Opioids and Immunosuppression: Clinical Evidence, Mechanisms of Action, and Potential Therapies.

Background: In addition to the more well-known adverse effects of opioids, such as constipation, mounting evidence supports underlying immunosuppressive effects as well. Methods: In this study, we provide a narrative review of preclinical and clinical evidence of opioid suppression of the immune system as well as possible considerations for therapies. Results: In vitro and animal studies have shown clear effects of opioids on inflammatory cytokine expression, immune cell activity, and pathogen susceptibility. Observational data in humans have so far supported preclinical findings, with multiple reports of increased rates of infections in various settings of opioid use. However, the extent to which this risk is due to the impact of opioids on the immune system compared with other risk factors associated with opioid use remains uncertain. Considering the data showing immunosuppression and increased risk of infection with opioid use, measures are needed to mitigate this risk in patients who require ongoing treatment with opioids. In preclinical studies, administration of opioid receptor antagonists blocked the immunomodulatory effects of opioids. Conclusions: As selective antagonists of peripheral opioid receptors, peripherally acting mu-opioid receptor (MOR) antagonists may be able to protect against immune impairment while still allowing for opioid analgesia. Future research is warranted to further investigate the relationship between opioids and infection risk as well as the potential application of peripherally acting MOR antagonists to counteract these risks.

Comparison between the Effects of Acute Physical and Psychosocial Stress on Feedback-Based Learning.

Stress modulates feedback-based learning, a process that has been implicated in declining mental function in aging and mental disorders. While acute physical and psychosocial stressors have been used interchangeably in studies on feedback-based learning, the two types of stressors involve distinct physiological and psychological processes. Whether the two types of stressors differentially influence feedback processing remains unclear. The present study compared the effects of physical and psychosocial stressors on feedback-based learning. Ninety-six subjects (Mage = 19.11 years; 50 female) completed either a cold pressor task (CPT) or mental arithmetic task (MAT), as the physical or psychosocial stressor, while electrocardiography and blood pressure were measured to assess cardiovascular stress reactivity (CVR). Self-ratings on the emotional valence of the stressors were also obtained. A probabilistic learning task was given prior to and after the stressors. Accuracy in selecting positive (Go accuracy) and avoiding negative stimuli (No-go accuracy) were recorded as learning outcomes. Repeated measures ANOVA and multiple regressions were used to compare the effects of two stressors and examine the effects of CVR and valence on the learning outcomes. The results showed that although the effects of CPT and MAT on feedback processing were not different, CVR and valence influenced Go and No-go accuracy, respectively. The results suggest that stress-modulated feedback-based learning involves multiple pathways and underscore the link between CVR and reward sensitivity. The findings have clinical implications and may contribute to a better understanding of human behavioral systems.

Participant diversity in Psychophysiology.

The Society for Psychophysiological Research and accompanying journal, Psychophysiology, have increasingly incorporated diversity and inclusion into their posted values, conference programming, and science. Much of this focus on equity, diversity, and inclusion work has occurred since 2010. The current review content analyzed the articles published in Psychophysiology from 2010 through 2020 to determine if SPR and Psychophysiology's commitment to diversity and inclusion has resulted in changes to reporting and analysis of participant demographics. Demographic reporting practices were compared to APA reporting standards and the use of demographic variables assessed according to the guidance proffered in the introduction to Psychophysiology's 2016 Special Issue on Diversity and Representation. Results of the content analysis indicated near perfect reporting of biological sex and frequent reporting of average age. Age range and educational attainment were reported in over half of studies, while race or ethnicity were reported in only 17%. Socioeconomic status, income, gender identity, and sexual orientation were almost never reported. In over 60% of studies at least one major demographic variable was reported, but was not used in preliminary, main, or supplementary analyses as a covariate, moderator, or otherwise. SPR and Psychophysiology should continue advocating for increased reporting of major demographic variables and ethical analysis of demographic modulation of various psychophysiological mechanisms. We provide a preliminary template of reporting standards and call for the inclusion of more open science practices by psychophysiologists.

Statistical considerations for testing automated sphygmomanometers in special patient populations.

The International Standards Organization 81060-2:2018 is the current global Standard for the validation of automated sphygmomanometers. It specifies the requirements for clinical studies on the general population, as well as additional requirements for special populations, which might have physiologic characteristics that affect the accuracy of blood pressure measurements. This paper summarizes the statistical methodology behind the sample size required to test automated sphygmomanometers in these special populations and specifically addresses the pregnant patient population.

How Long Is Long Enough? Controlling for Acute Caffeine Intake in Cardiovascular Research.

Caffeine substantially affects cardiovascular functioning, yet wide variability exists in caffeine control procedures in cardiovascular reactivity research. This study was conducted in order to identify a minimal abstention duration in habitual coffee consumers whereby cardiovascular reactivity is unconfounded by caffeine; Six hours (caffeine's average half-life) was hypothesized. Thirty-nine subjects (mean age: 20.9; 20 women) completed a repeated measures study involving hand cold pressor (CP) and memory tasks. Caffeinated and decaffeinated coffee were administered. The following cardiovascular indices were acquired during pre-task, task, and post-task epochs prior to coffee intake, 30 min-, and six hours post-intake: Heart rate (HR), high-frequency heart rate variability (HF-HRV), root mean squared successive differences (RMSSD), systolic and diastolic blood pressures (SBP, DBP), mean arterial pressure (MAP), pre-ejection period (PEP), left ventricular ejection time (LVET), systemic vascular resistance (SVR), systemic vascular resistance index (SVRI). Results support the adequacy of a six-hour abstention in controlling for caffeine-elicited cardiovascular changes. The current study offers a suggested guideline for caffeine abstention duration in cardiovascular research in psychophysiology. Consistent practice in caffeine abstention protocols would promote validity and reliability across such studies.

Cardiac timing and threatening stimuli influence response inhibition and ex-Gaussian parameters of reaction time in a Go/No-go task.

Sensorimotor responses vary as a function of the cardiac cycle phase. These effects, known as cardiac cycle time effects, have been explained by the inhibition of cardiac afferent signals on information processing. However, the validity of cardiac cycle time effects is challenged by mixed findings. Factors such as current information processing and affective context may modulate cardiac cycle time effects and account for inconsistencies in the literature. The current study examines the influence of cardiac cycle time and threatening stimuli on two aspects of sensorimotor processing, response speed and inhibition. Thirty-four participants (Mage  = 19.35 years; 29 female) completed an auditory Go/No-go task in no face, neutral face, and fearful face conditions. Faces were presented at either cardiac diastole or systole. Participants' reaction times (RTs) during Go trials and failures in response inhibition during No-go trials were recorded. The ex-Gaussian model was fit to RT data in each condition deriving the parameters, mu (µ) and tau (τ), that indicate response speed and attentional lapses, respectively. Repeated measures ANOVA were used to analyze behavioral data. Results showed that cardiac systole prolonged µ but decreased τ, and that cardiac diastole reduced inhibition errors in the fearful face condition but not in other conditions. These findings indicate that cardiac timing differentially modulates sensory-perceptual and top-down attentional processes and cardiac timing interacts with threatening contexts to influence response inhibition. These results highlight the specificity of cardiac cycle time effects on sensorimotor processing.

A Randomized Trial of Enteral Glutamine for Treatment of Burn Injuries.

BACKGROUND: Glutamine is thought to have beneficial effects on the metabolic and stress response to severe injury. Clinical trials involving patients with burns and other critically ill patients have shown conflicting results regarding the benefits and risks of glutamine supplementation. METHODS: In a double-blind, randomized, placebo-controlled trial, we assigned patients with deep second- or third-degree burns (affecting ≥10% to ≥20% of total body-surface area, depending on age) within 72 hours after hospital admission to receive 0.5 g per kilogram of body weight per day of enterally delivered glutamine or placebo. Trial agents were given every 4 hours through a feeding tube or three or four times a day by mouth until 7 days after the last skin grafting procedure, discharge from the acute care unit, or 3 months after admission, whichever came first. The primary outcome was the time to discharge alive from the hospital, with data censored at 90 days. We calculated subdistribution hazard ratios for discharge alive, which took into account death as a competing risk. RESULTS: A total of 1209 patients with severe burns (mean burn size, 33% of total body-surface area) underwent randomization, and 1200 were included in the analysis (596 patients in the glutamine group and 604 in the placebo group). The median time to discharge alive from the hospital was 40 days (interquartile range, 24 to 87) in the glutamine group and 38 days (interquartile range, 22 to 75) in the placebo group (subdistribution hazard ratio for discharge alive, 0.91; 95% confidence interval [CI], 0.80 to 1.04; P = 0.17). Mortality at 6 months was 17.2% in the glutamine group and 16.2% in the placebo group (hazard ratio for death, 1.06; 95% CI, 0.80 to 1.41). No substantial between-group differences in serious adverse events were observed. CONCLUSIONS: In patients with severe burns, supplemental glutamine did not reduce the time to discharge alive from the hospital. (Funded by the U.S. Department of Defense and the Canadian Institutes of Health Research; RE-ENERGIZE ClinicalTrials.gov number, NCT00985205.).

"Generalized unsafety" as fear inhibition to safety signals in adults with and without childhood trauma.

The Generalized Unsafety Theory of Stress posits that low heart rate variability contributes to a perception of "generalized unsafety" (i.e., constantly perceiving oneself to be unsafe), independent of stressful events or stress-related symptomatology. We tested this claim by examining if resting heart rate variability, trait worry, posttraumatic stress symptoms, trauma history, and age of onset predicted fear inhibition, a measure of generalized unsafety. A Pavlovian discriminant conditioning paradigm was used to assess fear inhibition level by comparing eyeblink startle potentiation to a threat cue (presented with air blast) with startle potentiation to a safety signal (never presented with air blast). Survey and laboratory responses were collected from 42 adults who were 20 years old on average, 86% Women, and 76% White. Heart rate variability did not independently predict variation in fear inhibition, as hypothesized. Rather, higher levels of posttraumatic stress symptoms and greater cumulative interpersonal trauma predicted lower fear inhibition. Individuals reporting childhood trauma had higher trait worry, which predicted more severe posttraumatic stress symptoms. These findings highlight the role of attenuated inhibitory learning in stress-related symptomatology and developmentally disruptive trauma. Ability to distinguish threat from safety is a plausible biobehavioral mechanism by which adversity impacts development.

Comparison of Functional Connectivity in the Prefrontal Cortex during a Simple and an Emotional Go/No-Go Task in Female versus Male Groups: An fNIRS Study.

Inhibitory control is a cognitive process to suppress prepotent behavioral responses to stimuli. This study aimed to investigate prefrontal functional connectivity during a behavioral inhibition task and its correlation with the subject's performance. Additionally, we identified connections that are specific to the Go/No-Go task. The experiment was performed on 42 normal, healthy adults who underwent a vanilla baseline and a simple and emotional Go/No-Go task. Cerebral hemodynamic responses were measured in the prefrontal cortex using a 16-channel near infrared spectroscopy (NIRS) device. Functional connectivity was calculated from NIRS signals and correlated to the Go/No-Go performance. Strong connectivity was found in both the tasks in the right hemisphere, inter-hemispherically, and the left medial prefrontal cortex. Better performance (fewer errors, faster response) is associated with stronger prefrontal connectivity during the simple Go/No-Go in both sexes and the emotional Go/No-Go connectivity in males. However, females express a lower emotional Go/No-Go connectivity while performing better on the task. This study reports a complete prefrontal network during a simple and emotional Go/No-Go and its correlation with the subject's performance in females and males. The results can be applied to examine behavioral inhibitory control deficits in population with neurodevelopmental disorders.

Only time will tell: Acute stress response patterns with time series analysis.

Acute stress is often conceptualized as a response pattern that activates the fight-or-flight response via the sympathetic nervous system (SNS). However, other stress response patterns can manifest as well, such as parasympathetic nervous system (PNS) shutdown, and SNS-PNS coactive hypervigilance. Each response pattern engages many dimensions, including physiological, emotional, and behavioral. As stress unfolds over time, these patterns can change to adjust to the changing nature of the stressor. This proof of concept study introduces novel time series methodology to track the multidimensional patterns of acute stress. The defense cascade provides a model with which to understand and predict response patterns over the time course of an acute stressor. The time series methodology introduced in this study holds promise for identifying mechanisms of change in therapy and clinical settings.

Resting heart rate variability modulates the effects of concurrent working memory load on affective startle modification.

Vagally mediated heart rate variability (vmHRV) is thought to index top-down control processes in emotion regulation. According to the Generalized Unsafety Theory of Stress (GUTS), resting vmHRV indexes top-down resources that are needed to inhibit subcortical threat circuits, which is important for context-appropriate affective responding. Although this notion has been supported by studies of affective startle (SR) modification, direct evidence that top-down resources are the linking mechanism between vmHRV and context-appropriate affective responding has been lacking. To investigate this possible mechanism, college-aged participants (n = 92) were recruited to complete a picture viewing task and a concurrent working memory (WM) task. Concurrent WM load was manipulated, and the auditory SR stimulus was delivered while viewing affective pictures. Electrocardiography and electromyography were recorded to assess vmHRV and SR eyeblink, respectively. Results showed that WM load attenuated affective SR modification. As expected, the attenuating effects of load on affective SR modification were stronger among low vmHRV relative to high vmHRV individuals, indicating that vmHRV is linked to context-appropriate affective responding through the mechanism of top-down resources. These results support the GUTS and suggest that atypical affective responding among low vmHRV individuals is attributed to the lack of WM resources. Our findings highlight the relation between vmHRV and top-down resources that have been implicated in emotion regulation and contribute to a better understanding of emotion dysregulation in psychopathology.

Treatment With Angiotensin II Is Associated With Rapid Blood Pressure Response and Vasopressor Sparing in Patients With Vasoplegia After Cardiac Surgery: A Post-Hoc Analysis of Angiotensin II for the Treatment of High-Output Shock (ATHOS-3) Study.

OBJECTIVE: The present study investigated outcomes in patients with vasoplegia after cardiac surgery treated with angiotensin II plus standard-of-care vasopressors. Vasoplegia is a common complication in cardiac surgery with cardiopulmonary bypass and is associated with significant morbidity and mortality. Approximately 250,000 cardiac surgeries with cardiopulmonary bypass are performed in the United States annually, with vasoplegia occurring in 20%to-27% of patients. DESIGN: Post-hoc analysis of the Angiotensin II for the Treatment of High-Output Shock (ATHOS-3) study. SETTING: Multicenter, multinational study. PARTICIPANTS: Sixteen patients with vasoplegia after cardiac surgery with cardiopulmonary bypass were enrolled. INTERVENTIONS: Angiotensin II plus standard-of-care vasopressors (n = 9) compared with placebo plus standard-of-care vasopressors (n = 7). MEASUREMENTS AND MAIN RESULTS: The primary endpoint was mean arterial pressure response (mean arterial pressure ≥75 mmHg or an increase from baseline of ≥10 mmHg at hour 3 without an increase in the dose of standard-of-care vasopressors). Vasopressor sparing and safety also were assessed. Mean arterial pressure response was achieved in 8 (88.9%) patients in the angiotensin II group compared with 0 (0%) patients in the placebo group (p = 0.0021). At hour 12, the median standard-of-care vasopressor dose had decreased from baseline by 76.5% in the angiotensin II group compared with an increase of 7.8% in the placebo group (p = 0.0013). No venous or arterial thrombotic events were reported. CONCLUSION: Patients with vasoplegia after cardiac surgery with cardiopulmonary bypass rapidly responded to angiotensin II, permitting significant vasopressor sparing.

Interplay between state anxiety, heart rate variability, and cognition: An ex-Gaussian analysis of response times.

The present study employed an ex-Gaussian model of response times (RTs) to elucidate the cognitive processes related to experimentally induced state anxiety (SA) and vagally mediated heart rate variability (vmHRV), an indicator of adaptive responses in both cognitive and affective domains. Participants (n = 110) completed a dual task composed of (i) a flanker attention and (2) working memory load task, while SA was induced by threat of noise. Electrocardiography was measured during the dual task and during four baseline periods in order to calculate vmHRV. RTs on the flanker task were fit to an ex-Gaussian distribution, which estimated three RT parameters: mu (Gaussian mean), sigma (Gaussian SD), and tau (combination of exponential mean and SD). First, findings indicate that threat of noise was associated with reductions in mu and tau, suggesting that SA might improve attention and motor responding. Second, higher resting vmHRV was associated with lower tau (averaged across conditions) and stronger threat-related decreases in tau. Third, intra-individual decreases in vmHRV were accompanied by concomitant decreases in tau. These findings support roles for trait and state vagal control in guiding adaptive anxiety-related (and anxiety-unrelated) attentional responses. Findings are consistent with extant theories that emphasize functional interrelations among emotion, cognition, and vagal function.

Probing Neurovisceral Integration via Functional Near-Infrared Spectroscopy and Heart Rate Variability.

The neurovisceral integration model (NVM) proposes that an organism's ability to flexibly adapt to its environment is related to biological flexibility within the central autonomic network (CAN). One important aspect of this flexibility is behavioral inhibition (Thayer and Friedman, 2002). During a behavioral inhibition task, the CAN, which comprises a series of feedback loops, must be able to integrate information and react to these inputs flexibly to facilitate optimal performance. The functioning of the CAN is shown to be associated with respiratory sinus arrhythmia (RSA), as the vagus nerve is part of this feedback system. Although the NVM has been examined through neural imaging and RSA, only a few studies have examined these measures simultaneously during the neuroimaging procedure. Furthermore, these studies were done at rest or used tasks that were not targeted at processes associated with the NVM, such as behavioral inhibition and cognitive flexibility. For this reason, the present study assessed RSA and neural activation in the pre-frontal cortex simultaneously while participants completed a behavior inhibition task. RSA and functional near-infrared spectroscopy were collected in 38 adults, and resting levels of pre-frontal activation were negatively related to RSA, but pre-frontal activation during the behavior inhibition task was not. The negative relationship between RSA and oxygenated hemoglobin is consistent with previous functional magnetic resonance imaging work examining the NVM at baseline and should be further studied. Additional research investigating how this relationship may change based on task demands or environmental contexts would help clarify the applicability of the model.

American Burn Association Guidelines on the Management of Acute Pain in the Adult Burn Patient: A Review of the Literature, a Compilation of Expert Opinion, and Next Steps.

The ABA pain guidelines were developed 14 years ago and have not been revised despite evolution in the practice of burn care. A sub-committee of the American Burn Association's Committee on the Organization and Delivery of Burn Care was created to revise the adult pain guidelines. A MEDLINE search of English-language publications from 1968 to 2018 was conducted using the keywords "burn pain," "treatment," and "assessment." Selected references were also used from the greater pain literature. Studies were graded by two members of the committee using Oxford Centre for Evidence-based Medicine-Levels of Evidence. We then met as a group to determine expert consensus on a variety of topics related to treating pain in burn patients. Finally, we assessed gaps in the current knowledge and determined research questions that would aid in providing better recommendations for optimal pain management of the burn patient. The literature search produced 189 papers, 95 were found to be relevant to the assessment and treatment of burn pain. From the greater pain literature 151 references were included, totaling 246 papers being analyzed. Following this literature review, a meeting to establish expert consensus was held and 20 guidelines established in the areas of pain assessment, opioid medications, nonopioid medications, regional anesthesia, and nonpharmacologic treatments. There is increasing research on pain management modalities, but available studies are inadequate to create a true standard of care. We call for more burn specific research into modalities for burn pain control as well as research on multimodal pain control.

Clinical Experience with Telavancin for the Treatment of Patients with Bacteremia and Endocarditis: Real-World Results from the Telavancin Observational Use Registry (TOUR™).

BACKGROUND: Bacteremia and endocarditis caused by Staphylococcus aureus (S. aureus), particularly methicillin-resistant S. aureus (MRSA), are challenging to treat and are associated with high morbidity and mortality. Telavancin is a lipoglycopeptide antibacterial active against susceptible Gram-positive pathogens, including MRSA. OBJECTIVE: This registry study assessed the real-world use and clinical outcomes of telavancin in patients with bacteremia or endocarditis enrolled in the Telavancin Observation Use Registry (TOUR™). METHODS: The subset of patients enrolled in TOUR who were diagnosed with endocarditis and/or bacteremia with a known or unknown primary source (N = 151) were analyzed. Data including demographics, infection type, baseline pathogens, prior or concomitant antimicrobial therapy, dosing regimen, clinical response, treatment-emergent adverse events (TEAEs) of interest, and mortality were collected by retrospective medical chart review. RESULTS: Telavancin was primarily used as a second-line or greater therapy (n = 132, 87.4%). MRSA was present in 87 (57.6%) patients. Median telavancin dose was 740.6 mg (interquartile range (IQR) 206.0 mg) and median duration of therapy was 9.0 days (IQR 24.0 days). Of the 132/151 (87.4%) patients with an available assessment at the end of telavancin therapy, a positive clinical response was achieved in 98/132 (74.2%), while 14/132 (10.6%) failed therapy and 20/132 (15.2%) had an indeterminant outcome. TEAEs occurred in 24 (15.9%) patients. The most frequent TEAE was renal failure (n = 12, 7.9%); seven of these patients were receiving concomitant nephrotoxic medications. There was no change in creatinine clearance for 67/89 (75.3%) patients with values recorded at the beginning and the end of telavancin therapy. CONCLUSIONS: In real-world clinical practice, overall positive clinical outcomes are observed in patients with bacteremia or endocarditis treated with telavancin, including in those patients infected with MRSA or another S. aureus pathogen. Telavancin may be an alternative treatment option for these patients. TRIAL REGISTRATION: This trial was registered with clinicaltrials.gov (NCT02288234) on 11 November 2014.

Evaluating the impact of motion artifact on noninvasive blood pressure devices.

Most automated sphygmomanometers use oscillometric algorithms. Motion, either patient-based or environmental, will affect the ability of a device to record an accurate blood pressure (BP). Members of the Association for the Advancement of Medical Instrumentation (AAMI) Sphygmomanometer Committee have been studying this problem for more than a decade. The AAMI TIR44 was the first publication to address the challenges of motion tolerance. The concepts described in TIR44 have led to the development of a draft of ISO 81060-4, a new standard for testing devices for which the manufacturer wishes to claim motion tolerance. The current ISO 81060-2 addresses both stress testing and 24-hour ambulatory BP monitoring. Recent publications have reported on testing of devices in response to voluntary and involuntary patient motion. The ISO 81060-4 will address testing in the presence of patient transport by ground, fixed-wing, and rotary (helicopter) ambulances. The protocol will utilize noise profiles recorded under those three conditions. The profiles will be digitally stored on a library with free access. The proposed testing will be performed using patient simulators introducing the noise library files into known BP oscillometric envelopes. The specifications of the data capture and playback devices are specified, as is the evaluation statistical testing. The authors expect that the final draft will be published in 2020.