Development of process control methodology for tracking the quality and safety of pain, agitation and sedation management in critical care units

Objective: To develop sedation, pain, and agitation quality measures using process control methodology and evaluate their properties in clinical practice. Design: A Sedation Quality Assessment Tool was developed and validated to capture data for 12-hour periods of nursing care. Domains included pain/discomfort and sedation-agitation behaviors; sedative, analgesic, and neuromuscular blocking drug administration; ventilation status; and conditions potentially justifying deep sedation. Predefined sedation-related adverse events were recorded daily. Using an iterative process, algorithms were developed to describe the proportion of care periods with poor limb relaxation, poor ventilator synchronization, unnecessary deep sedation, agitation, and an overall optimum sedation metric. Proportion charts described processes over time (2 monthly intervals) for each ICU. The numbers of patients treated between sedation-related adverse events were described with G charts. Automated algorithms generated charts for 12 months of sequential data. Mean values for each process were calculated, and variation within and between ICUs explored qualitatively. Setting: Eight Scottish ICUs over a 12-month period. Patients: Mechanically ventilated patients. Interventions: None. Measurements and Main Results: The Sedation Quality Assessment Tool agitation-sedation domains correlated with the Richmond Sedation Agitation Scale score (Spearman [rho] = 0.75) and were reliable in clinician-clinician (weighted kappa; [kappa] = 0.66) and clinician-researcher ([kappa] = 0.82) comparisons. The limb movement domain had fair correlation with Behavioral Pain Scale ([rho] = 0.24) and was reliable in clinician-clinician ([kappa] = 0.58) and clinician-researcher ([kappa] = 0.45) comparisons. Ventilator synchronization correlated with Behavioral Pain Scale ([rho] = 0.54), and reliability in clinician-clinician ([kappa] = 0.29) and clinician-researcher ([kappa] = 0.42) comparisons was fair-moderate. Eight hundred twenty-five patients were enrolled (range, 59-235 across ICUs), providing 12,385 care periods for evaluation (range 655-3,481 across ICUs). The mean proportion of care periods with each quality metric varied between ICUs: excessive sedation 12-38%; agitation 4-17%; poor relaxation 13-21%; poor ventilator synchronization 8-17%; and overall optimum sedation 45-70%. Mean adverse event intervals ranged from 1.5 to 10.3 patients treated. The quality measures appeared relatively stable during the observation period. Conclusions: Process control methodology can be used to simultaneously monitor multiple aspects of pain-sedation-agitation management within ICUs. Variation within and between ICUs could be used as triggers to explore practice variation, improve quality, and monitor this over time

An investigation into mechanisms of visceral pain in rodents

Visceral pain is a debilitating symptom of irritable bowel syndrome (IBS), a disorder affecting up to 30% of adults. A better understanding of the mechanisms underlying visceral hypersensitivity may facilitate development of more targeted therapies, improving the quality of life of these individuals. The studies performed in this thesis were designed to investigate important factors of visceral pain, including early-life manipulations, genetic predisposition and sex hormones. Maternal separation (MS) consistently reproduces visceral hypersensitivity and altered anxiety-like behaviours in rats, symptoms associated with IBS. It has been found that 5-HT2B receptor antagonism blocks visceral pain but no difference in relative 5-HT2B receptor mRNA expression was found in hippocampus, amygdala and colon. The neuronal activation patterns of prefrontal cortex and amygdala of MS rats were then investigated. MS animals are characterised by differential activation of the prefrontal cortex (anterior cingulate cortex (ACC), infralibic cortex, prelimbic cortex) as well as the central nucleus of the amygdala (CeA). Genetic factors also contribute to pain syndromes such as IBS. We utilised the Wistar Kyoto (WKY) rat, a stress-sensitive strain, as an animal model of brain-gut axis dysfunction. WKY rats have a lower expression of the glutamate transporter EAAT2 and mGlu4 receptor in the ACC. Another early-life factor that can increase susceptibility to functional gastrointestinal symptoms later life is disruption of the gut microbiota, thus early-life antibiotic treatment was used to assess this effect. Antibiotic treatment induced visceral hypersensitivity in adulthood and may be related to observed reductions in spinal cord alpha-2A adrenoreceptor (adra2A) mRNA. Lastly, we investigated sex differences in visceral sensitivity. EAAT1 & 2 mRNA levels are lower in females, potentially increasing glutamatergic concentration at the symaptic level. Moreover, NR1 and NR2B subunits mRNA of NMDA receptor were increased in caudal ACC of females. These findings may account for sex differences in visceral sensitivity.

Stress-induced visceral pain in rodents: neurochemical, hormonal, immune and epigenetic mechanisms

Visceral pain is a debilitating disorder which affects up to 25% of the population at any one time. It is a global term used to describe pain originating from the internal organs, which is distinct from somatic pain. Currently the treatment strategies are unsatisfactory, with development of novel therapeutics hindered by a lack of detailed knowledge of the underlying mechanisms. The work presented in this thesis aimed to redress this issue and look in more detail at the molecular mechanisms of visceral pain in preclinical models. Stress has long been implicated in the pathophysiology of visceral pain in both preclinical and clinical studies. Here a mouse model of early-life stress-induced visceral hypersensitivity was validated. Moreover, mouse strain differences were also apparent in visceral sensitivity suggesting a possible genetic component to the underlying pathophysiology. Furthermore, gender and sex hormones were also implicated in stress sensitivity and visceral pain. Using the rat model of maternal separation, some of the epigenetic mechanisms underpinning visceral hypersensitivity, specifically the contribution of histone acetylation were unravelled. Glutamate has been well established in somatic pain processing, however, its contribution to visceral pain has not been extensively characterised. It was found that glutamate uptake is impaired in viscerally hypersensitive animals, an effect which could be reversed by treatment with riluzole, a glutamate uptake activator. Moreover, negative modulation of the metabotropic glutamate (mGlu) receptor 7 was sufficient to reverse visceral hypersensitivity in a stress sensitive rat strain, the Wistar Kyoto rat. Furthermore, toll-like receptor 4 (TLR4) was implicated in chronic stress-induced visceral hypersensitivity. Taken together, these findings have furthered our knowledge of the pathophysiology of visceral pain. In addition, we have identified glutamate transporters, mGlu7 receptor, histone acetylation and TLR4 as novel targets, amenable to pharmacological manipulation for the specific treatment of visceral pain.

Interleukin 10 reduces the incidence of pancreatitis after therapeutic endoscopic retrograde cholangiopancreatography.

BACKGROUND & AIMS: Prophylactic administration of interleukin (IL)-10 decreases the severity of experimental pancreatitis. Prevention of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis in humans is a unique model to study the potential role of IL-10 in this setting. METHODS: In a single-center, double-blind, randomized, placebo-controlled study, the effect of a single injection of 4 microg/kg (group 1) or 20 microg/kg (group 2) IL-10 was compared with that of placebo (group 0), all administered 30 minutes before therapeutic ERCP. The primary endpoint was the effect of IL-10 on serum levels of amylases and lipases measured 4, 24, and 48 hours after ERCP. The secondary objective was to evaluate changes in plasma cytokines (IL-6, IL-8, tumor necrosis factor) at the same time points and the incidence of acute pancreatitis in the 3 groups. Subjects undergoing a first therapeutic ERCP were eligible for inclusion. RESULTS: A total of 144 patients were included. Seven were excluded based on intention to treat (n = 1) or per protocol (n = 6). Forty-five, 48, and 44 patients remained in groups 0, 1, and 2, respectively. The 3 groups were comparable for age, sex, underlying disease, indication for treatment, type of treatment, and plasma levels of C-reactive protein (CRP), cytokines, and hydrolases at baseline. No significant difference was observed in CRP, cytokine, and hydrolase plasma levels after ERCP. Forty-three patients developed hyperhydrolasemia (18 in group 0, 14 in group 1, and 11 in group 2; P = 0.297), and 19 patients developed acute clinical pancreatitis (11 in group 0, 5 in group 1, 3 in group 2; P = 0.038). Two severe cases were observed in the placebo group. No mortality related to ERCP was observed. Logistic regression identified 3 independent risk factors for post-therapeutic ERCP pancreatitis: IL-10 administration (odds ratio [OR], 0.46; 95% confidence interval [95% CI], 0.22-0.96; P = 0.039), pancreatic sphincterotomy (OR, 5.04; 95% CI, 1.53-16.61; P = 0.008), and acinarization (OR, 8.19; 95% CI, 1.83-36.57; P = 0.006). CONCLUSIONS: A single intravenous dose of IL-10, given 30 minutes before the start of the procedure, independently reduces the incidence of post-therapeutic ERCP pancreatitis.

Variation in the type and frequency of postoperative invasive Staphylococcus aureus infections according to type of surgical procedure.

OBJECTIVE: To determine the epidemiological characteristics of postoperative invasive Staphylococcus aureus infection following 4 types of major surgical procedures.design. Retrospective cohort study. SETTING: Eleven hospitals (9 community hospitals and 2 tertiary care hospitals) in North Carolina and Virginia. PATIENTS: Adults undergoing orthopedic, neurosurgical, cardiothoracic, and plastic surgical procedures. METHODS: We used previously validated, prospectively collected surgical surveillance data for surgical site infection and microbiological data for bloodstream infection. The study period was 2003 through 2006. We defined invasive S. aureus infection as either nonsuperficial incisional surgical site infection or bloodstream infection. Nonparametric bootstrapping was used to generate 95% confidence intervals (CIs). P values were generated using the Pearson chi2 test, Student t test, or Wilcoxon rank-sum test, as appropriate. RESULTS: In total, 81,267 patients underwent 96,455 procedures during the study period. The overall incidence of invasive S. aureus infection was 0.47 infections per 100 procedures (95% CI, 0.43-0.52); 227 (51%) of 446 infections were due to methicillin-resistant S.aureus. Invasive S. aureus infection was more common after cardiothoracic procedures (incidence, 0.79 infections per 100 procedures [95%CI, 0.62-0.97]) than after orthopedic procedures (0.37 infections per 100 procedures [95% CI, 0.32-0.42]), neurosurgical procedures (0.62 infections per 100 procedures [95% CI, 0.53-0.72]), or plastic surgical procedures (0.32 infections per 100 procedures [95% CI, 0.17-0.47]) (P < .001). Similarly, S. aureus bloodstream infection was most common after cardiothoracic procedures (incidence, 0.57 infections per 100 procedures [95% CI, 0.43-0.72]; P < .001, compared with other procedure types), comprising almost three-quarters of the invasive S. aureus infections after these procedures. The highest rate of surgical site infection was observed after neurosurgical procedures (incidence, 0.50 infections per 100 procedures [95% CI, 0.42-0.59]; P < .001, compared with other procedure types), comprising 80% of invasive S.aureus infections after these procedures. CONCLUSION: The frequency and type of postoperative invasive S. aureus infection varied significantly across procedure types. The highest risk procedures, such as cardiothoracic procedures, should be targeted for ongoing preventative interventions.

Neuropathic pain activates the endogenous kappa opioid system in mouse spinal cord and induces opioid receptor tolerance.

Release of endogenous dynorphin opioids within the spinal cord after partial sciatic nerve ligation (pSNL) is known to contribute to the neuropathic pain processes. Using a phosphoselective antibody [kappa opioid receptor (KOR-P)] able to detect the serine 369 phosphorylated form of the KOR, we determined possible sites of dynorphin action within the spinal cord after pSNL. KOR-P immunoreactivity (IR) was markedly increased in the L4-L5 spinal dorsal horn of wild-type C57BL/6 mice (7-21 d) after lesion, but not in mice pretreated with the KOR antagonist nor-binaltorphimine (norBNI). In addition, knock-out mice lacking prodynorphin, KOR, or G-protein receptor kinase 3 (GRK3) did not show significant increases in KOR-P IR after pSNL. KOR-P IR was colocalized in both GABAergic neurons and GFAP-positive astrocytes in both ipsilateral and contralateral spinal dorsal horn. Consistent with sustained opioid release, KOR knock-out mice developed significantly increased tactile allodynia and thermal hyperalgesia in both the early (first week) and late (third week) interval after lesion. Similarly, mice pretreated with norBNI showed enhanced hyperalgesia and allodynia during the 3 weeks after pSNL. Because sustained activation of opioid receptors might induce tolerance, we measured the antinociceptive effect of the kappa agonist U50,488 using radiant heat applied to the ipsilateral hindpaw, and we found that agonist potency was significantly decreased 7 d after pSNL. In contrast, neither prodynorphin nor GRK3 knock-out mice showed U50,488 tolerance after pSNL. These findings suggest that pSNL induced a sustained release of endogenous prodynorphin-derived opioid peptides that activated an anti-nociceptive KOR system in mouse spinal cord. Thus, endogenous dynorphin had both pronociceptive and antinociceptive actions after nerve injury and induced GRK3-mediated opioid tolerance.

Changes in midbrain pain receptor expression, gait and behavioral sensitivity in a rat model of radiculopathy.

Intervertebral disc herniation may contribute to inflammatory processes that associate with radicular pain and motor deficits. Molecular changes at the affected dorsal root ganglion (DRG), spinal cord, and even midbrain, have been documented in rat models of radiculopathy or nerve injury. The objective of this study was to evaluate gait and the expression of key pain receptors in the midbrain in a rodent model of radiculopathy. Radiculopathy was induced by harvesting tail nucleus pulposus (NP) and placing upon the right L5 DRG in rats (NP-treated, n=12). Tail NP was discarded in sham-operated animals (n=12). Mechanical allodynia, weight-bearing, and gait were evaluated in all animals over time. At 1 and 4 weeks after surgery, astrocyte and microglial activation was tested in DRG sections. Midbrain sections were similarly evaluated for immunoreactivity to serotonin (5HT(2B)), mu-opioid (µ-OR), and metabotropic glutamate (mGluR4 and 5) receptor antibodies. NP-treated animals placed less weight on the affected limb 1 week after surgery and experienced mechanical hypersensitivity over the duration of the study. Astroctye activation was observed at DRGs only at 4 weeks after surgery. Findings for pain receptors in the midbrain of NP-treated rats included an increased expression of 5HT(2B) at 1, but not 4 weeks; increased expression of µ-OR and mGluR5 at 1 and 4 weeks (periaqueductal gray region only); and no changes in expression of mGluR4 at any point in this study. These observations provide support for the hypothesis that the midbrain responds to DRG injury with a transient change in receptors regulating pain responses.

Reduced length of hospital stay in colorectal surgery after implementation of an enhanced recovery protocol.

BACKGROUND: Enhanced recovery after surgery (ERAS) is a multimodal approach to perioperative care that combines a range of interventions to enable early mobilization and feeding after surgery. We investigated the feasibility, clinical effectiveness, and cost savings of an ERAS program at a major U. S. teaching hospital. METHODS: Data were collected from consecutive patients undergoing open or laparoscopic colorectal surgery during 2 time periods, before and after implementation of an ERAS protocol. Data collected included patient demographics, operative, and perioperative surgical and anesthesia data, need for analgesics, complications, inpatient medical costs, and 30-day readmission rates. RESULTS: There were 99 patients in the traditional care group, and 142 in the ERAS group. The median length of stay (LOS) was 5 days in the ERAS group compared with 7 days in the traditional group (P < 0.001). The reduction in LOS was significant for both open procedures (median 6 vs 7 days, P = 0.01), and laparoscopic procedures (4 vs 6 days, P < 0.0001). ERAS patients had fewer urinary tract infections (13% vs 24%, P = 0.03). Readmission rates were lower in ERAS patients (9.8% vs 20.2%, P = 0.02). DISCUSSION: Implementation of an enhanced recovery protocol for colorectal surgery at a tertiary medical center was associated with a significantly reduced LOS and incidence of urinary tract infection. This is consistent with that of other studies in the literature and suggests that enhanced recovery programs could be implemented successfully and should be considered in U.S. hospitals.

Postoperative statin use and risk of biochemical recurrence following radical prostatectomy: results from the Shared Equal Access Regional Cancer Hospital (SEARCH) database.

OBJECTIVE: To investigate the effect of statin use after radical prostatectomy (RP) on biochemical recurrence (BCR) in patients with prostate cancer who never received statins before RP. PATIENTS AND METHODS: We conducted a retrospective analysis of 1146 RP patients within the Shared Equal Access Regional Cancer Hospital (SEARCH) database. Multivariable Cox proportional hazards analyses were used to examine differences in risk of BCR between post-RP statin users vs nonusers. To account for varying start dates and duration of statin use during follow-up, post-RP statin use was treated as a time-dependent variable. In a secondary analysis, models were stratified by race to examine the association of post-RP statin use with BCR among black and non-black men. RESULTS: After adjusting for clinical and pathological characteristics, post-RP statin use was significantly associated with 36% reduced risk of BCR (hazard ratio [HR] 0.64, 95% confidence interval [CI] 0.47-0.87; P = 0.004). Post-RP statin use remained associated with reduced risk of BCR after adjusting for preoperative serum cholesterol levels. In secondary analysis, after stratification by race, this protective association was significant in non-black (HR 0.49, 95% CI 0.32-0.75; P = 0.001) but not black men (HR 0.82, 95% CI 0.53-1.28; P = 0.384). CONCLUSION: In this retrospective cohort of men undergoing RP, post-RP statin use was significantly associated with reduced risk of BCR. Whether the association between post-RP statin use and BCR differs by race requires further study. Given these findings, coupled with other studies suggesting that statins may reduce risk of advanced prostate cancer, randomised controlled trials are warranted to formally test the hypothesis that statins slow prostate cancer progression.

In vivo luminescence imaging of NF-κB activity and serum cytokine levels predict pain sensitivities in a rodent model of osteoarthritis.

OBJECTIVE: To investigate the relationship between NF-κB activity, cytokine levels, and pain sensitivities in a rodent model of osteoarthritis (OA). METHODS: OA was induced in transgenic NF-κB-luciferase reporter mice via intraarticular injection of monosodium iodoacetate (MIA). Using luminescence imaging we evaluated the temporal kinetics of NF-κB activity and its relationship to the development of pain sensitivities and serum cytokine levels in this model. RESULTS: MIA induced a transient increase in joint-related NF-κB activity at early time points (day 3 after injection) and an associated biphasic pain response (mechanical allodynia). NF-κB activity, serum interleukin-6 (IL-6), IL-1β, and IL-10 levels accounted for ∼75% of the variability in pain-related mechanical sensitivities in this model. Specifically, NF-κB activity was strongly correlated with mechanical allodynia and serum IL-6 levels in the inflammatory pain phase of this model (day 3), while serum IL-1β was strongly correlated with pain sensitivities in the chronic pain phase of the model (day 28). CONCLUSION: Our findings suggest that NF-κB activity, IL-6, and IL-1β may play distinct roles in pain sensitivity development in this model of arthritis and may distinguish the acute pain phase from the chronic pain phase. This study establishes luminescence imaging of NF-κB activity as a novel imaging biomarker of pain sensitivities in this model of OA.

Outcomes After Total Ankle Replacement in Association With Ipsilateral Hindfoot Arthrodesis.

BACKGROUND: Ipsilateral hindfoot arthrodesis in combination with total ankle replacement (TAR) may diminish functional outcome and prosthesis survivorship compared to isolated TAR. We compared the outcome of isolated TAR to outcomes of TAR with ipsilateral hindfoot arthrodesis. METHODS: In a consecutive series of 404 primary TARs in 396 patients, 70 patients (17.3%) had a hindfoot fusion before, after, or at the time of TAR; the majority had either an isolated subtalar arthrodesis (n = 43, 62%) or triple arthrodesis (n = 15, 21%). The remaining 334 isolated TARs served as the control group. Mean patient follow-up was 3.2 years (range, 24-72 months). RESULTS: The SF-36 total, AOFAS Hindfoot-Ankle pain subscale, Foot and Ankle Disability Index, and Short Musculoskeletal Function Assessment scores were significantly improved from preoperative measures, with no significant differences between the hindfoot arthrodesis and control groups. The AOFAS Hindfoot-Ankle total, function, and alignment scores were significantly improved for both groups, albeit the control group demonstrated significantly higher scores in all 3 scales. Furthermore, the control group demonstrated a significantly greater improvement in VAS pain score compared to the hindfoot arthrodesis group. Walking speed, sit-to-stand time, and 4-square step test time were significantly improved for both groups at each postoperative time point; however, the hindfoot arthrodesis group completed these tests significantly slower than the control group. There was no significant difference in terms of talar component subsidence between the fusion (2.6 mm) and control groups (2.0 mm). The failure rate in the hindfoot fusion group (10.0%) was significantly higher than that in the control group (2.4%; p < 0.05). CONCLUSION: To our knowledge, this study represents the first series evaluating the clinical outcome of TARs performed with and without hindfoot fusion using implants available in the United States. At follow-up of 3.2 years, TAR performed with ipsilateral hindfoot arthrodesis resulted in significant improvements in pain and functional outcome; in contrast to prior studies, however, overall outcome was inferior to that of isolated TAR. LEVEL OF EVIDENCE: Level II, prospective comparative series.

The Body in Pain: What do people of faith have to say about torture

An examination of why American Protestant churches have a higher likelihood to support torture

Selected Gamma Aminobutyric Acid (GABA) Esters may Provide Analgesia for Some Central Pain Conditions.

Central pain is an enigmatic, intractable condition, related to destruction of thalamic areas, resulting in likely loss of inhibitory synaptic transmission mediated by GABA. It is proposed that treatment of central pain, a localized process, may be treated by GABA supplementation, like Parkinson's disease and depression. At physiologic pH, GABA exists as a zwitterion that is poorly permeable to the blood brain barrier (BBB). Because the pH of the cerebral spinal fluid (CSF) is acidic relative to the plasma, ion trapping may allow a GABA ester prodrug to accumulate and be hydrolyzed within the CSF. Previous investigations with ester local anesthetics may be applicable to some GABA esters since they are weak bases, hydrolyzed by esterases and cross the BBB. Potential non-toxic GABA esters are discussed. Many GABA esters were investigated in the 1980s and it is hoped that this paper may spark renewed interest in their development.

Lack of evidence for ectopic sprouting of genetically labeled Aβ touch afferents in inflammatory and neuropathic trigeminal pain.

BACKGROUND: Mechanical and in particular tactile allodynia is a hallmark of chronic pain in which innocuous touch becomes painful. Previous cholera toxin B (CTB)-based neural tracing experiments and electrophysiology studies had suggested that aberrant axon sprouting from touch sensory afferents into pain-processing laminae after injury is a possible anatomical substrate underlying mechanical allodynia. This hypothesis was later challenged by experiments using intra-axonal labeling of A-fiber neurons, as well as single-neuron labeling of electrophysiologically identified sensory neurons. However, no studies have used genetically labeled neurons to examine this issue, and most studies were performed on spinal but not trigeminal sensory neurons which are the relevant neurons for orofacial pain, where allodynia oftentimes plays a dominant clinical role. FINDINGS: We recently discovered that parvalbumin::Cre (Pv::Cre) labels two types of Aβ touch neurons in trigeminal ganglion. Using a Pv::CreER driver and a Cre-dependent reporter mouse, we specifically labeled these Aβ trigeminal touch afferents by timed taxomifen injection prior to inflammation or infraorbital nerve injury (ION transection). We then examined the peripheral and central projections of labeled axons into the brainstem caudalis nucleus after injuries vs controls. We found no evidence for ectopic sprouting of Pv::CreER labeled trigeminal Aβ axons into the superficial trigeminal noci-receptive laminae. Furthermore, there was also no evidence for peripheral sprouting. CONCLUSIONS: CreER-based labeling prior to injury precluded the issue of phenotypic changes of neurons after injury. Our results suggest that touch allodynia in chronic orofacial pain is unlikely caused by ectopic sprouting of Aβ trigeminal afferents.