Patterns of unexpected in-hospital deaths: a root cause analysis

<p>Abstract</p> <p>Background</p> <p>Respiratory alarm monitoring and rapid response team alerts on hospital general floors are based on detection of simple numeric threshold breaches. Although some uncontrolled observation trials in select patient populations have been encouraging, randomized controlled trials suggest that this simplistic approach may not reduce the unexpected death rate in this complex environment. The purpose of this review is to examine the history and scientific basis for threshold alarms and to compare thresholds with the actual pathophysiologic patterns of evolving death which must be timely detected.</p> <p>Methods</p> <p>The Pubmed database was searched for articles relating to methods for triggering rapid response teams and respiratory alarms and these were contrasted with the fundamental timed pathophysiologic patterns of death which evolve due to sepsis, congestive heart failure, pulmonary embolism, hypoventilation, narcotic overdose, and sleep apnea.</p> <p>Results</p> <p>In contrast to the simplicity of the numeric threshold breach method of generating alerts, the actual patterns of evolving death are complex and do not share common features until near death. On hospital general floors, unexpected clinical instability leading to death often progresses along three distinct patterns which can be designated as Types I, II and III. Type I is a pattern comprised of hyperventilation compensated respiratory failure typical of congestive heart failure and sepsis. Here, early hyperventilation and respiratory alkalosis can conceal the onset of instability. Type II is the pattern of classic CO2 narcosis. Type III occurs only during sleep and is a pattern of ventilation and SPO2 cycling caused by instability of ventilation and/or upper airway control followed by precipitous and fatal oxygen desaturation if arousal failure is induced by narcotics and/or sedation.</p> <p>Conclusion</p> <p>The traditional threshold breach method of detecting instability on hospital wards was not scientifically derived; explaining the failure of threshold based monitoring and rapid response team activation in randomized trials. Furthermore, the thresholds themselves are arbitrary and capricious. There are three common fundamental pathophysiologic patterns of unexpected hospital death. These patterns are too complex for early detection by any unifying numeric threshold. New methods and technologies which detect and identify the actual patterns of evolving death should be investigated.</p

Pharma-engineering of multifunctional microneedle array device for application in chronic pain

Chronic pain poses a major concern to modern medicine and is frequently undertreated, causing suffering and disability. Transdermal delivery is the pivot to which analgesic research in drug delivery has centralized especially with the confines of needle phobias and associated pain related to traditional injections, and the existing limitations associated with oral drug delivery. Highlighted within this thesis is the possibility of further developing transdermal drug delivery for chronic pain treatment using an Electro-Modulated Hydrogel- Microneedle array (EMHM) prototype device for the delivery of analgesic medicatio

Magnetic Field Effects On The Neuroprocessing Of Pain

Magnetic fields can affect behaviour in a variety of ways, in a manner that is dependent on the particulars of the magnetic field exposure. A specific pulsed magnetic field with analgesic properties was investigated using functional magnetic resonance imaging with acute thermal pain. The functional activation of pain was significantly different pre/post exposure vs. a sham condition within areas of the brain associated with the affective component of pain, in particular the anterior cingulate and the right insula. Sleep was found to be a significant confound with a 45-minute exposure. This was the first time fMRI has been used as a tool to investigate bioelectromagnetics effects, and demonstrates that an MR system can be used for both image acquisition and exposure. This technique will have applications to functional tasks beyond the acute thermal pain tested here

Guidelines for translational research in heart failure

Heart failure (HF) remains a major cause of death and hospitalization worldwide. Despite medical advances, the prognosis of HF remains poor and new therapeutic approaches are urgently needed. The development of new therapies for HF is hindered by inappropriate or incomplete preclinical studies. In these guidelines, we present a number of recommendations to enhance similarity between HF animal models and the human condition in order to reduce the chances of failure in subsequent clinical trials. We propose different approaches to address safety as well as efficacy of new therapeutic products. We also propose that good practice rules are followed from the outset so that the chances of eventual approval by regulatory agencies increase. We hope that these guidelines will help improve the translation of results from animal models to humans and thereby contribute to more successful clinical trials and development of new therapies for HF.European Union [CardioNeT-ITN-289600, CardioNext-ITN-608027, FP7-IMI-JU-SAFET-115003]; Spanish Ministry of Economy [SAF2012-31451]; Regional Government of Madrid [2010-BMD-2321]; Spanish Ministry of Economy; Pro-CNIC Foundation; NIH [HL-120732, HL100401]; AHA [14SFRN20740000]; CPRIT [RP110486P3]; Leducq Foundation [11CVD04]; MINECO-SAF [2013-42962R]; Instituto Carlos III [TERCEL-RD-12/00190026, RIC12/00420024]S

Contextual factors, placebo and nocebo effects in physical therapy: clinical relevance and impact on research

A brief overview on placebo and nocebo effects Placebo and nocebo effects represent one of the most fascinating topics in the healthcare field. They represent complex and distinct psychoneurobiological phenomena where behavioural and neurophysiological changes occur during an interaction between the patient and the healthcare context (1). Placebo effects (Latin \u201cI shall please\u201d) are produced by a psychosocial context that is capable of positively affecting the patient's brain and therapeutic outcomes (2-4). On the contrary, nocebo effects (Latin \u201cI shall harm\u201d) are consequences of the negative perception of the ritual and therapeutic act on the patient's mind and body, so much so that it generates unwanted effects and side effects (5-7). Throughout the history of medicine, placebo and nocebo have been traditionally viewed as bothersome variables to check for in a clinical trial. In the last four decades, in light of some significant clinical and laboratory findings, they have become a source of research interest. Indeed, placebo and nocebo have been adopted as a conceptual model to examine the body-mind interaction and the human body systems, exploring their connection with different systems, mechanisms, diseases and therapeutic interventions (8, 9). In particular, placebo and nocebo effects have been studied in mood (10), cardiovascular, respiratory (11), gastrointestinal (12, 13), motor (14), immune and endocrine (15), and pain systems (16-18). Clinically, not all improvement or aggravation of patients\u2019 symptoms is due to placebo and nocebo effects. It is necessary to rule out the patients\u2019 modifications created by placebo and nocebo effects from the changes of outcomes related to other confounding elements. The elements which could create misinterpretations of the patients\u2019 clinical picture are: the spontaneous remission of the disease and symptom fluctuation (also called the natural history), the regression to the mean (a statistical phenomenon caused by selection biases), the patient\u2019s and clinician\u2019s biases during the reports of clinical conditions, and unidentified effects of concomitant co-interventions (8, 9). Different psychoneurobiological findings allowed the scientific community to begin to understand the underlying mechanisms of placebo and nocebo effects. From a theoretical perspective, two main psychological subjective constructs have been suggested to explain how placebo or nocebo effects act: the expectation and the conditioning. The social learning, reward, anxiety reduction, desire, motivation, memory, somatic focus, genetic and personality traits also represent alternative theories (19-25). \u201cAlternative\u201d however does not mean that these psychological mechanisms are mutually exclusive: they can interact simultaneously (26). Regarding the actual findings, placebo and nocebo interact with the brain modulatory systems at a neurochemical level, through the release of specific neurotransmitters. For instance, considering pain outcome as a model, the endogenous opioids, dopamine, cannabinoids, oxytocin and vasopressin are involved in placebo analgesia, while cholecystokinin, dopamine, opioid deactivation and cyclooxygenaseprostaglandins activation are implicated in nocebo hyperalgesia (27-29). Furthermore, recent advances in neuroimaging techniques, such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), suggest an involvement of specific neural correlates during placebo and nocebo effects, mainly the pain one. In fact, placebo and nocebo are able to activate or deactivate the four key brain regions commonly associated with the descending pain processing pathway: the dorsolateral prefrontal cortex, the rostral anterior cingulate cortex, the periaqueductal gray and the dorsal horn of spine (16). Nevertheless, they represent only a part of brain areas showing a change in their activity during placebo or nocebo (30-32). Therefore, the previously described evidence suggests that placebo and nocebo effects are concrete and genuine phenomena, triggered by different contexts, and capable of impacting the patients\u2019 brain. It is necessary to define what the context is, and why its parts are important from a clinical perspective (33). The healthcare context as a trigger of placebo and nocebo effects In 1955 Balint described the context as the \u201cwhole atmosphere around the therapy\u201d (34). The context is not a vacuum, but it embodies a healing space composed by internal, external and relational elements capable of interacting with the patient\u2019s disease (35). The internal elements consist of memories, emotions, expectations and psychological characteristics of the patient. The external elements include the physical aspects of therapy, such as the kind of treatment (pharmacological or manual) and the place in which the treatment is delivered. Relational elements are represented by all the social cues that characterize the patient-clinician relationship, such as the verbal information that the clinicians give to the patient, the communication style or the body language (36). In 2001, Di Blasi et al. defined these elements as \u201ccontextual factors\u201d. These factors have been grouped, from a clinical practice point of view, in five categories: a) clinician features, b) patient features, c) patient-clinician relationship, d) intervention features, and e) healthcare setting features (37). As a whole, contextual factors constitute the therapeutic ritual and healing symbols surrounding the patient-clinician encounter, capable of producing changes in the patient at perceptual, neurophysiological and cognitive levels (38). Indeed, contextual factors convey a hidden meaning, actively detected and analysed by the patient, which is essential for the perception of care and the interpretation of the therapeutic intervention (39, 40). When these contextual stimuli and cues are filtered by the patient\u2019s perspective and mind-set (41), they are translated into a complex cascade of psycho-neuroimmunoendocrine events, thus triggering placebo and nocebo effects and influencing the course of illness (42, 43). From a clinical perspective, the contextual factors pervade every healthcare action (history taking, physical examination, therapy and prognosis) and directly affect the quality of the health-related outcome (44-46). A positive context, that is characterized by the presence of positive contextual factors, can improve therapeutic outcome by producing placebo effects, while a negative context, characterized by the presence of negative contextual factors, can aggravate therapeutic outcome by creating nocebo effects(47, 48). For example, during the same treatment delivery (e.g. painkillers), the use of positive verbal suggestion (e.g. \u201cThis therapy will help you and it will decrease pain\u201d) can improve musculoskeletal pain, while the adoption of verbal suggestion of uncertainty (e.g. \u201cThis therapy could help you and sometimes it decrease pain\u201d) can aggravate patient\u2019s pain (49). The presented studies offer a starting point for reflection about the role of the contextual factors surrounding the administration of a healthcare treatment: they can be a source of improvement of the efficacy of the therapy or implicated in the manifestation of adverse effects. The logical consequence is to wonder whether context, placebo and nocebo effects have been taken into consideration in a specific healthcare field, such as physical therapy. The link between placebo, nocebo effects and physical therapy Throughout the history of physical therapy and rehabilitation, placebo and nocebo effects have been considered as problematic phenomena for two main reasons. From a research point of view, they have represented confounding factors capable of limiting the internal validity of the study design and reducing the external validity of the findings (50). From a clinical point of view, they have embodied troublesome and nonspecific variables able to attenuate the therapeutic role of specific therapies such as massage, joint mobilization and therapeutic exercise (51, 52). As a consequence, for many years the role of placebo and nocebo effects was debated worldwide by clinicians and researchers (53-55). At the end of the first decade of the twenty-first century the scientific community began to investigate the mechanisms of action of joint, soft tissue and neural therapeutic intervention, consequently revaluing the role of placebo and nocebo effects in physiotherapy (56). Recent studies have suggested a mechanical and neurophysiological mechanism (peripheral, spinal and supraspinal) linked to the therapeutic strategies adopted by physical therapists (57). Among the supraspinal mechanisms, the placebo and nocebo effects have assumed an important top-down role in inducing changes in patient\u2019s symptoms (58), thus becoming elements that clinicians should adopt in clinical practice (59). Recently, also the context in which interventions are delivered has been suggested as a moderator of clinical effects (60). A new line of research has indicated the context as responsible for a larger non-specific component of treatment efficacy in physical therapy (61). Despite these promising advances, the following issues remain unexplored: 1) What are the contextual factors? 2) How can the contextual factors trigger placebo and nocebo effects? 3) Which therapeutic outcomes can be influenced by the contextual factors? 4) Are the physical therapists aware of the use of contextual factors in clinical practice? 5) What is the role of contextual factors in research? General organization of the research project The main goal of this PhD research project is to investigate the relevance of the contextual factors as triggers of placebo/nocebo effects and their impact on therapeutic outcomes in physiotherapy. Different studies were conducted during the 3-year period of PhD training (2015-2018). The results, relative discussions and implications are reported in the chapters of the present dissertation as follows: \u2022 Chapter I: a conceptual model regarding the role of the contextual factors as triggers of placebo, nocebo responses and influencers of physical therapy outcomes; \u2022 Chapter II: the model of contextual factors regarding musculoskeletal pain, which is a common outcome encountered by physical therapists; \u2022 Chapter III: the link between the determinants of patient satisfaction in outpatient musculoskeletal physiotherapy clinics and the contextual factors; \u2022 Chapter IV: the knowledge, attitude and behaviour of Italian physiotherapists specialized in manual therapy towards contextual factors; \u2022 Chapter V: the translational value of contextual factors and their relevance for physical therapy research

Effect of Labor Epidural Analgesia With Hydromorphone on Neonatal Neurobehavior and Breastfeeding Behavior in the First 24 Hours of Life

Epidural opioids and local anesthetics may depress the neonatal reflexes necessary for breastfeeding success. Literature review yielded no data for hydromorphone and conflicting results for fentanyl. This study investigated whether breastfeeding effectiveness would be less in infants whose mothers received epidural analgesia with hydromorphone compared with those whose mothers received no analgesia, and whether the total amount of drugs given or the presence of multiple stressful events or interventions would be related to the effectiveness of breastfeeding. Breastfeeding behaviors were studied in 51 infants whose mothers chose epidural analgesia compared with 51 infants whose mothers chose to have no analgesia. Women with epidural analgesia received 1.5% lidocaine with 1:200,000 epinephrine as a test dose and/or 0.25% bupivacaine with 1:200,000 epinephrine as a bolus, and 100 µg hydromorphone followed by continuous infusion of 0.05% bupivacaine with 3 µg/mL hydromorphone at 14 mL/hour. The hospital setting strongly supported breastfeeding. Effectiveness of breastfeeding was measured with the LATCH Breastfeeding Assessment Tool at 3, 12, and 24 hours after birth. LATCH scores did not differ significantly between groups at any time point and were not related to total amount of drugs administered. The presence of multiple stressful events and interventions, e.g., long duration of labor, large amount of IV fluids, oxytocin administration, induction of labor, and meconium staining/suctioning of the baby, did not significantly affect breastfeeding behavior in the overall study population (n=102), altogether contributing not more than 8% of the variability of LATCH scores in the regression model. The group receiving epidural analgesia (n=51) had significantly longer duration of labor, higher rates of oxytocin administration and induction of labor, and larger amounts of IV fluid administration. These factors contributed approximately 30% of the variability of LATCH scores at 3 and 24 hours. However, this finding was not significant. Although the study was limited by its nonrandomized nature, these data indicate that, by itself, epidural analgesia with hydromorphone does not decrease effectiveness of breastfeeding behaviors. Epidural analgesia increases risk of multiple stressful events or interventions, which may contribute to breastfeeding difficulties and necessitate intensive help from the nurse to achieve success in breastfeeding

Cannabinoids, the endocannabinoid system, and pain: a review of preclinical studies

This narrative review represents an output from the International Association for the Study of Pain's global task force on the use of cannabis, cannabinoids, and cannabis-based medicines for pain management, informed by our companion systematic review and meta-analysis of preclinical studies in this area. Our aims in this review are (1) to describe the value of studying cannabinoids and endogenous cannabinoid (endocannabinoid) system modulators in preclinical/animal models of pain; (2) to discuss both pain-related efficacy and additional pain-relevant effects (adverse and beneficial) of cannabinoids and endocannabinoid system modulators as they pertain to animal models of pathological or injury-related persistent pain; and (3) to identify important directions for future research. In service of these goals, this review (1) provides an overview of the endocannabinoid system and the pharmacology of cannabinoids and endocannabinoid system modulators, with specific relevance to animal models of pathological or injury-related persistent pain; (2) describes pharmacokinetics of cannabinoids in rodents and humans; and (3) highlights differences and discrepancies between preclinical and clinical studies in this area. Preclinical (rodent) models have advanced our understanding of the underlying sites and mechanisms of action of cannabinoids and the endocannabinoid system in suppressing nociceptive signaling and behaviors. We conclude that substantial evidence from animal models supports the contention that cannabinoids and endocannabinoid system modulators hold considerable promise for analgesic drug development, although the challenge of translating this knowledge into clinically useful medicines is not to be underestimated