Measurements of adequacy of anesthesia and level of consciousness during surgery and intensive care

The adequacy of anesthesia has been studied since the introduction of balanced general anesthesia. Commercial monitors based on electroencephalographic (EEG) signal analysis have been available for monitoring the hypnotic component of anesthesia from the beginning of the 1990s. Monitors measuring the depth of anesthesia assess the cortical function of the brain, and have gained acceptance during surgical anesthesia with most of the anesthetic agents used. However, due to frequent artifacts, they are considered unsuitable for monitoring consciousness in intensive care patients. The assessment of analgesia is one of the cornerstones of general anesthesia. Prolonged surgical stress may lead to increased morbidity and delayed postoperative recovery. However, no validated monitoring method is currently available for evaluating analgesia during general anesthesia. Awareness during anesthesia is caused by an inadequate level of hypnosis. This rare but severe complication of general anesthesia may lead to marked emotional stress and possibly posttraumatic stress disorder. In the present series of studies, the incidence of awareness and recall during outpatient anesthesia was evaluated and compared with that of in inpatient anesthesia. A total of 1500 outpatients and 2343 inpatients underwent a structured interview. Clear intraoperative recollections were rare the incidence being 0.07% in outpatients and 0.13% in inpatients. No significant differences emerged between outpatients and inpatients. However, significantly smaller doses of sevoflurane were administered to outpatients with awareness than those without recollections (p<0.05). EEG artifacts in 16 brain-dead organ donors were evaluated during organ harvest surgery in a prospective, open, nonselective study. The source of the frontotemporal biosignals in brain-dead subjects was studied, and the resistance of bispectral index (BIS) and Entropy to the signal artifacts was compared. The hypothesis was that in brain-dead subjects, most of the biosignals recorded from the forehead would consist of artifacts. The original EEG was recorded and State Entropy (SE), Response Entropy (RE), and BIS were calculated and monitored during solid organ harvest. SE differed from zero (inactive EEG) in 28%, RE in 29%, and BIS in 68% of the total recording time (p<0.0001 for all). The median values during the operation were SE 0.0, RE 0.0, and BIS 3.0. In four of the 16 organ donors, EEG was not inactive, and unphysiologically distributed, nonreactive rhythmic theta activity was present in the original EEG signal. After the results from subjects with persistent residual EEG activity were excluded, SE, RE, and BIS differed from zero in 17%, 18%, and 62% of the recorded time, respectively (p<0.0001 for all). Due to various artifacts, the highest readings in all indices were recorded without neuromuscular blockade. The main sources of artifacts were electrocauterization, electromyography (EMG), 50-Hz artifact, handling of the donor, ballistocardiography, and electrocardiography. In a prospective, randomized study of 26 patients, the ability of Surgical Stress Index (SSI) to differentiate patients with two clinically different analgesic levels during shoulder surgery was evaluated. SSI values were lower in patients with an interscalene brachial plexus block than in patients without an additional plexus block. In all patients, anesthesia was maintained with desflurane, the concentration of which was targeted to maintain SE at 50. Increased blood pressure or heart rate (HR), movement, and coughing were considered signs of intraoperative nociception and treated with alfentanil. Photoplethysmographic waveforms were collected from the contralateral arm to the operated side, and SSI was calculated offline. Two minutes after skin incision, SSI was not increased in the brachial plexus block group and was lower (38 ± 13) than in the control group (58 ± 13, p<0.005). Among the controls, one minute prior to alfentanil administration, SSI value was higher than during periods of adequate antinociception, 59 ± 11 vs. 39 ± 12 (p<0.01). The total cumulative need for alfentanil was higher in controls (2.7 ± 1.2 mg) than in the brachial plexus block group (1.6 ± 0.5 mg, p=0.008). Tetanic stimulation to the ulnar region of the hand increased SSI significantly only among patients with a brachial plexus block not covering the site of stimulation. Prognostic value of EEG-derived indices was evaluated and compared with Transcranial Doppler Ultrasonography (TCD), serum neuron-specific enolase (NSE) and S-100B after cardiac arrest. Thirty patients resuscitated from out-of-hospital arrest and treated with induced mild hypothermia for 24 h were included. Original EEG signal was recorded, and burst suppression ratio (BSR), RE, SE, and wavelet subband entropy (WSE) were calculated. Neurological outcome during the six-month period after arrest was assessed with the Glasgow-Pittsburgh Cerebral Performance Categories (CPC). Twenty patients had a CPC of 1-2, one patient had a CPC of 3, and nine patients died (CPC 5). BSR, RE, and SE differed between good (CPC 1-2) and poor (CPC 3-5) outcome groups (p=0.011, p=0.011, p=0.008, respectively) during the first 24 h after arrest. WSE was borderline higher in the good outcome group between 24 and 48 h after arrest (p=0.050). All patients with status epilepticus died, and their WSE values were lower (p=0.022). S-100B was lower in the good outcome group upon arrival at the intensive care unit (p=0.010). After hypothermia treatment, NSE and S-100B values were lower (p=0.002 for both) in the good outcome group. The pulsatile index was also lower in the good outcome group (p=0.004). In conclusion, the incidence of awareness in outpatient anesthesia did not differ from that in inpatient anesthesia. Outpatients are not at increased risk for intraoperative awareness relative to inpatients undergoing general anesthesia. SE, RE, and BIS showed non-zero values that normally indicate cortical neuronal function, but were in these subjects mostly due to artifacts after clinical brain death diagnosis. Entropy was more resistant to artifacts than BIS. During general anesthesia and surgery, SSI values were lower in patients with interscalene brachial plexus block covering the sites of nociceptive stimuli. In detecting nociceptive stimuli, SSI performed better than HR, blood pressure, or RE. BSR, RE, and SE differed between the good and poor neurological outcome groups during the first 24 h after cardiac arrest, and they may be an aid in differentiating patients with good neurological outcomes from those with poor outcomes after out-of-hospital cardiac arrest.Anestesian syvyyden riittävyyttä on tutkittu yhtä kauan kuin yleisanestesioita on annettu. Rutiinikäyttöön soveltuvia aivosähkökäyrään (EEG) perustuvia anestesian syvyyttä mittaavia laitteita on ollut markkinoilla 1990-luvulta alkaen. Nämä aivojen kortikaalista toimintaa mittaavat laitteet kuvaavat unen syvyyttä ja toimivat luotettavasti yleisimmin käytössä olevien nukutusaineiden kanssa. Lukuisat ulkoiset tekijät aiheuttavat kuitenkin häiriöitä indekseihin, mikä on toistaiseksi estänyt mittarien luotettavan käytön tehohoidossa. Vaikka kivunhoito on yksi merkittävimmistä yleisanestesian komponenteista, luotettavaa kipumittaria ei toistaiseksi ole ollut markkinoilla. Anestesian aikainen hereilläolo on harvinainen mutta vakava komplikaatio, joka voi johtaa huomattavalla osalla potilaista posttraumaattisen stressireaktion syntyyn. Tutkimuksessa verrattiin 1500 päiväkirurgista potilasta 2343 vuodeosastolta käsin leikattuun potilaaseen. Haastattelututkimukseen perustuen selkeitä anestesian aikaisia muistikuvia esiintyi 0.07 % päiväkirurgisista ja 0.13 % osastopotilaista. Ryhmien välillä ei todettu tilastollisesti merkitsevää eroa. Ne päiväkirurgiset potilaat, joilla todettiin anestesian aikainen hereillä olo, saivat merkittävästi vähemmän hypnoottista ainetta (sevofluraania) kuin ne potilaat, joilla tätä komplikaatiota ei esiintynyt. Aivosähkökäyrään vaikuttavia häiriötekijöitä tutkittiin 16 kliinisesti aivokuolleelta elinluovuttajalta. Anestesian aikana käytettäviä unen syvyyttä kuvaavia mittareita, BIS (bispektraali-indeksi)- ja Entropia-monitoria (SE= State Entropy, RE= Response Entropy), käytettiin otsalta kerätyn biosignaalin rekisteröimiseen. Tutkimuksen hypoteesina oli, että valtaosa rekisteröidystä biosignaalista koostuisi aivokuolleilla elinluovuttajilla EEG-rekisteröintiä häiritsevistä artefakteista. Elinluovutusleikkauksen aikana BIS oli herkempi häiriötekijöille ja erosi indeksi-luvusta nolla (inaktiivinen EEG) 68 % rekisteröintiajasta. SE poikkesi nollasta 28 ja RE 29 % rekisteröintiajasta. Leikkauksen yhteydessä käytettävien sähköisten laitteiden, elinluovuttajan liikuttelun sekä jäljellä olevan lihas- ja sydämen sähköisen toiminnan aiheuttamat muutokset olivat pääasialliset BIS- ja Entropia-monitorointia häiritsevät tekijät elinluovutusleikkauksen aikana. Anestesian aikaista reagoimattomuutta kipuun tutkittiin uuden, kajoamattoman mittarin, SSI:n (Surgical Stress Index, myöhemmin SPI, Surgical Pleth Index) avulla 26 olkapääleikkaukseen tulleella potilaalla. SSI lasketaan sormesta mitattavan sykeaallon amplitudiin ja sydämen syketaajuuteen perustuen, joten sen lukuarvo suurenee sympaattisen stimulaation lisääntyessä. SSI-lukema oli alhaisempi potilailla, jotka saivat leikkausta edeltävästi olkapunoksen sentraalisen puudutuksen kuin potilailla, jotka leikattiin ilman puudutusta. Kaikki potilaat nukutettiin toimenpiteen ajaksi ja anestesian syvyyttä kontrolloitiin pitämällä SE tasolla 50 desfluraani-annosta nostamalla tai laskemalla. Kohonnut pulssi- tai verenpainetaso, potilaan liikkuminen, kyynelehtiminen tai yskiminen tulkittiin merkiksi riittämättömästä kipulääketasosta, mikä hoidettiin alfentaniili-lääkityksellä. Kahden minuutin kuluttua ihoviillosta mitattuna SSI ei noussut alkutasoon verrattuna olkapunospuudutuksen saaneilla potilailla ja oli merkitsevästi matalampi kuin puuduttamattomilla verrokkipotilailla. Verrokkipotilailla minuutti ennen kipulääketarvetta mitattu SSI oli huomattavasti korkeampi kuin SSI samoilla potilailla ajanjaksoina, jolloin kipulääkitystä ei tarvittu. Leikkauksenaikainen kumulatiivinen kipulääkityksen määrä oli suurempi potilailla, jotka eivät saaneet puudutusta leikkausta edeltävästi. Olkapunoksen puudutuksen saaneiden potilaiden joukossa standardisoituna kipuärsytyksenä käytetty tetaaninen ärsytys nosti SSI-lukemaa ainoastaan niillä potilailla, joilla puutunut alue ei kattanut kipuärsytysaluetta. Onnistuneestikin elvytetyille sydämenpysähdyspotilaille jää usein eriasteisia neurologisia vaurioita. Aikaisemmissa tutkimuksissa on saatu viitteitä siitä, että aivosähkökäyrä (EEG) kertoo neurologisesta toipumisesta, mutta tulkinnan vaikeus on rajoittanut sen käyttöä teho-osastoilla. EEG:stä johdettujen indeksien toimivuutta neurologisen ennustearvion tekemisessä tutkittiin kolmellakymmenellä sairaalan ulkopuolella kammiovärinästä elvytetyllä potilaalla, jotka saivat teho-osastolla aivoja suojaavan viilennyshoidon. EEG:stä johdettiin seuraavat kvantitatiiviset suureet: purskevaimentumasuhde (burst suppression ratio, BSR), tilaentropia (state entropy, SE), vaste-entropia (response entropy, RE) ja aallokemuunnoksen osakaistan entropia (wavelet subband entropy, WSE). Iskeemisen aivovaurion merkkiaineista määritettiin seerumin neuronispesifinen enolaasi ja S-100B. Aivojen verenkiertoa mitattiin transkraniaalisella kaikututkimuksella. Tutkimukseen otetuista potilaista 20 toipui neurologisesti hyväkuntoisiksi, yhden potilaan toipuminen oli heikkoa ja yhdeksän potilasta kuoli. Tutkimus osoitti, että neurologisesti hyvin ja heikosti toipuneet erottuivat EEG:n kvantitatiivisten suureiden perusteella jo ensimmäisen tehohoitovuorokauden aikana. Lisäksi kaikki potilaat, joiden EEG:n jälkianalyysissä todettiin kouristukseton epileptinen sarjakohtaus, menehtyivät ja heidän aallokemuunnoksen osakaistan entropiansa oli pienempi kuin neurologisesti hyväkuntoisiksi toipuneilla. Tuloksen perusteella näyttäisi siltä, että aallokemuunnoksen osakaistan vähenevä entropia auttaa havaitsemaan kouristuksettoman epileptisen sarjakohtauksen, jonka ilmaantuminen viittaa erittäin huonoon toipumisennusteeseen. Huonoon ennusteeseen liittyivät myös transkraniaalisen kaikututkimuksen pulssisuusindeksin, S100B:n ja neuronispesifisen enolaasin suuret arvot. Tutkimuksen yhteenvetona voidaan todeta, että päiväkirurgiseen yleisanestesiaan ei liity lisääntynyttä anestesian aikaisen hereillä olon riskiä. Anestesian syvyysmittareiden herkkyys lukuisille häiriötekijöille osoitettiin myös tässä väitöskirjatyössä. Entropia-monitori tunnisti häiriötekijät BIS-monitoria paremmin. Yleisanestesian aikana SSI (SPI)-monitori kuvasi luotettavasti kipulääkityksen (tai kivunhoitotekniikan) ja kirurgisen ärsytyksen välistä tasapainotilaa. EEG:stä johdetut indeksit ennustivat neurologista toipumista luotettavasti jo ensimmäisen elvytyksen jälkeisen vuorokauden aikana. Käytetyt parametrit yksinkertaistavat aivosähkökäyrän tulkintaa ja pitkän aikavälin tavoitteena on kehittää keskushermoston monitorointia siten, että aivojen tilan jatkuva seuranta teho-osastoilla olisi mahdollista ja että hoitohenkilökunta voisi reagoida heti potilaan aivotoiminnan muutoksiin

Novel insights on association and reactivity of Bispectral Index, frontal electromyogram, and autonomic responses in nociception-sedation monitoring of critical care patients

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Dramatic increase in serum trypsinogens, SPINK1 and hCG beta in aortic surgery patients after hypothermic circulatory arrest

The concentrations of several diagnostic markers have been found to increase dramatically in critically ill patients with a severe disturbance of normal physiological homeostasis, without indication of the diseases they are normally associated with. To prevent false diagnoses and inappropriate treatments of critically ill patients, it is important that the markers aiding the selection of second-line treatments are evaluated in such patients and not only in the healthy population and patients with diseases the markers are associated with. The levels of trypsinogen isoenzymes, the trypsin inhibitor serine peptidase inhibitor Kazal type 1 (SPINK1), hCG and hCG beta, which are used as pancreatitis and cancer markers, were analyzed by immunoassays from serum samples of 17 adult patients who have undergone surgery of the ascending aorta during hypothermic circulatory arrest (HCA) with optional selective cerebral perfusion. Highly elevated levels of trypsinogen-1, -2 and -3, SPINK1 and hCG beta were observed in patients after HCA. This was accompanied by increased concentrations of S100 beta and NSE. In conclusion, this study highlights the importance of critically evaluating the markers used for aiding selection of second line of treatments in critically ill patients.Peer reviewe

Noninterventional follow-up vs fluid bolus in RESPONSE to oliguria-The RESPONSE trial protocol and statistical analysis plan

Background Oliguria is a frequent trigger for administering a fluid bolus, but the effect of fluid bolus in improving urine output is inadequately demonstrated. Here, we summarize the protocol and detailed statistical analysis plan of the randomized, controlled RESPONSE trial comparing follow-up as the experimental group and a 500 mL crystalloid fluid bolus as the control group for oliguria in critically ill oliguric patients. Methods Our trial is an investigator-initiated, randomized, controlled, pilot trial conducted in three ICUs in two centers. We aim to randomize 1:1 altogether 130 hemodynamically stable oliguric patients either to a 2-hour follow-up without interventions or to receive a crystalloid bolus of 500 mL over 30 minutes. The primary outcome is the change in individual urine output during the 2-hour period compared to 2 hours preceding randomization. Doubling of the urine output is considered clinically significant. Additionally, we record the duration of oliguria, physiological and biochemical variables, adverse events, and the incidences of acute kidney injury and renal replacement therapy. Conclusions Oliguria is a frequent trigger for potentially harmful fluid loading. Therefore, the RESPONSE trial will give information of the potential effect of fluid bolus on oliguria in critically ill patients. Trial registration clinical.trials.gov, NCT02860572.Peer reviewe

Effect of Inhaled Xenon on Cardiac Function in Comatose Survivors of Out-of-Hospital Cardiac Arrest-A Substudy of the Xenon in Combination With Hypothermia After Cardiac Arrest Trial

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Effect of Inhaled Xenon on Cardiac Function in Comatose Survivors of Out-of-Hospital Cardiac Arrest—A Substudy of the Xenon in Combination With Hypothermia After Cardiac Arrest Trial

OBJECTIVES: This explorative substudy aimed at determining the effect ofinhaled xenon on left ventricular function by echocardiography in comatose survivorsof out-of-hospital cardiac arrest.DESIGN: A randomized two-group single-blinded phase 2 clinical drug trial.SETTING: A multipurpose ICU in two university hospitals.PATIENTS: Of the 110 randomized comatose survivors after out-of-hospital cardiacarrest with a shockable rhythm in the xenon in combination with hypothermiaafter cardiac arrest trial, 38 patients (24–76 yr old) with complete echocardiographywere included in this study.INTERVENTIONS: Patients were randomized to receive either inhaled xenoncombined with hypothermia (33 C) for 24 hours or hypothermia treatment alone.Echocardiography was performed at hospital admission and 24 4 hours afterhypothermia.MEASUREMENTS AND MAIN RESULTS: Left ventricular ejection fraction,myocardial longitudinal systolic strain, and diastolic function were analyzedblinded to treatment. There were 17 xenon and 21 control patients in whom echocardiographywas completed. Clinical characteristics did not differ significantlybetween the groups. At admission, ejection fraction was similar in xenon and controlpatients (39% 10% vs 38% 11%; p = 0.711) but higher in xenon thancontrol patients after hypothermia (50% 10% vs 42% 10%; p = 0.014).Global longitudinal systolic strain was similar in xenon and control patients atadmission (–9.0% 3.8% vs –8.1% 3.6%; p = 0.555) but better in xenonthan control patients after hypothermia (–14.4.0% 4.0% vs –10.5% 4.0%;p = 0.006). In patients with coronary artery disease, longitudinal strain improved inthe nonischemic myocardial segments in xenon patients. There were no changesin diastolic function between the groups.</p

Responsiveness Index versus the RASS-Based Method for Adjusting Sedation in Critically Ill Patients

Publisher Copyright: © 2021 Johanna E. Wennervirta et al.Background. Sedation of intensive care patients is needed for patient safety, but deep sedation is associated with adverse outcomes. Frontal electromyogram-based Responsiveness Index (RI) aims to quantify the level of sedation and is scaled 0-100 (low index indicates deep sedation). We compared RI-based sedation to Richmond Agitation-Sedation Scale- (RASS-) based sedation. Our hypothesis was that RI-controlled sedation would be associated with increased total time alive without mechanical ventilation at 30 days without an increased number of adverse events. Methods. 32 critically ill adult patients with mechanical ventilation and administration of sedation were randomized to either RI- or RASS-guided sedation. Patients received propofol and oxycodone, if possible. The following standardized sedation protocol was utilized in both groups to achieve the predetermined target sedation level: either RI 40-80 (RI group) or RASS -3 to 0 (RASS group). RI measurement was blinded in the RASS group, and the RI group was blinded to RASS assessments. State Entropy (SE) values were registered in both groups. Results. RI and RASS groups did not differ in total time alive in 30 days without mechanical ventilation (p=0.72). The incidence of at least one sedation-related adverse event did not differ between the groups. Hypertension was more common in the RI group (p=0.01). RI group patients were in the target RI level 22% of the time and RASS group patients had 57% of scores within the target RASS level. The RI group spent significantly more time in their target sedation level than the RASS group spent in the corresponding RI level (p=0.03). No difference was observed between the groups (p=0.13) in the corresponding analysis for RASS. Propofol and oxycodone were administered at higher RI and SE values and lower RASS values in the RI group than in the RASS group. Conclusion. Further studies with a larger sample size are warranted to scrutinize the optimal RI level during different phases of critical illness.Peer reviewe