Evaluation of Postsurgical Hyperalgesia and Sensitization After Open Inguinal Hernia Repair: A Useful Model for Neuropathic Pain?

Cutaneous mechanical hyperalgesia can be induced in healthy volunteers in early phase analgesic studies to model central sensitization, a key mechanism of persistent pain. However, such hyperalgesia is short-lived (a matter of hours), and is used only for assessing only single drug doses. In contrast, postsurgical peri-incisional hyperalgesia may be more persistent and hence be a more useful model for the assessment of the efficacy of new analgesics. We undertook quantitative sensory testing in 18 patients at peri-incisional and nonoperated sites before open inguinal hernia repair and up to the 24th postsurgical week. The spatial extent of punctate hyperalgesia and brush allodynia at the peri-incisional site were greatest at weeks 2 and 4, but had resolved by week 24. Heat allodynia, suggestive of local inflammation or peripheral sensitization, was not observed; instead, there were deficits in cold and heat sensory detection that persisted until week 24. The findings suggest that central sensitization contributes significantly to mechanical hyperalgesia at the peri-incisional site. The prolonged duration of hyperalgesia would be advantageous as a pain model, but there was considerable variability of mechanical hyperalgesia in the cohort; the challenges of recruitment may limit its use to small, early phase analgesic studies. PERSPECTIVE: Peri-incisional mechanical hyperalgesia persists for ≥4 weeks after open inguinal hernia repair and reflects central sensitization; this may have usefulness as a model of chronic pain to assess the potential of antineuropathic analgesics.

Hospitalization due to acute exacerbation of chronic pain: An intervention study in a university hospital.

BACKGROUND AND AIMS: Hospitalization as a result of acute exacerbation of complex chronic pain is a largely hidden problem, as patients are often admitted to hospital under a variety of specialities, and there is frequently no overarching inpatient chronic pain service dedicated to their management. Our institution had established an inpatient acute pain service overseen by pain physicians and staffed by specialist nurses that was intended to focus on the management of perioperative pain. We soon observed an increasing number of nurse-to-nurse referrals of non-surgical inpatients admitted with chronic pain. Some of these patients had seemingly intractable and highly complex pain problems, and consequently we initiated twice-weekly attending physician-led inpatient pain rounds to coordinate their management. From these referrals, we identified a cohort of 20 patients who were frequently hospitalized for long periods with exacerbations of chronic pain. We sought to establish whether the introduction of the physician-led inpatient pain ward round reduced the number and duration of hospitalizations, and costs of treatment. METHODS: We undertook a retrospective, observational, intervention cohort study. We recorded acute Emergency Department (ED) attendances, hospital admissions, and duration and costs of hospitalization of the cohort of 20 patients in the year before and year after introduction of the inpatient pain service. RESULTS: The patients' mean age was 38.2 years (±standard deviation 13.8 years, range 18-68 years); 13 were women (65.0%). The mode number of ED attendances was 4 (range 2-15) pre-intervention, and 3 (range 0-9) afterwards (p=0.116). The mode bed occupancy was 32 days (range 9-170 days) pre-intervention and 19 days (range 0-115 days) afterwards (p=0.215). The total cost of treating the cohort over the 2-year study period was £733,010 (US$1.12m), comprising £429,479 (US$656,291) of bed costs and £303,531 (US$463,828) of investigation costs. The intervention did not achieve significant improvements in the total costs, bed costs or investigation costs. CONCLUSIONS: Despite our attending physician-led intervention, the frequency, duration and very substantial costs of hospitalization of the cohort were not significantly reduced, suggesting that other strategies need to be identified to help these complex and vulnerable patients. IMPLICATIONS: Frequent hospitalization with acute exacerbation of chronic pain is a largely hidden problem that has very substantial implications for patients, their carers and healthcare providers. Chronic pain services tend to focus on outpatient management. Breaking the cycle of frequent and recurrent hospitalization using multidisciplinary chronic pain management techniques has the potential to improve patients' quality of life and reduce hospital costs. Nonetheless, the complexity of these patients' chronic pain problems should not be underestimated and in some cases are very challenging to treat.

Retesting the Hypothesis of a Clinical Randomized Controlled Trial in a Simulation Environment to Validate Anesthesia Simulation in Error Research (the VASER Study).

BACKGROUND: Simulation has been used to investigate clinical questions in anesthesia, surgery, and related disciplines, but there are few data demonstrating that results apply to clinical settings. We asked "would results of a simulation-based study justify the same principal conclusions as those of a larger clinical study?" METHODS: We compared results from a randomized controlled trial in a simulated environment involving 80 cases at three centers with those from a randomized controlled trial in a clinical environment involving 1,075 cases. In both studies, we compared conventional methods of anesthetic management with the use of a multimodal system (SAFERsleep; Safer Sleep LLC, Nashville, Tennessee) designed to reduce drug administration errors. Forty anesthesiologists each managed two simulated scenarios randomized to conventional methods or the new system. We compared the rate of error in drug administration or recording for the new system versus conventional methods in this simulated randomized controlled trial with that in the clinical randomized controlled trial (primary endpoint). Six experts were asked to indicate a clinically relevant effect size. RESULTS: In this simulated randomized controlled trial, mean (95% CI) rates of error per 100 administrations for the new system versus conventional groups were 6.0 (3.8 to 8.3) versus 11.6 (9.3 to 13.8; P = 0.001) compared with 9.1 (6.9 to 11.4) versus 11.6 (9.3 to 13.9) in the clinical randomized controlled trial (P = 0.045). A 10 to 30% change was considered clinically relevant. The mean (95% CI) difference in effect size was 27.0% (-7.6 to 61.6%). CONCLUSIONS: The results of our simulated randomized controlled trial justified the same primary conclusion as those of our larger clinical randomized controlled trial, but not a finding of equivalence in effect size.

Pictorial prescribing reduces fentanyl drug administration errors: a simulated controlled study.

OBJECTIVES: Transmucosal fentanyl is used to treat transient exacerbations of cancer pain. Several immediate release products are available, presented as intranasal sprays, sublingual and buccal tablets, or lozenges. These are not interchangeable, creating potential for medication errors. We compared the incidence of medication errors in a simulated scenario using handwritten drug charts and charts labelled with preprinted self-adhesive stickers with full pictorial fentanyl prescriptions. METHODS: 54 nurses were shown 5 handwritten drug charts and 5 with self-adhesive pictorial labels. Nurses indicated which preparation and dose they would administer from boxes of Instanyl, Abstral, Effentora and Actiq (Nycomed, ProStrakan, Cephalon and Teva, respectively). We measured the frequency of drug administration errors and asked them to rate the prescriptions for clarity on four-point Likert items. RESULTS: The use of pictorial self-adhesive prescriptions significantly reduced errors in choice of preparation, from 20 with traditional handwritten charts to 6 with self-adhesive labels (OR 3.52, 95% CI 1.39 to 8.90, p=0.006), but the incidence of dose error was not significantly different (OR 1.47, 95% CI 0.80 to 2.70, p=0.281). Analysis of Likert items showed using pictorial printed labels significantly improved nurses' understanding of choice of preparation, dose and maximum four hourly dose (p<0.0001, p=0.006 and p=0.028, respectively). CONCLUSIONS: The use of pictorial prescribing appears to be a promising strategy that could reduce medication errors in choice of fentanyl preparations. There may be a wider use for pictorial prescribing where non-interchangeable preparations of the same drug exist.

Case Report: Neuropathic pain in a patient with congenital insensitivity to pain.

We report a unique case of a woman with Channelopathy-associated Insensitivity to Pain (CIP) Syndrome, who developed features of neuropathic pain after sustaining pelvic fractures and an epidural hematoma that impinged on the right fifth lumbar (L5) nerve root. Her pelvic injuries were sustained during painless labor, which culminated in a Cesarean section. She had been diagnosed with CIP as child, which was later confirmed when she was found to have a null mutation of the SCN9a gene that encodes the voltage-gated sodium channel Nav1.7. She now complains of troubling continuous buzzing in both legs and a vice-like squeezing in the pelvis on walking. Quantitative sensory testing showed that sensory thresholds to mechanical stimulation of the dorsum of both feet had increased more than 10-fold on both sides compared with tests performed before her pregnancy. These findings fulfill the diagnostic criteria for neuropathic pain. Notably, she only experiences the negative symptoms (such as numbness and tingling) and she has not reported sharp, burning or electric shock sensations, although the value of verbal descriptors is somewhat limited in a person who has never felt pain before. However, her case strongly suggests that at least some of the symptoms of neuropathic pain can persist despite the absence of the Nav1.7 channel. Pain is a subjective experience and this case sheds light on the transmission of neuropathic pain in humans that cannot be learned from knockout mice.

Synthetic self-assembling clostridial chimera for modulation of sensory functions.

Clostridial neurotoxins reversibly block neuronal communication for weeks and months. While these proteolytic neurotoxins hold great promise for clinical applications and the investigation of brain function, their paralytic activity at neuromuscular junctions is a stumbling block. To redirect the clostridial activity to neuronal populations other than motor neurons, we used a new self-assembling method to combine the botulinum type A protease with the tetanus binding domain, which natively targets central neurons. The two parts were produced separately and then assembled in a site-specific way using a newly introduced 'protein stapling' technology. Atomic force microscopy imaging revealed dumbbell shaped particles which measure ∼23 nm. The stapled chimera inhibited mechanical hypersensitivity in a rat model of inflammatory pain without causing either flaccid or spastic paralysis. Moreover, the synthetic clostridial molecule was able to block neuronal activity in a defined area of visual cortex. Overall, we provide the first evidence that the protein stapling technology allows assembly of distinct proteins yielding new biomedical properties.

The nature and prevalence of chronic pain in homeless persons: an observational study.

BACKGROUND: Homeless people are known to suffer disproportionately with health problems that reduce physical functioning and quality of life, and shorten life expectancy. They suffer from a wide range of diseases that are known to be painful, but little information is available about the nature and prevalence of chronic pain in this vulnerable group. This study aimed to estimate the prevalence of chronic pain among homeless people, and to examine its location, effect on activities of daily living, and relationship with alcohol and drugs. METHODS: We conducted face-to-face interviews with users of homeless shelters in four major cities in the United Kingdom, in the winters of 2009-11. Participants completed the Brief Pain Inventory, Short Form McGill Pain questionnaire, Leeds Assessment of Neuropathic Symptoms and Signs, and detailed their intake of prescribed and unprescribed medications and alcohol. We also recorded each participant's reasons for homelessness, and whether they slept rough or in shelters. FINDINGS: Of 168 shelter users approached, 150 (89.3%) participated: 93 participants (63%) reported experiencing pain lasting longer than three months; the mean duration of pain experienced was 82.2 months. The lower limbs were most frequently affected. Opioids appeared to afford a degree of analgesia for some, but whilst many reported symptoms suggestive of neuropathic pain, very few were taking anti-neuropathic drugs. INTERPRETATION: The prevalence of chronic pain in the homeless appears to be substantially higher than the general population, is poorly controlled, and adversely affects general activity, walking and sleeping. It is hard to discern whether chronic pain is a cause or effect of homelessness, or both. Pain is a symptom, but in this challenging group it might not always be possible to treat the underlying cause. Exploring the diagnosis and treatment of neuropathic pain may offer a means of improving the quality of these vulnerable people's lives.

Assessment of post-operative pain in children: who knows best?

Pain assessment in children can be extremely challenging. Most professional bodies recommend that parents or carers should be involved with their child's pain assessment; but the evidence that parents can accurately report pain on behalf of their children is mixed. Our objective was to examine whether there were differences in post-operative pain score ratings between the child, nurse and parent or carer after surgery. Cognitively intact children aged four upwards, undergoing all surgical procedures, whose parents were present in the post-anaesthetic recovery unit (PACU), were studied. Thirty-three children were included in the study. The numerical rating scale was used to rate the child's pain by the child, nurse and parent on arrival to the PACU and prior to discharge. We found strong correlations between children's, nurses' and parent's pain scores on admission and discharge from PACU. The intraclass correlation coefficient of pain scores reported by children, nurses and parents was 0.94 (95% confidence intervals 0.91-0.96, P<0.0001). In cognitively intact children, it is adequate to manage pain based upon the assessment of children's and nurses' pain scores alone. The numerical rating scale appeared to be suitable for younger children. Whilst there are benefits of parents being present in recovery, it is not essential for optimizing the assessment of pain.

Optical detection of the anesthetic agent propofol in the gas phase.

The anesthetic agent propofol (2,6-diisopropylphenol) is the most widely used intravenously administered drug in general anesthesia. However, a viable online capability to monitor metabolized levels of propofol in patients does not currently exist. Here we show for the first time that optical spectroscopy has good potential to detect metabolized propofol from patients' exhaled breath. We present quantitative absorption measurements of gas phase propofol both in the ultraviolet and middle-infrared spectral regions. We demonstrate that a detection limit in the subparts-per-billion concentration range can be reached with photoacoustic spectroscopy in the UV spectral region, paving the way for the development of future optical monitors.

Anaesthetic impairment of immune function is mediated via GABA(A) receptors.

BACKGROUND: GABA(A) receptors are members of the Cys-loop family of neurotransmitter receptors, proteins which are responsible for fast synaptic transmission, and are the site of action of wide range of drugs. Recent work has shown that Cys-loop receptors are present on immune cells, but their physiological roles and the effects of drugs that modify their function in the innate immune system are currently unclear. We are interested in how and why anaesthetics increase infections in intensive care patients; a serious problem as more than 50% of patients with severe sepsis will die. As many anaesthetics act via GABA(A) receptors, the aim of this study was to determine if these receptors are present on immune cells, and could play a role in immunocompromising patients. PRINCIPAL FINDINGS: We demonstrate, using RT-PCR, that monocytes express GABA(A) receptors constructed of α1, α4, ß2, γ1 and/or δ subunits. Whole cell patch clamp electrophysiological studies show that GABA can activate these receptors, resulting in the opening of a chloride-selective channel; activation is inhibited by the GABA(A) receptor antagonists bicuculline and picrotoxin, but not enhanced by the positive modulator diazepam. The anaesthetic drugs propofol and thiopental, which can act via GABA(A) receptors, impaired monocyte function in classic immunological chemotaxis and phagocytosis assays, an effect reversed by bicuculline and picrotoxin. SIGNIFICANCE: Our results show that functional GABA(A) receptors are present on monocytes with properties similar to CNS GABA(A) receptors. The functional data provide a possible explanation as to why chronic propofol and thiopental administration can increase the risk of infection in critically ill patients: their action on GABA(A) receptors inhibits normal monocyte behaviour. The data also suggest a potential solution: monocyte GABA(A) receptors are insensitive to diazepam, thus the use of benzodiazepines as an alternative anesthetising agent may be advantageous where infection is a life threatening problem.

Factors affecting the concentration of electrolyte infusions prepared from stock solutions.

BACKGROUND: Wide variation in the concentrations of electrolyte infusions prepared from stock solutions has previously been reported. Layering of viscous stock electrolyte solutions in their diluent can lead to high concentrations being delivered during the infusion, resulting in potentially very serious medication errors which have caused deaths. OBJECTIVE: To determine the safest way of preparing homogenous electrolyte solutions for parenteral infusion. METHODS: The study examined how the concentration of potassium and magnesium varied during infusions after concentrated stock solutions had been diluted to 400 mmol/l with 0.9% sodium chloride. It also examined the use of syringes compared to polyvinyl chloride (PVC) bags, agitating vigorously with a 'vortex' mixer compared to inversion, and the influence of allowing the infusions to stand for 24 h before administration. The study was conducted in November 2009. Results It was found that, in general, the concentrations of potassium and magnesium solutions are less variable if they are prepared in PVC bags rather than syringes. Vigorous mixing of concentrated stock solutions with diluent and allowing preparations to stand for 24 h also improved the homogeneity of the infusions. However, even with meticulous preparation, some infusions deviated from the expected concentration by more than 10%. CONCLUSION: It is recommended that electrolyte infusions are prepared and provided by the pharmaceutical industry in prefilled syringes or bags. Given the likely cost of these products, an alternative would be to prepare infusions in pharmacy in advance, using PVC bags rather than syringes, and that they should be agitated vigorously with a 'vortex' mixer.

Physician assistants as servant leaders: meeting the needs of the underserved.

PURPOSE: The purpose of this study was to determine if the level of servant leader characteristics in clinically practicing physician assistants (PAs) in underserved populations differed from PAs serving in other locales. METHODS: Five subscales of servant leadership: altruistic calling, emotional healing, wisdom, persuasive mapping, and organizational stewardship, were measured in a quantitative study of clinically practicing PAs using a self-rating survey and a similar survey by others rating the PA. RESULTS: Of 777 PAs invited, 321 completed the survey. On a scale of 1 to 5, mean PA self-ratings ranged from 3.52 (persuasive mapping) to 4.05 (wisdom). Other raters' scores paired with the self-rated PA scores were comparable in all subscales except wisdom, which was rated higher by the other raters (4.32 by other raters, 4.01 by PAs, P= .002). There was no significant difference in the measures of servant leadership reported by PAs serving the underserved compared to PAs serving in other populations. Servant leader subscales were higher for PAs compared to previous studies of other health care or community leader populations. CONCLUSION: The results found that the PA population studied had a prominent level of servant leadership characteristics that did not differ between those working with underserved and nonunderserved populations.

Room air dilution of heliox given by facemask.

OBJECTIVES: To measure the extent of dilution of helium-oxygen (heliox) by room air when given via high concentration reservoir mask to spontaneously breathing subjects. Substantial dilution of heliox by room air under these circumstances might alter its physical properties sufficiently to negate any potential clinical benefit in obstructive respiratory failure. DESIGN: Healthy volunteers breathing different concentrations of helium in oxygen via two different masks in a randomised crossover design. SETTING: Operating theatre in a university hospital. PATIENTS AND PARTICIPANTS: Six healthy volunteers. INTERVENTIONS: The concentrations of helium, nitrogen and oxygen were measured in the trachea of each volunteer using a mass spectrometer during normal breathing, hyperventilation and hypoventilation. MEASUREMENTS AND RESULTS: During normal breathing of Heliox21 (79% helium) via a standard non-rebreathe reservoir mask, within subject median percentage tracheal helium was 37.2% (range 29.3-52.2%) and nitrogen was 41.7% (27.4-49.4%). Air entrainment was affected by changes in breathing pattern: tracheal nitrogen concentration was greater during hyperventilation (55.4%; range 49.4-63.5%) and less during hypoventilation (33.1%; range 24.6-39.6%, p=0.043). Tracheal nitrogen could be almost completely abolished by administering heliox via a tightly fitting cushioned facemask, even during hyperventilation (2.2%; range 0.6-6.1%, p=0.028). CONCLUSIONS: Heliox administration via a standard high-concentration reservoir mask leads to significant dilution by room air. For the full potential benefits of heliox to be realised in spontaneously breathing patients, it should be administered via a system that achieves a gas tight seal, with no leaks between the delivery device and the surroundings.

The effect of drug concentration expression on epinephrine dosing errors: a randomized trial.

BACKGROUND: The expression of drug concentration as a ratio may cause dosing errors. OBJECTIVE: To examine the effect of ratio expressions on drug administration. DESIGN: Randomized, blinded, controlled study. SETTING: Simulation center in an urban hospital. PARTICIPANTS: 28 physicians. INTERVENTION: Participants managed a simulated pediatric acute anaphylaxis scenario by using epinephrine ampules labeled with mass concentration (1 mg in 1 mL) or a ratio (1 mL of a 1:1000 solution). MEASUREMENTS: The amount of epinephrine given and the time taken to administer it. RESULTS: Compared with providers using ampules with mass concentration labels, those using ratio labels gave more epinephrine (adjusted mean dose, 213 microg above target [95% CI, 76.4 to 350.1 microg]; P = 0.003), and took longer to do so (adjusted mean delay, 91 seconds, [CI, 61.0 to 122.1 seconds]; P < or = 0.0001). LIMITATIONS: Performance in simulated scenarios may not reflect clinical practice. In reality, ampule labels provide both expressions of concentration. CONCLUSION: The use of ratios to express drug concentration may be a source of drug administration error. Patient safety might be improved by expressing drug concentrations exclusively as mass concentration.

Calculation of doses of drugs in solution: are medical students confused by different means of expressing drug concentrations?

INTRODUCTION: Our hypothesis was that clinical medical students find the different means of expressing the concentration of drugs in solution confusing. We are concerned that lack of formal teaching on this topic may make students liable to make drug dosing errors after they have qualified. Administering the wrong volume of a drug may have serious consequences for patient safety. STUDY DESIGN AND PARTICIPANT GROUP: Web-based electronic multiple-choice examination of clinical medical students. METHODS: We asked clinical medical students at our university three multiple-choice questions concerning the concentration of lidocaine (lignocaine) and epinephrine (adrenaline) in solution and the maximal recommended dose of lidocaine. The incorrect options were wrong by factors of between 4 and 1000. RESULTS: One hundred and sixty-eight clinical students out of 350 contacted responded to an invitation to participate (response rate 48%). Twenty-seven percent answered every question incorrectly and 10% answered all three correctly. The mean score for all students was only 1.24 out of 3 (standard error 0.96). However, final-year students performed significantly better (p = 0.016), implying that some knowledge had been acquired informally. Their higher mean score resulted from correctly identifying the amount of epinephrine (p = 0.005) and lidocaine (p = 0.018) more frequently. Only 27% knew the maximal recommended dose of lidocaine, with no difference between years (p = 0.724). CONCLUSIONS: A substantial majority of medical students are unable to calculate the mass of a drug in solution correctly. There is evidence that some students are picking up this skill during the course, because final-year students performed significantly better than first-year students. Modern medical student pharmacology teaching is highly sophisticated, encompassing genomics, molecular and cell biology. The ability to calculate drug doses safely appears to have been overlooked. Students should be familiar with these concepts, so as to avoid dose errors and associated morbidity, mortality and cost when they begin prescribing. To simplify calculations, drug packaging should express the concentration of drugs in solution solely as mass per unit volume, e.g. milligrams per millilitre.

Motivation, altruism, and generalized compliance: a field study of organizational citizenship behaviors.

This study tests the relations among five sources of motivation and two organizational citizenship behaviors. 175 employees from 31 locations of two agriculturally based companies completed the Motivation Sources Inventory and were rated by their supervisors for demonstrated organizational citizenship behaviors. There were significant positive correlations for employees' Self-concept-Internal Motivation with Altruistic Behavior of employees; while employees' Self-concept-External Motivation showed a significant negative relation with Altruistic Behavior by employees. Surprisingly, no correlation between employees' Goal Internalization Motivation and Altruistic Behavior by employees was found. Interpretation of these findings and further research are suggested.