Remifentanil alters sensory neuromodulation of swallowing in healthy volunteers: quantification by a novel pressure-impedance analysis.

Exposure to remifentanil contributes to an increased risk of pulmonary aspiration, likely through reduced pharyngeal contractile vigor and diminished bolus propulsion during swallowing. We employed a novel high-resolution pressure-flow analysis to quantify the biomechanical changes across the upper esophageal sphincter (UES). Eleven healthy young (23.3 ± 3.1 yr old) participants (7 men and 4 women) received remifentanil via intravenous target-controlled infusion with an effect-site concentration of 3 ng/ml. Before and 30 min following commencement of remifentanil administration, participants performed ten 10-ml saline swallows while pharyngoesophageal manometry and electrical impedance data were recorded using a 4.2-mm-diameter catheter housing 36 circumferential pressure sensors. Remifentanil significantly shortened the duration of UES opening (P < 0.001) and increased residual UES pressure (P = 0.003). At the level of the hypopharynx, remifentanil significantly shortened the latency from maximum bolus distension to peak contraction (P = 0.004) and significantly increased intrabolus distension pressure (P = 0.024). Novel mechanical states analysis revealed that the latencies between the different phases of the stereotypical UES relaxation sequence were shortened by remifentanil. Reduced duration of bolus flow during shortened UES opening, in concert with increased hypopharyngeal distension pressures, is mechanically consistent with increased flow resistance due to a more rapid bolus flow rate. These biomechanical changes are congruent with modification of the physiological neuroregulatory mechanism governing accommodation to bolus volume.

Effects of remifentanil on esophageal motility: a double-blind, randomized, cross-over study in healthy volunteers.

BACKGROUND: Recent studies have shown that remifentanil increases the risk of aspiration and induces subjective swallowing difficulties. The mechanisms are not completely understood. Here, we investigated whether remifentanil impairs esophageal motility and hypothesized that this is one possible underlying mechanism. Naloxone was used to evaluate whether the effects of remifentanil are mediated through opioid receptors. We also examined subjective swallowing difficulties and the influence of metoclopramide on remifentanil-induced effects. METHODS: Fourteen healthy volunteers participated in a double-blind, randomized, 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 naloxone given as a bolus of 6 µg/kg followed by an infusion of 0.1 µg/kg/min, or saline 5 min before target-controlled infusions of remifentanil at three target-site concentrations: 1, 2, and 3 ng/ml. On both occasions, 0.2 mg/kg metoclopramide was given before the final measurement. Five swallows were performed during each measuring condition, and the metrics defining esophageal motility were measured by high-resolution manometry. Outcomes were differences in the metrics at baseline vs. during remifentanil infusion, with naloxone vs. placebo, and with remifentanil before and after metoclopramide administration. Differences in swallowing difficulties were also recorded. RESULTS: Remifentanil decreased swallow-evoked esophagogastric junction relaxation and the latency time of esophageal peristalsis. There were no significant effects of naloxone or metoclopramide on remifentanil-induced effects, and we detected no differences in swallowing difficulties. CONCLUSIONS: Remifentanil induces dysfunction of esophageal motility; this may contribute to the elevated risk of regurgitation and aspiration.

Effects of cricoid pressure and remifentanil on the esophageal sphincters using high-resolution solid-state manometry.

BACKGROUND: Cricoid pressure has been shown to decrease the pressure in the lower esophageal sphincter (LES), increasing the risk of aspiration. Whether this reaction is due to pain associated with the application of cricoid pressure has not been studied. The aim of this study was to compare the effects of cricoid pressure with those of peripheral pain on pressures in the LES, and to study whether remifentanil influences these effects. Data from the upper esophageal sphincter (UES) are also described. METHODS: Continuous solid-state manometry was performed in 14 healthy volunteers. Initially, the effect of remifentanil (target-controlled infusion with a plasma target concentration of 5.0 ng/ml) was studied, and thereafter, the effects of cricoid pressure and peripheral pain stimulation (cold stimulation). Finally, these two interventions were repeated under ongoing remifentanil infusion. RESULTS: Remifentanil decreased the LES pressure significantly [ΔP-6.5 mmHg, 95% confidence interval (95% CI) -1.7 to -11.2]. Cricoid pressure application decreased the LES pressure significantly (ΔP-3.7 mmHg, 95% CI -1.4 to 6.1), whereas peripheral pain did not (ΔP 1.2 mmHg, 95% CI -3.5 to 1.1). Under ongoing remifentanil infusion, no cricoid pressure-induced LES relaxation was observed. Cricoid pressure induced high pressures in the area of the UES, 215.7 (±91.2) mmHg without remifentanil vs. 219.4 (±74.2) mmHg with remifentanil. CONCLUSIONS: Remifentanil as well as cricoid pressure per se induced decreases in LES pressure. However, cricoid pressure-induced changes of the barrier pressure were not significant whether induced with or without an infusion of remifentanil.

Effects of remifentanil on esophageal and esophagogastric junction (EGJ) bolus transit in healthy volunteers using novel pressure-flow analysis.

BACKGROUND: Remifentanil is associated with subjective dysphagia and an objective increase in aspiration risk. Studies of opioid effects have shown decreased lower esophageal sphincter relaxation. We assessed bolus transit through the esophagus and esophagogastric junction (EGJ) during remifentanil administration using objective pressure-flow analysis. METHODS: Data from 11 healthy young participants (23±3 years, 7 M) were assessed for bolus flow through the esophagus and EGJ using high-resolution impedance manometry (Manoscan™, Sierra Scientific Instruments, Inc., LES Angeles, CA, USA) with 36 pressure and 18 impedance segments. Data were analyzed for esophageal pressure topography and pressure-flow analysis using custom Matlab analyses (Mathworks, Natick, USA). Paired t tests were performed with a P-value of < .05 regarded as significant. KEY RESULTS: Duration of bolus flow through (remifentanil/R 3.0±0.3 vs baseline/B 5.0 ± 0.4 seconds; P < .001) and presence at the EGJ (R 5.1 ± 0.5 vs B 7.1 ± 0.5 seconds; P = .001) both decreased during remifentanil administration. Distal latency (R 5.2 ± 0.4 vs B 7.5 ± 0.2 seconds; P < .001) and distal esophageal distension-contraction latency (R 3.5 ± 0.1 vs B 4.7 ± 0.2 seconds; P < .001) were both reduced. Intrabolus pressures were increased in both the proximal (R 5.3 ± 0.9 vs B 2.6 ± 1.3 mm Hg; P = .01) and distal esophagus (R 8.6 ± 1.7 vs B 3.1 ± 0.8 mm Hg; P = .001). There was no evidence of increased esophageal bolus residue. CONCLUSIONS AND INFERENCES: Remifentanil-induced effects were different for proximal and distal esophagus, with a reduced time for trans-sphincteric bolus flow at the EGJ, suggestive of central and peripheral µ-opioid agonism. There were no functional consequences in healthy subjects.

Development of an ICU discharge instrument predicting psychological morbidity: a multinational study.

PURPOSE: To develop an instrument for use at ICU discharge for prediction of psychological problems in ICU survivors. METHODS: Multinational, prospective cohort study in ten general ICUs in secondary and tertiary care hospitals in Sweden, Denmark and the Netherlands. Adult patients with an ICU stay ≥ 12 h were eligible for inclusion. Patients in need of neurointensive care, with documented cognitive impairment, unable to communicate in the local language, without a home address or with more than one limitation of therapy were excluded. Primary outcome was psychological morbidity 3 months after ICU discharge, defined as Hospital Anxiety and Depression Scale (HADS) subscale score ≥ 11 or Post-traumatic Stress Symptoms Checklist-14 (PTSS-14) part B score > 45. RESULTS: A total of 572 patients were included and 78% of patients alive at follow-up responded to questionnaires. Twenty percent were classified as having psychological problems post-ICU. Of 18 potential risk factors, four were included in the final prediction model after multivariable logistic regression analysis: symptoms of depression [odds ratio (OR) 1.29, 95% confidence interval (CI) 1.10-1.50], traumatic memories (OR 1.44, 95% CI 1.13-1.82), lack of social support (OR 3.28, 95% CI 1.47-7.32) and age (age-dependent OR, peak risk at age 49-65 years). The area under the receiver operating characteristics curve (AUC) for the instrument was 0.76 (95% CI 0.70-0.81). CONCLUSIONS: We developed an instrument to predict individual patients' risk for psychological problems 3 months post-ICU, http://www.imm.ki.se/biostatistics/calculators/psychmorb/ . The instrument can be used for triage of patients for psychological ICU follow-up. TRIAL REGISTRATION: The study was registered at clinicaltrials.gov, NCT02679157.