Response to Letter to the Editor.

It is crucial to consider the possible influence of anesthetic agents on esophageal function testing. Dexmedetomidine has been shown to affect primary peristalsis during esophageal manometry. In the two case reports presented by Toaz et al., secondary peristalsis during FLIP panometry was also affected. This may be attributed to an alternate pharmacodynamic effect, with a transient direct α2-mediated effect on esophageal smooth muscle, associated with a high plasma concentration following bolus injection, prior to the onset of sympathetic inhibition.

Effects of dexmedetomidine on pharyngeal swallowing and esophageal motility-A double-blind randomized cross-over study in healthy volunteers.

BACKGROUND: Sedative agents increase the risk of pulmonary aspiration, where an intact swallowing function is an important defense mechanism. Dexmedetomidine is an α2 -adrenoceptor agonist widely used during procedural sedation due to beneficial properties with minimal respiratory effects. The effects of dexmedetomidine on pharyngeal swallowing and esophageal motility are not known in detail. METHODS: To determine the effects of dexmedetomidine on pharyngeal swallowing and esophageal motility, nineteen volunteers were included in this double-blinded, randomized placebo-controlled cross-over study. Study participants received target-controlled dexmedetomidine and placebo infusions. Recordings of pressure and impedance data were acquired using a manometry and impedance solid-state catheter. Data were analyzed from three bolus swallows series: baseline, during dexmedetomidine/placebo infusion at target plasma concentrations 0.6 ng ml-1 and 1.2 ng ml-1 . Subjective swallowing difficulties were also recorded. KEY RESULTS: On pharyngeal swallowing, dexmedetomidine affected the upper esophageal sphincter with decreased pre- and post-swallow contractile pressures and an increase in residual pressure during swallow-related relaxation. On esophageal function, dexmedetomidine decreased contractile vigor of the proximal esophagus and increased velocity of the peristaltic contraction wave. Residual pressures during swallow-related esophagogastric junction (EGJ) relaxation decreased, as did basal EGJ resting pressure. The effects on the functional variables were not clearly dose-dependent, but mild subjective swallowing difficulties were more common at the higher dose level. CONCLUSIONS AND INFERENCES: Dexmedetomidine induces effects on pharyngeal swallowing and esophageal motility, which should be considered in clinical patient management and also when a sedative agent for procedural sedation or for manometric examination is to be chosen.

Serum concentration of extracellular cold-inducible RNA-binding protein is associated with respiratory failure in COVID-19.

Uncontrolled release of damage-associated molecular patterns (DAMPs) is suggested to be a major trigger for the dysregulated host immune response that leads to severe COVID-19. Cold-inducible RNA-binding protein (CIRP), is a newly identified DAMP that aggravates inflammation and tissue injury, and induces respiratory failure in sepsis. Whether CIRP contributes to the pathogenesis of respiratory failure in COVID-19 has not yet been explored. Aim: To investigate if the concentration of extracellular CIRP (eCIRP) in serum associates with respiratory failure and lung involvement by chest computed tomography (CT) in COVID-19. Methods: Herein we report a prospective observational study of patients with COVID-19 included at two University Hospitals in Sweden between April 2020 and May 2021. Serum from hospitalized patients in Örebro (N=97) were used to assess the association between eCIRP and the level of respiratory support and its correlation with pulmonary involvement on chest CT and inflammatory biomarkers. A cohort of hospitalized and non-hospitalized patients from Umeå (N=78) was used as an external validation cohort. The severity of disease was defined according to the highest degree of respiratory support; mild disease (no oxygen), non-severe hypoxemia (conventional oxygen or high-flow nasal oxygen, HFNO <50% FiO2), and severe hypoxemia (HFNO ≥50% FiO2, mechanical ventilation). Unadjusted and adjusted linear regression was used to evaluate peak eCIRP day 0-4 in respect to severity, age, sex, Charlson comorbidity score, symptom duration, and BMI. Results: Peak eCIRP concentrations were higher in patients with severe hypoxemia and were independently associated with the degree of respiratory support in both cohorts (Örebro; p=0.01, Umeå; p<0.01). The degree of pulmonary involvement measured by CT correlated with eCIRP, rs=0.30, p<0.01 (n=97). Conclusion: High serum levels of eCIRP are associated with acute respiratory failure in COVID-19. Experimental studies are needed to determine if treatments targeting eCIRP reduces the risk of acute respiratory failure in COVID-19.

Caregiver burden and emotional wellbeing in informal caregivers to ICU survivors-A prospective cohort study.

BACKGROUND: Informal caregivers to intensive care unit (ICU) survivors may develop post-intensive care syndrome family (PICS-F), including depression, anxiety and post-traumatic stress (PTS). Our primary aim was to investigate associations between caregiver burden in informal caregivers cohabiting with ICU survivors and patients' physical and psychological outcomes. METHODS: A prospective, multicentre cohort study in four ICUs in Sweden. Adults cohabiting with ICU patients included in a previous study were eligible for inclusion. Three months post-ICU, informal caregivers received questionnaires assessing caregiver burden, health-related quality of life (HRQL) and symptoms of depression, anxiety and PTS. In parallel, patients reported their three-month physical and psychological status via validated questionnaires. The primary outcome of this study was to compare caregiver burden in informal caregivers to patients with and without adverse physical and psychological outcomes 3 months post-ICU. Secondary outcomes were correlations between caregiver burden and informal caregivers' mental HRQL. RESULTS: Among 62 included informal caregivers, 55 (89%) responded to the follow-up questionnaires. Caregiver burden was higher among informal caregivers to patients with an adverse outcome, compared to informal caregivers to patients without an adverse outcome, caregiver burden scale score mean (±standard deviation) 52 (11) and 41 (13) respectively (p = 0.003). There was strong negative correlation between caregiver burden and informal caregivers' mental HRQL (rs -0.74, p < 0.001). CONCLUSION: Informal caregivers to ICU survivors with adverse physical or psychological outcome experience a higher caregiver burden. A higher caregiver burden correlates with worse caregiver mental HRQL. ICU follow-up programs should consider screening and follow-up of informal caregivers for mental health problems.

Pharyngo-Esophageal Modulatory Swallow Responses to Bolus Volume and Viscosity Across Time.

OBJECTIVES/HYPOTHESIS: Modulation of the pharyngeal swallow to bolus volume and viscosity is important for safe swallowing and is commonly studied using high-resolution pharyngeal manometry (HRPM). Use of unidirectional pressure sensor technology may, however, introduce variability in swallow measures and a fixed bolus administration protocol may induce time and order effects. We aimed to overcome these limitations and to investigate the effect of time by repeating randomized measurements using circumferential pressure sensor technology. STUDY DESIGN: Sub-set analysis of data from the placebo arm of a randomized, repeated measures trial. METHODS: HRPM with impedance was recorded using a solid-state catheter with 36 circumferential pressure sensors and 18 impedance segments straddling from hypopharynx to stomach. Testing included triplicates of 5, 10, and 20 ml thin liquid and 10 ml thick liquid boluses, the order of the thin liquid boluses was randomized. The swallow challenges were repeated approximately 10 minutes after finishing the baseline measurement. RESULTS: We included 19 healthy adults (10/9 male/female; age 24.5 ± 4.1 year). Intrabolus pressure, all upper esophageal sphincter (UES) opening and relaxation metrics, and flow timing metrics increased with larger volumes. A thicker viscosity decreased UES relaxation time, UES basal pressure, and flow timing metrics, whereas UES opening extent increased. Pre-swallow UES basal pressure and post-swallow UES contractile integral decreased over time. CONCLUSION: Using circumferential pressure sensor technology, the effects of volume and viscosity were largely consistent with previous reports. UES contractile pressures reduced over time. The growing body of literature offers a benchmark for recognizing aberrant pharyngo-esophageal motor responses. LEVEL OF EVIDENCE: 3 Laryngoscope, 132:1817-1824, 2022.

Effects of remifentanil on pharyngeal swallowing and esophageal motility: no impact of different bolus volumes and partial antagonism by methylnaltrexone.

Remifentanil impairs swallowing, and disturbed accommodation to bolus volume may be one of the underlying causes. It is not fully understood whether remifentanil-induced swallowing dysfunction is mediated by peripheral or central mechanisms. So, this study aimed to investigate if remifentanil-induced swallowing dysfunction is dependent on the bolus volume and whether the effect of remifentanil could be counteracted by methylnaltrexone, a peripherally acting opioid antagonist. Nineteen healthy volunteers were included in this double-blinded, randomized, placebo-controlled, crossover study. Study participants received target-controlled remifentanil infusions and placebo infusions in a randomized order. Methylnaltrexone was administered by intravenous injection of doses of 0.3 mg/kg. Recordings of pressure and impedance data were acquired using a combined manometry and impedance solid-state catheter. Data were analyzed from three series of bolus swallows, baseline, during study medication exposure, and 15 min after methylnaltrexone. Remifentanil induced significant effects on multiple pharyngeal and esophageal function parameters. No significant differences in remifentanil-induced swallowing dysfunction related to different bolus volumes were found. Pharyngeal effects of remifentanil were not significantly counteracted by methylnaltrexone, whereas on the distal esophageal level, effects on distension pressures were counteracted. Changes in pharyngeal and esophageal pressure flow variables were consistent with previous results on remifentanil-induced swallowing dysfunction and uniform across all bolus volumes. The effects of remifentanil on the pharyngeal level and on the proximal esophagus appear to be predominantly centrally mediated, whereas the effects of remifentanil on the distal esophagus may be mediated by both central and peripheral mechanisms.NEW & NOTEWORTHY In this randomized controlled trial, we used the "Swallow Gateway" online platform to analyze the effects of remifentanil on pharyngeal and esophageal swallowing. It is not fully understood whether remifentanil-induced swallowing dysfunction is mediated by peripheral or central mechanisms. By using methylnaltrexone, we demonstrated that effects of remifentanil on pharyngeal swallowing were predominantly centrally mediated, whereas its effects on the distal esophagus may be mediated by both central and peripheral mechanisms.

ICU discharge screening for prediction of new-onset physical disability-A multinational cohort study.

BACKGROUND: Methods to identify patients at risk for incomplete physical recovery after intensive care unit (ICU) stay are lacking. Our aim was to develop a method for prediction of new-onset physical disability at ICU discharge. METHODS: Multinational prospective cohort study in 10 general ICUs in Sweden, Denmark, and the Netherlands. Adult patients with an ICU stay ≥12 hours were eligible for inclusion. Sixteen candidate predictors were analyzed with logistic regression for associations with the primary outcome; new-onset physical disability 3 months post-ICU, defined as a ≥10 score reduction in the Barthel Index (BI) compared to baseline. RESULTS: Of the 572 included patients, follow-up data are available on 78% of patients alive at follow-up. The incidence of new-onset physical disability was 19%. Univariable and multivariable modeling rendered one sole predictor for the outcome: physical status at ICU discharge, assessed with the five first items of the Chelsea critical care physical assessment tool (CPAx) (odds ratio 0.87, 95% confidence interval (CI) 0.81-0.93), a higher score indicating a lower risk, with an area under the receiver operating characteristics curve of 0.68 (95% CI 0.61-0.76). Negative predictive value for a low-risk group (CPAx score >18) was 0.88, and positive predictive value for a high-risk group (CPAx score ≤18) was 0.32. CONCLUSION: The ICU discharge assessment described in this study had a moderate AUC but may be useful to rule out patients unlikely to need physical interventions post-ICU. For high-risk patients, research to determine post-ICU risk factors for an incomplete rehabilitation is mandated.

The Reliability of Pharyngeal High Resolution Manometry with Impedance for Derivation of Measures of Swallowing Function in Healthy Volunteers.

Purpose. We evaluated the intra- and interrater agreement and test-retest reliability of analyst derivation of swallow function variables based on repeated high resolution manometry with impedance measurements. Methods. Five subjects swallowed 10 × 10 mL saline on two occasions one week apart producing a database of 100 swallows. Swallows were repeat-analysed by six observers using software. Swallow variables were indicative of contractility, intrabolus pressure, and flow timing. Results. The average intraclass correlation coefficients (ICC) for intra- and interrater comparisons of all variable means showed substantial to excellent agreement (intrarater ICC 0.85-1.00; mean interrater ICC 0.77-1.00). Test-retest results were less reliable. ICC for test-retest comparisons ranged from slight to excellent depending on the class of variable. Contractility variables differed most in terms of test-retest reliability. Amongst contractility variables, UES basal pressure showed excellent test-retest agreement (mean ICC 0.94), measures of UES postrelaxation contractile pressure showed moderate to substantial test-retest agreement (mean Interrater ICC 0.47-0.67), and test-retest agreement of pharyngeal contractile pressure ranged from slight to substantial (mean Interrater ICC 0.15-0.61). Conclusions. Test-retest reliability of HRIM measures depends on the class of variable. Measures of bolus distension pressure and flow timing appear to be more test-retest reliable than measures of contractility.

Effects of remifentanil on pharyngeal swallowing: A double blind randomised cross-over study in healthy volunteers.

BACKGROUND: Exposure to remifentanil increases the incidence of pulmonary aspiration in healthy volunteers. This effect may be explained by impairment of airway defence mechanisms and/or altered swallowing function. Pressure-flow analysis is a technique that allows objective assessment of swallowing based on pressure-impedance patterns recorded during bolus swallowing. OBJECTIVES: The aim of this study was to use pressure-flow analysis to quantify the effect of remifentanil on healthy pharyngeal swallowing and to compare these effects with morphine. DESIGN: A double-blind, randomised, cross-over study. SETTING: A tertiary care teaching hospital. VOLUNTEERS: Eleven young volunteers (mean age, 23 years) and seven older volunteers (mean age, 73 years). INTERVENTIONS: Volunteers were studied twice and received either a target-controlled remifentanil infusion (target concentrations: young, 3 ng ml; old, 2 ng ml) or a bolus injection of morphine (dose: young, 0.1 mg kg; old, 0.07 mg kg). Pharyngeal pressure and impedance were recorded with an indwelling catheter while swallowing 10 boluses of liquid during each measuring phase. Variables defining swallowing function were calculated and compared to determine drug effects. MAIN OUTCOME MEASURES: Pharyngeal pressure-flow variables following remifentanil exposure. RESULTS: Changes produced by remifentanil in the measured variables were consistent with greater dysfunction of swallowing. Both the strength of the pharyngeal contractions and pharyngeal bolus propulsion were reduced, whereas flow resistance was increased. The swallow risk index, a global index of swallowing dysfunction, increased overall. At the experimental doses tested, morphine produced similar, but less extensive effects on swallowing. CONCLUSION: Remifentanil induced dysfunction of the pharyngeal swallowing mechanism. This may contribute to an increased risk of aspiration. TRIAL REGISTRATION: NCT01924234 (www.clinicaltrials.gov).

Aspiration induced by remifentanil: a double-blind, randomized, crossover study in healthy volunteers.

BACKGROUND: Remifentanil is widely used for monitored anesthesia care in spontaneously breathing patients. However, the authors' previous studies have shown that remifentanil induces subjective swallowing difficulties, which may increase the risk of aspiration. METHODS: Twenty-five healthy volunteers participated in a double-blind, randomized, crossover trial at the University Hospital in Örebro, Örebro, Sweden. The volunteers were studied on two different occasions during which they received either remifentanil with an effect-site target concentration of 3 ng/ml or saline over 1 h. A radionuclide tracer was infused simultaneously into the nasopharynx at a rate of 0.1 ml/min. Aspiration was determined by lung scans, and subjective swallowing difficulties and grip strength were evaluated. The primary outcome was the difference in occurrence of aspiration between remifentanil and placebo treatments. The secondary outcomes were differences in swallowing difficulty and grip strength and the association between aspiration and swallowing difficulty. RESULTS: During remifentanil and placebo infusion, 48 and 12% of the volunteers aspirated, respectively, difference: 36% (95% CI, 10 to 62%). A similar significant difference was found for swallowing difficulties but not for the association between aspiration and swallowing. No difference was found in grip strength between the two treatments. CONCLUSIONS: Remifentanil infusion at concentrations used in monitored anesthesia care increases the incidence of aspiration. However, the subjective swallowing difficulty induced by remifentanil is not indicative of the aspiration risk.

Effects of remifentanil on the esophagogastric junction and swallowing.

BACKGROUND: A recent study demonstrated that reflux is associated with impaired pressure augmentation in the esophagogastric junction (EGJ), caused by diaphragmal contractions during inspiration. It is unknown whether this augmentation is influenced by opioids. Swallowing difficulties can be a poorly recognised side effect of remifentanil. Here, we investigated whether remifentanil influences inspiratory EGJ augmentation and evaluated subjective swallowing difficulties induced by remifentanil. We also used the peripheral opioid receptor antagonist methylnaltrexone to evaluate whether these effects are centrally or peripherally mediated. METHODS: Ten healthy volunteers participated in a double-blind, randomised, cross-over trial at the University Hospital in Örebro, Sweden. They were studied on two different occasions, during which they were randomly assigned to receive either methylnaltrexone 0.15 mg/kg or saline subcutaneously 30 min before the target-controlled infusion of remifentanil of 3 ng/mL. EGJ pressures were measured by high-resolution manometry. Swallowing difficulties were assessed when volunteers performed dry swallows. The outcomes were the differences in EGJ pressures at baseline and during remifentanil infusion and with methylnaltrexone vs. placebo. Differences in swallowing difficulties before and during remifentanil, and with methylnaltrexone vs. placebo were also recorded. RESULTS: Remifentanil decreased the inspiratory EGJ augmentation and induced swallowing difficulties. No statistically significant differences between methylnaltrexone and placebo occasions were found. CONCLUSIONS: Remifentanil may increase risk for gastroesophageal reflux by decreasing the inspiratory EGJ augmentation. The clinical significance of remifentanil-induced swallowing difficulties is to be studied further. Given the limited sample size, it cannot be concluded whether these effects are centrally or peripherally mediated.