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Background: Optimal sedation of patients in intensive care units (ICUs) requires the avoidance of pain, agitation, and unnecessary deep sedation, but these outcomes are challenging to achieve. Excessive sedation can prolong ICU stay, whereas light sedation can increase pain and frightening memories, which are commonly recalled by ICU survivors. We aimed to assess the effectiveness of three interventions to improve sedation and analgesia quality: an online education programme; regular feedback of sedation-analgesia quality data; and use of a novel sedation-monitoring technology (the Responsiveness Index [RI])., Methods: We did a cluster randomised trial in eight ICUs, which were randomly allocated to receive education alone (two ICUs), education plus sedation-analgesia quality feedback (two ICUs), education plus RI monitoring technology (two ICUs), or all three interventions (two ICUs). Randomisation was done with computer-generated random permuted blocks, stratified according to recruitment start date. A 45 week baseline period was followed by a 45 week intervention period, separated by an 8 week implementation period in which the interventions were introduced. ICU and research staff were not masked to study group assignment during the intervention period. All mechanically ventilated patients were potentially eligible. We assessed patients' sedation-analgesia quality for each 12 h period of nursing care, and sedation-related adverse events daily. Our primary outcome was the proportion of care periods with optimal sedation-analgesia, defined as being free from excessive sedation, agitation, poor limb relaxation, and poor ventilator synchronisation. Analysis used multilevel generalised linear mixed modelling to explore intervention effects in a single model taking clustering and patient-level factors into account. A concurrent mixed-methods process evaluation was undertaken to help understand the trial findings. The trial is registered with ClinicalTrials.gov, number NCT01634451., Findings: Between June 1, 2012, and Dec 31, 2014, we included 881 patients (9187 care periods) during the baseline period and 591 patients (6947 care periods) during the intervention period. During the baseline period, optimal sedation-analgesia was present for 5150 (56%) care periods. We found a significant improvement in optimal sedation-analgesia with RI monitoring (odds ratio [OR] 1·44 [95% CI 1·07-1·95]; p=0·017), which was mainly due to increased periods free from excessive sedation (OR 1·59 [1·09-2·31]) and poor ventilator synchronisation (OR 1·55 [1·05-2·30]). However, more patients experienced sedation-related adverse events (OR 1·91 [1·02-3·58]). We found no improvement in overall optimal sedation-analgesia with education (OR 1·13 [95% CI 0·86-1·48]), but fewer patients experienced sedation-related adverse events (OR 0·56 [0·32-0·99]). The sedation-analgesia quality data feedback did not improve quality (OR 0·74 [95% CI 0·54-1·00]) or sedation-related adverse events (OR 1·15 [0·61-2·15]). The process evaluation suggested many clinicians found the RI monitoring useful, but it was often not used for decision making as intended. Education was valued and considered useful by staff. By contrast, sedation-analgesia quality feedback was poorly understood and thought to lack relevance to bedside nursing practice., Interpretation: Combination of RI monitoring and online education has the potential to improve sedation-analgesia quality and patient safety in mechanically ventilated ICU patients. The RI monitoring seemed to improve sedation-analgesia quality, but inconsistent adoption by bedside nurses limited its impact. The online education programme resulted in a clinically relevant improvement in patient safety and was valued by nurses, but any changes to behaviours did not seem to alter other measures of sedation-analgesia quality. Providing sedation-analgesia quality feedback to ICUs did not appear to improve any quality metrics, probably because staff did not think it relevant to bedside practice., Funding: Chief Scientist Office, Scotland; GE Healthcare., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Introduction: Deep sedation is associated with adverse patient outcomes. We recently described a novel sedation-monitoring technology, the Responsiveness Index (RI), which quantifies patient arousal using processed frontal facial EMG data. We explored the potential effectiveness and safety of continuous RI monitoring during early intensive care unit (ICU) care as a nurse decision-support tool., Methods: In a parallel-group controlled single centre proof of concept trial, patients requiring mechanical ventilation and sedation were randomized via sequential sealed envelopes following ICU admission. Control group patients received hourly clinical sedation assessment and daily sedation holds; the RI monitor was connected but data were concealed from clinical staff. The intervention group received control group care, but RI monitoring was visible and nurses were asked to adjust sedation to maintain patients with an RI>20 whenever possible. Traffic-light colour coding (RI<20, Red; 20-40, Amber; >40, Green) simplified decision-making. The intervention lasted up to 48 hours. Sixteen nurses were interviewed to explore their views of the novel technology., Results: We analysed 74 patients treated per protocol (36 intervention; 38 control). The proportion of patients with RI<20 was identical at the start of monitoring (54% both groups). Overall, the proportion of time with RI<20 trended to lower values for the intervention group (median 16% (1-3rd quartile 8-30%) versus 33% (10-54%); P = 0.08); sedation and analgesic use was similar. A post hoc analysis restricted to patients with RI<20 when monitoring started, found intervention patients spent less time with low RI value (16% (11-45%) versus 51% (33-72%); P = 0.02), cumulative propofol use trended to lower values (median 1090 mg versus 2390 mg; P = 0.14), and cumulative alfentanil use was lower (21.2 mg versus 32.3 mg; P = 0.01). RASS scores were similar for both groups. Sedation related adverse event rates were similar (7/36 versus 5/38). Similar proportions of patients had sedation holds (83% versus 87 %) and were extubated (47% versus 44%) during the intervention period. Nurses valued the objective visible data trends and simple colour prompts, and found RI monitoring a useful adjunct to existing practice., Conclusions: RI monitoring was safe and acceptable. Data suggested potential to modify sedation decision-making. Larger trials are justified to explore effects on patient-centred outcomes., Trial Registration: NCT01361230 (registered April 19, 2010).

Purpose: The purpose of this study is to explore the validity of a novel sedation monitoring technology based on facial electromyelography (EMG) in sedated critically ill patients., Materials and Methods: The Responsiveness Index (RI) integrates the preceding 60 minutes of facial EMG data. An existing data set was used to derive traffic light cut-offs for low (red), intermediate (amber), and higher (green) states of patient arousal. The validity of these was prospectively evaluated in 30 sedated critically ill patients against hourly Richmond Agitation Sedation Scale (RASS) assessments with concealment of RI data from clinical staff., Results: With derivation data, an RI less than or equal to 35 had best discrimination for a Ramsay score of 5/6 (sensitivity, 90%; specificity, 79%). For traffic lights, we chose RI less than or equal to 20 as red, 20 to 40 as amber, and more than 40 as green. In the prospective study, RI values were red/amber for 76% of RASS -5/-4 assessments, but RI varied dynamically over time in many patients, and discordance with RASS may have resulted from the use of 1 hour of data for RI calculations. We also noted that red/amber values resulted from sleep, encephalopathy, and low levels of stimulation., Conclusions: Responsiveness Index is not directly comparable with clinical sedation scores but is a potential continuous alert to possible deep sedation in critically ill patients., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: The surgical stress index (SSI), derived from a combination of heart rate (HR) and photoplethysmographic amplitude (PPGA) time series, is a novel method for continuous monitoring of intraoperative stress and has been validated in adults. The applicability of SSI and its constituents to monitoring children has not been previously evaluated., Methods: In this controlled trial, 22 anaesthetized patients, aged 4-17 yr, undergoing strabismus surgery were randomized into two groups, Group LL and Group BSS. Patients in Group LL received topical conjunctival anaesthesia with a 1:1 mixture of lidocaine 2% and levobupivacaine 0.75%, and patients in Group BSS received balanced salt solution., Results: Endotracheal intubation (n=22) increased median (range) SSI from 39.2 (22.6-55.6) to 53.6 (35.8-63.3) (P<0.001), decreased PPGA from 5.62 (2.79-9.69) to 5.27 (2.59-7.54)% (P=0.001), and increased the difference of response entropy (RE) and state entropy (SE) of frontal biopotentials (RE-SE) from 3.1 (0.06-9.1) to 5.7 (0.6-9.4) (P=0.01). Conventional haemodynamic variables also increased, median (range) HR from 72.9 (56.7-113.8) to 84.2 (60.4-124.8) beats min(-1) (P<0.001), and systolic non-invasive arterial pressure (S-NIBP) from 87 (78-143) to 103 (79-125) (P=0.007). When 3 min baseline before surgery was compared with 12 min of surgery, median (range) SSI increased from 43.3 (31.2-58.0) to 49.9 (39.3-57.2) (P=0.042) vs from 46.6 (26.8-57.8) to 52.1 (31.7-60.1) (P=0.024) and PPGA decreased from 6.60 (3.10-8.24) to 5.80 (3.03-7.65)% (P<0.001) vs from 5.51 (3.25-9.84) to 5.06 (3.08-8.99)% (P=0.042), in Groups LL and BSS, respectively, but SSI or other indicators did not differ significantly between the groups., Conclusions: SSI, PPGA, HR, NIBP, RE, and RE-SE detect autonomic responses to nociceptive stimuli in anaesthetized children undergoing strabismus surgery.

Background: The surgical stress index (SSI) is based on a sum of the normalized pulse beat interval (PBI) and the pulse wave amplitude (PPGA) time series of the photoplethysmography. As a measure of the nociception-anti-nociception balance in response to a standardized pain stimulus, SSI was compared with EEG changes in state and response entropy (SE and RE), PPGA, and heart rate (HR) during various targeted pseudo-steady-state concentrations of propofol and remifentanil., Methods: Forty ASA I patients were allocated to one of the four groups to receive a remifentanil step-up/-down effect-compartment target-controlled infusion (Ce(remi)) of 0, 2, 6, 2, 0 ng ml(-1), or 6, 2, 0, 2, 6 ng ml(-1), and an effect-compartment target-controlled propofol infusion (Ce(prop)) to keep the SE between 30 and 50 or 15 and 30, respectively. At each steady-state Ce(remi), maximum change in SSI, SE, RE, PPGA, and HR after a noxious stimulus was compared with the baseline value. A correlation and prediction probability (P(K)) with Ce(prop) and Ce(remi) was measured., Results: Static and dynamic values of SSI correlated to Ce(remi) better than SE, RE, HR, and PPGA. SSI was independent of Ce(prop), in contrast to SE and RE. The P(K) for Ce(remi) both before and during a noxious stimulus was better with SSI., Conclusions: SSI appeared to be a better measure of nociception-anti-nociception balance than SE, RE, HR, or PPGA.

Background: Monitoring of analgesia remains a challenge during general anaesthesia. The surgical stress index (SSI) is derived from the photoplethysmographic waveform amplitude and the heart beat-to-beat interval. We evaluated the ability of SSI to measure surgical stress in patients undergoing gynaecological laparoscopy. Our hypothesis was that while keeping State Entropy (SE) at a predetermined level, SSI would be higher in patients receiving a beta-blocking agent (esmolol) than in those receiving an opioid (remifentanil) during laparoscopy., Methods: Thirty women undergoing gynaecological laparoscopy were assigned randomly to receive esmolol (n = 15) or remifentanil (n = 15). Anaesthesia was induced with propofol and fentanyl and maintained with desflurane and nitrous oxide 50% in oxygen to keep SE at 50(5). The infusion of esmolol or remifentanil was started before laparoscopy and adjusted to keep the systolic blood pressure at -20 to +10% from the preoperative value., Results: During the fentanyl phase, before surgery, both groups behaved similarly, with an increase in SSI after intubation. In the patients receiving esmolol, the SSI reacted to the initial incision (P < 0.05), and remained high after trocar insertion (P < 0.05). In patients receiving remifentanil, it did not react to the initial incision, but increased after trocar insertion (P < 0.05), and it remained lower both after incision (P < 0.05) and after trocar insertion (P < 0.05)., Conclusion: SSI was higher in patients receiving esmolol. The index seems to reflect the level of surgical stress and may help guide the use of opioids during general anaesthesia.

Background: Inadequate analgesia during general anaesthesia may present as undesirable haemodynamic responses. No objective measures of the adequacy of analgesia exist. We aimed at developing a simple numerical measure of the level of surgical stress in an anaesthetized patient., Methods: Sixty and 12 female patients were included in the development and validation data sets, respectively. All patients had elective surgery with propofol-remifentanil target controlled anaesthesia. Finger photoplethysmography and electrocardiography waveforms were recorded throughout anaesthesia and various waveform parameters were extracted off-line. Total surgical stress (TSS) for a patient was estimated based on stimulus intensity and remifentanil concentration. The surgical stress index (SSI) was developed to correlate with the TSS estimate in the development data set. The performance of SSI was validated within the validation data set during and before surgery, especially at skin incision and during changes of the predicted remifentanil effect-site concentration., Results: SSI was computed as a combination of normalized heart beat interval (HBI(norm)) and plethysmographic pulse wave amplitude (PPGA(norm)): SSI = 100-(0.7*PPGA(norm)+0.3*HBI(norm)). SSI increased at skin incision and stayed higher during surgery than before surgery; SSI responded to remifentanil concentration changes and was higher at the lower concentrations of remifentanil., Conclusions: SSI reacts to surgical nociceptive stimuli and analgesic drug concentration changes during propofol-remifentanil anaesthesia. Further validation studies of SSI are needed to elucidate its usefulness during other anaesthetic and surgical conditions.

We studied attentional modulation of cortical processing of faces and houses with functional MRI and magnetoencephalography (MEG). MEG detected an early, transient face-selective response. Directing attention to houses in "double-exposure" pictures of superimposed faces and houses strongly suppressed the characteristic, face-selective functional MRI response in the fusiform gyrus. By contrast, attention had no effect on the M170, the early, face-selective response detected with MEG. Late (>190 ms) category-related MEG responses elicited by faces and houses, however, were strongly modulated by attention. These results indicate that hemodynamic and electrophysiological measures of face-selective cortical processing complement each other. The hemodynamic signals reflect primarily late responses that can be modulated by feedback connections. By contrast, the early, face-specific M170 that was not modulated by attention likely reflects a rapid, feed-forward phase of face-selective processing.

Magnetoencephalographic(MEG) data are typically interpreted using source models because of the nonunique inverse problem. Although single current dipoles, adequately representing local active areas, can be identified accurately, multiple and overlapping sources form a challenge for MEG modeling. We tested the performances of multidipole modeling and minimum current estimate (MCE) in the analysis of complicated source configurations. Simulated current sources were placed to physiologically meaningful areas of the human visual cortices. Ten volunteers from the laboratory staff analyzed four different simulations with both dipole modeling and MCE without prior information of the sources. In general, the same sources were found using both modeling methods. The subjects tended to report more false sources with MCE than with dipole model, in part due to their inexperience with the method. Dipole model was more accurate than MCE both in time and space for nonsimultaneous sources but both methods performed similarly when sources overlapped in time. For all source configurations, considerably smaller source amplitudes were reported with MCE than with dipole model.

Numerous studies have demonstrated activation of the classical left-hemisphere language areas when native signers process sign language. More recently, specific sign language-related processing has been suggested to occur in homologous areas of the right hemisphere as well. We now show that these cortical areas are also activated in hearing non-signers during passive viewing of signs that for them are linguistically meaningless. Neuromagnetic activity was stronger in deaf signers than in hearing non-signers in the region of the right superior temporal sulcus and the left dorsal premotor cortex, probably reflecting familiarity and linguistic meaningfulness of the observed movement sequences. In contrast, the right superior parietal lobule, the mesial parieto-occipital region, and the mesial paracentral lobule were more strongly activated in hearing non-signers, apparently reflecting active visuomotor encoding of complex unfamiliar movement sequences.

Proper understanding of processes underlying visual perception requires information on the activation order of distinct brain areas. We measured dynamics of cortical signals with magnetoencephalography while human subjects viewed stimuli at four visual quadrants. The signals were analyzed with minimum current estimates at the individual and group level. Activation emerged 55-70 ms after stimulus onset both in the primary posterior visual areas and in the anteromedial part of the cuneus. Other cortical areas were active after this initial dual activation. Comparison of data between species suggests that the anteromedial cuneus either comprises a homologue of the monkey area V6 or is an area unique to humans. Our results show that visual stimuli activate two cortical areas right from the beginning of the cortical response. The anteromedial cuneus has the temporal position needed to interact with the primary visual cortex V1 and thereby to modify information transferred via V1 to extrastriate cortices.

Letters of the alphabet have auditory (phonemic) and visual (graphemic) qualities. To investigate the neural representations of such audiovisual objects, we recorded neuromagnetic cortical responses to auditorily, visually, and audiovisually presented single letters. The auditory and visual brain activations first converged around 225 ms after stimulus onset and then interacted predominantly in the right temporo-occipito-parietal junction (280345 ms) and the left (380-540 ms) and right (450-535 ms) superior temporal sulci. These multisensory brain areas, playing a role in audiovisual integration of phonemes and graphemes, participate in the neural network supporting the supramodal concept of a "letter." The dynamics of these functions bring new insight into the interplay between sensory and association cortices during object recognition.

When attending to a visual object, peripheral stimuli must be monitored for appropriate redirection of attention and gaze. Earlier work has revealed precentral and posterior parietal activation when attention has been directed to peripheral vision. We wanted to find out whether similar cortical areas are active when stimuli are presented in nonattended regions of the visual field. The timing and distribution of neuromagnetic responses to a peripheral luminance stimulus were studied in human subjects with and without attention to fixation. Cortical current distribution was analyzed with a minimum L1-norm estimate. Attention enhanced responses 100-160 ms after the stimulus onset in the right precentral cortex, close to the known location of the right frontal eye field. In subjects whose right precentral region was not distinctly active before 160 ms, focused attention commonly enhanced right inferior parietal responses between 180 and 240 ms, whereas in the subjects with clear earlier precentral response no parietal enhancement was detected. In control studies both attended and nonattended stimuli in the peripheral visual field evoked the right precentral response, whereas during auditory attention the visual stimuli failed to evoke such response. These results show that during focused visual attention the right precentral cortex is sensitive to stimuli in all parts of the visual field. A rapid response suggests bypassing of elaborate analysis of stimulus features, possibly to encode target location for a saccade or redirection of attention. In addition, load for frontal and parietal nodi of the attentional network seem to vary between individuals.

Developmental dyslexia is often associated with problems in phonological processing based on, or accompanied by, deficits in the perception of rapid auditory changes. Thirteen dyslexic adults and 18 control subjects were tested on sequences of alternating tones of high (1000 Hz) and low (400 Hz) pitch, which at short stimulus onset asynchronies (SOAs) led to perceptual separation of the sound sequence into high- and low-pitched streams. The control subjects perceived the tone sequence as connected down to SOAs of 130 ms, with segregation of the streams at shorter SOAs; in dyslexic subjects the segregation occurred already at 210 ms. Auditory stream segregation has previously been shown to impair the detection of phoneme order in segments of speech sounds. The observed aberrant segregation of sound streams in dyslexic subjects might thus contribute to their difficulties in achieving awareness of phonemes or phoneme order and in the acquisition of literacy.