenation measured at rest by non-infrared spectroscopy in patients with and without diabetes undergoing haemodialysis.

INTRODUCTION: Haemodialysis has direct and indirect effects on skin and muscle microcirculatory regulation that are severe enough to worsen tolerance to physical exercise and muscle asthenia in patients undergoing dialysis, thus compromising patients' quality of life and increasing the risk of mortality. In diabetes these circumstances are further complicated, leading to an approximately sixfold increase in the incidence of critical limb ischaemia and amputation. Our aim in this study was to investigate in vivo whether haemodialysis induces major changes in skeletal muscle oxygenation and blood flow, microvascular compliance and tissue metabolic rate in patients with and without diabetes. METHODS: The study included 20 consecutive patients with and without diabetes undergoing haemodialysis at Sant Andrea University Hospital, Rome from March to April 2007. Near-infrared spectroscopy (NIRS) quantitative measurements of tissue haemoglobin concentrations in oxygenated [HbO2] and deoxygenated forms [HHb] were obtained in the calf once hourly for 4 hours during dialysis. Consecutive venous occlusions allowed one to obtain muscular blood flow (mBF), microvascular compliance and muscle oxygen consumption (mVO2). The tissue oxygen saturation (StO2) and content (CtO2) as well as the microvascular bed volume were derived from the haemoglobin concentration. Nonparametric tests were used to compare data within each group and among the groups and with a group of 22 matched healthy controls. RESULTS: The total haemoglobin concentration and [HHb] increased significantly during dialysis in patients without and with diabetes. Only in patients with diabetes, dialysis involved a [HbO2], CtO2 and increase but left mVO2 unchanged. Multiple regression StO2 analysis disclosed a significant direct correlation of StO2 with HbO2 and an inverse correlation with mVO2. Dialysis increased mBF only in diabetic patients. Microvascular compliance decreased rapidly and significantly during the first hour of dialysis in both groups. CONCLUSIONS: Our NIRS findings suggest that haemodialysis in subjects at rest brings about major changes in skeletal muscle oxygenation, blood flow, microvascular compliance and tissue metabolic rate. These changes differ in patients with and without diabetes. In all patients haemodialysis induces changes in tissue haemoglobin concentrations and microvascular compliance, whereas in patients with diabetes it alters tissue blood flow, tissue oxygenation (CtO2, [HbO2]) and the metabolic rate (mVO2). In these patients the mVO2 is correlated to the blood supply. The effects of haemodialysis on cell damage remain to be clarified. The absence of StO2 changes is probably linked to an opposite [HbO2] and mVO2 pattern.

Does local anesthetic dilution influence the clinical effectiveness of multiple-injection axillary brachial plexus block?: a prospective, double-blind, randomized clinical trial in patients undergoing upper limb surgery.

OBJECTIVES: The relationship between the dose, volume, and concentration of local anesthetic and the quality and success of regional anesthesia remains unclear. Our aim was to test whether using 3 different volumes of the same local anesthetic dose influences the success rate of an axillary brachial plexus block with a multiple-injection technique in patients undergoing upper limb surgery. METHODS: One hundred sixty-five patients were prospectively randomized to 1 of 3 groups. Each group received an axillary block with mepivacaine 400 mg, diluted in 3 different volumes (20, 30, and 40 mL). Outcome measures recorded were the block success rate at 30 mins, sensory and motor onset times, and length of postoperative sensory and motor blockade. RESULTS: No difference was found in the rate of successful axillary plexus blocks determined when the 30-min follow-up ended among the 3 groups: 94% for 20-mL volume, 94% for 30-mL volume, and 98% for 40-mL volume. The median sensory and motor onset times of anesthesia did not differ. However, postoperative motor blockade and sensory analgesia lasted significantly longer in the patients receiving mepivacaine 400 mg diluted in a volume of 30 mL than in the other groups. CONCLUSIONS: An axillary brachial plexus block induced with a multiple-injection technique with mepivacaine 400 mg yields a high success rate regardless of the volume of anesthetic injected.

Ondansetron inhibits the analgesic effects of tramadol: a possible 5-HT(3) spinal receptor involvement in acute pain in humans.

UNLABELLED: To investigate a possible antinociceptive role of serotonin receptor subtype 3 (5-HT(3)), we evaluated the effects of a coadministration of ondansetron, a 5-HT(3) selective antagonist, and tramadol, a central analgesic dependent on enhanced serotonergic transmission. Fifty-nine patients undergoing ear, throat, and nose surgery, using tramadol for 24-h postoperative patient-controlled analgesia (bolus = 30 mg; lockout interval = 10 min) were randomly allocated either to a group receiving ondansetron continuous infusion (1 mg. mL(-1). h(-1)) for postoperative nausea and vomiting (Group O) or to a control group receiving saline (Group T). Pain and vomiting scores and tramadol consumption were evaluated at 4, 8, 12, and 24 h. Pain scores were never >4, according to a 0-10 numerical rating scale, in both groups. Group O required significantly larger doses of tramadol at 4 h (213 versus 71 mg, P < 0.001), 8 h (285 versus 128 mg, P < 0.002), and 12 h (406 versus 190 mg, P < 0.002). Vomiting scores were higher in Group O at 4 h (P < 0.05) and 8 h (P = 0.05). We conclude that ondansetron reduced the overall analgesic effect of tramadol, probably blocking spinal 5-HT(3) receptors. IMPLICATIONS: Serotonin is an important neurotransmitter of the descending pathways that down-modulate spinal nociception. In postoperative pain, ondansetron, a selective 5-HT(3) receptor antagonist, increased the analgesic dose of tramadol. We suggest that, when antagonized for antiemetic purpose, 5-HT(3) receptors foster nociception, because of their site-dependent action.