Early inhaled isoflurane sedation in neurocritical patients with invasive intracranial pressure monitoring: The NEURO-CONDA randomized pilot trial

Early inhaled isoflurane sedation in neurocritical patients with invasive intracranial pressure monitoring: The NEURO-CONDA randomized pilot trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Early inhaled isoflurane sedation in neurocritical patients with invasive intracranial pressure monitoring: The NEURO-CONDA randomized pilot trial Cristina Murcia-Gubianas, Marina Vilà-Rivas, Laia Tarré Ferré, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9150218/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 11 You are reading this latest preprint version Abstract Purpose: Evidence regarding inhaled sedation in neurocritically ill patients remains limited, mainly due to concerns about potential increases in intracranial pressure (ICP). We aimed to evaluate the efficacy and safety of isoflurane compared with propofol in invasively monitored neurocritical patients. Methods: NEURO-CONDA is a phase IV, randomized, open-label, parallel-group pilot trial conducted in a tertiary ICU (May 2024–October 2025). Adult neurocritical patients requiring ICP monitoring and without intracranial hypertension were randomized to receive either propofol or isoflurane. The primary endpoints were efficacy (assessed with RASS and BIS™) and safety, defined as the occurrence of serious adverse drug reactions (ADRs), including sustained ICP elevation or cerebral perfusion pressure (CPP) <60 mmHg requiring increased vasopressor support. Nociception (NOL®) and other systemic parameters were recorded for up to 72 hours. Analyses were performed according to the intention-to-treat principle. Results: Thirty patients were included (15 per group), with comparable baseline characteristics; 17 had traumatic brain injury (TBI). Sedation efficacy was 100% in both groups. No serious ADRs occurred. ICP and CPP remained stable throughout the study period and were not increased in the isoflurane group at any time point. Vasopressor requirements, ICU length of stay, and mortality were similar between groups. Conclusions: In this randomized pilot trial, early sedation with isoflurane was feasible and achieved reliable deep sedation without compromising intracranial or cerebral perfusion parameters in invasively monitored neurocritical patients. Larger randomized studies are warranted to confirm these findings and assess long-term neurological outcomes. Figures Figure 1 Figure 2 Figure 3 INTRODUCTION Sedation and analgesia are essential components of the management of critically ill patients, allowing for the control of pain, anxiety, and agitation, as well as adequate adaptation to mechanical ventilation (MV). In neurocritically ill patients, sedation acquires additional complexity, as it must contribute to the control of intracranial pressure (ICP), preserve cerebral perfusion, decrease cerebral metabolic demand, and prevent secondary insults that could worsen the primary brain injury, such as the onset of seizures or cortical spreading depression (CSD) ( 1 – 3 ). Traditionally, intravenous sedation with propofol or benzodiazepines has been the predominant strategy in intensive care units (ICUs). However, prolonged administration is associated with several limitations, including metabolite accumulation, development of tolerance and tachyphylaxis, prolonged times to awakening, an increased risk of delirium, risk of hypertriglyceridemia, and propofol-related infusion syndrome (PRIS). These drawbacks have driven the search for alternative strategies. Inhalation sedation with isoflurane, widely used in surgical settings, has recently been introduced in ICUs, primarily in Europe ( 4 ). Its pharmacodynamic and pharmacokinetic characteristics could offer significant advantages in the sedation of patients with acute brain injury. These include minimal renal and hepatic metabolism, shorter time to cognitive recovery, the absence of tachyphylaxis, tolerance, and withdrawal, the ability to promote spontaneous ventilation by facilitating respiratory drive, the potential opioid-sparing and muscle-relaxant effect, and other neuroprotective properties under investigation (anticonvulsant, preconditioning to cerebral hypoxia) ( 5 ). Despite this, its use to date has been limited, mainly due to concerns about a possible increase in ICP and a decrease in cerebral perfusion pressure (CPP) secondary to its cerebral and systemic vasodilatory effects, respectively ( 6 ). Consequently, scientific evidence for the use of isoflurane in neurocritically ill patients is scarce. METHODS Study design and population This is a phase IV, randomized, open-label, parallel-group pilot trial that included neurocritical patients with traumatic brain injury (TBI), stroke and intracranial hemorrhage. The recruitment period spanned from May 2024 to October 2025. Patients underwent an inclusion process followed by randomization, and each enrolled patient was assigned to one of two treatment arms (allocation ratio 1:1): a control group receiving propofol or an experimental group receiving isoflurane via the Sedaconda ACD-S® device (Sedana Medical). Data were collected at six time points (0, 1 12, 24, 48 and 72 hours). The study was approved by the Research Ethics Committee for Medicinal Products of our center (CEIm 2024.011) and the Spanish Agency for Medicines and Health Products (AEMPS -CTIS 2024-512077-27-00) and was conducted in accordance with the principles of the Declaration of Helsinki. Given the clinical status of the included patients, informed consent was obtained from their legal representatives. Patients over 18 years who, due to their clinical condition and the criteria of their attending physician, required ICP monitoring and whose ICP value was within the normal range (< 22 mmHg) were included. Patients with intracranial hypertension, initial values of regional cerebral oxygen saturation (rSO2) < 50%, severe hypoxemia (pO2 0.6) and/or high positive end-expiratory pressure (PEEP) values (> 10cmH2O), shock with vasoactive support with norepinephrine > 0.5 mcg/kg/min and/or lactate > 2.5mmol/L, pregnant patients, patients with any contraindication to isoflurane administration, patients at the end of life or admitted for donation purposes, and those with refusal of informed consent by family member/legal representative were excluded. Objectives The primary objective was to evaluate the efficacy and safety of isoflurane compared to propofol. Efficacy was defined as the sedative’s ability to achieve the target level of sedation. Safety was defined by the percentage of serious adverse drug reactions (ADRs) detected in each group: increased intracranial pressure (ICP) > 25 mmHg for > 5 minutes, ICP > 22 mmHg for 30 minutes or unresponsive to standard treatment, cerebral perfusion pressure (CPP) 20% of usual doses, or rSO2 20% from baseline. These criteria were used to discontinue the sedative therapy under study. Secondary objectives were to assess analgesic status using data provided by NOL® (Medasense), record various complementary neuromonitoring parameters, and perform exhaustive monitoring of respiratory and hemodynamic parameters as well as the need for vasoactive support throughout the various study cut-off points. Demographic and systemic variables Baseline variables collected included demographic data, comorbidity (Charlson Comorbidity Index (CCI)), and severity (Simplified Acute Physiology Score (SAPS II)), as well as hospital admission characteristics (days of MV, length of stay, and mortality in the ICU and hospital), neurological diagnosis at admission, and initial Glasgow Coma Scale (GCS) score. In addition, vital signs, vasopressor doses, laboratory and respiratory variables were recorded at each cutoff point during the study period. Monitoring of sedation and nociception In all patients, the degree of sedation was monitored using the Bispectral Index System (BIS™, Medtronic) and the Richmond Agitation-Sedation Scale (RASS), both standard monitoring methods used in cases of deep sedation in the ICU. For patients sedated with isoflurane, the level of expired gas was also monitored using a dedicated gas analyzer (Phillips). Nociception was assessed using the Nociception Level Index (NOL®) device with the PMD200 platform (Medasense). In patients requiring neuromuscular blockade, the Train of Four (TOF®- Phillips NMT module) was used, although subsequent analysis was not performed because only two patients required it. The presence of subsequent delirium was not monitored because the Confusion Assessment Method in the ICU (CAM-ICU) scale is not validated in neurocritically ill patients ( 2 ). Neuromonitoring Neuromonitoring included continuous ICP measurement using a parenchymal sensor (Raumedic) and calculation of CPP (CPP = Mean Arterial Pressure - ICP). Additionally, rSO2 was monitored using an INVOS 7100 monitor with bifrontal near-infrared spectroscopy (NIRS) technology (Medtronic), as well as various cerebral blood flow parameters assessed by transcranial Doppler (TCD) and optic nerve sheath diameter (ONSD) (GE Healthcare). Statistical analysis and sample size calculation The statistical analysis was conducted according to the intention-to-treat principle and included all randomized patients according to their assigned group, regardless of the strategy ultimately received or any potential protocol deviations. The distribution of continuous variables was evaluated through graphical inspection and the Shapiro-Wilk test. Variables with an approximately normal distribution were described as mean and standard deviation, whereas those not normally distributed were expressed as median and interquartile range. Categorical variables were summarized as absolute frequencies and percentages. Baseline comparability between the inhaled sedation group with isoflurane and the conventional intravenous sedation group with propofol was evaluated using the Student's t-test for independent samples or the Mann-Whitney U test as appropriate, and using the chi-square test or Fisher's exact test for categorical variables. Given the pilot nature of the study, these comparisons were considered descriptive and no adjustments for multiplicity were performed. An exploratory analysis was performed in the subpopulation of patients with traumatic brain injury, replicating the main analytical strategy. These results were considered descriptive given the limitation of the sample size. All statistical tests were two-sided and a value of less than 0.05 was considered statistically significant. Statistical analyzes were performed using RStudio statistical software, version 4.5.2. Given the design of the study, a formal sample size calculation was not required ( 7 ). However, general rules for determining an appropriate sample size for a pilot study have been described in the scientific literature. For two-group studies, it is recommended to recruit between 24 and 40 patients in total ( 8 , 9 ). Therefore, with 15 patients per group, we meet these general recommendations. RESULTS Study population Thirty patients were included, reaching the sample size planned for the pilot study (Fig. 1). Demographic, clinical, and severity characteristics are shown in Table 1 , revealing statistically comparable groups. The process resulted in a balanced distribution of patients with traumatic brain injury (TBI), thus classifying them as a comparable, homogeneous subpopulation. Efficacy and safety The sedation target set by the attending physician during the study period was deep sedation. Efficacy was 100%, with no differences in RASS and BIS™ values obtained according to the sedative (Table 2 , Fig. 2) . Exhaled gas values measured by the analyzer ranged from 0.2 to 0.5%. Neuromonitoring safety parameters including ICP and CPP, remained stable throughout the study period in both groups. Lower ICP values were detected at 48 and 72 hours, and higher CPP values were observed at 72 hours in the isoflurane study group (Table 2 , Fig. 3 ). The required norepinephrine doses were not statistically different. Furthermore, no patients experienced serious ADRs, nor were any hepatic ( 10 ) or renal ( 11 ) related to sedation recorded during the study period. Finally, ICU and hospital mortality rates were similar. Analgesia and other parameters According to the established interpretation ranges, NOL® values 25 with underanalgesia ( 12 ). At almost all of the analyzed cut-off points, more than 70% of patients presented NOL® values < 10, with no differences between groups ( Supplementary Table 1 ). Additional monitoring using NIRS and DTT was available for all patients ( Supplementary Table 2 ). The ICP waveform morphology showed a similar distribution between groups, with adequate compliance in 17 patients and impaired compliance in 12 (1 missing value). The analytical evaluation and respiratory parameters are detailed in Supplementary Tables 3 and 4. Subanalysis in TBI In the subgroup of patients with TBI (n = 17), baseline characteristics were comparable between both groups ( Supplementary Table 5 ). Sedation efficacy was 100% throughout the study period ( Supplementary Table 6 ), and no significant differences were found in any of the variables studied ( Supplementary Tables 6 and 7 ). Supplementary Fig. 1 shows the evolution of ICP values over the study period in both groups. Neurological follow-up was available at 6 months in this subgroup using the Glasgow Outcome Scale–Extended (GOSE) ( 13 ) in 10 patients. The distribution of scores is specified in Supplementary Fig. 2 . PRACTICAL APPROACH First, we believe that administering inhaled sedation requires a learning curve for the entire treatment team through the application of standardized protocols. An interesting finding, likely resulting from prior experience, is that the initial isoflurane doses required averaged 1.8 cc/h, lower than the standard (3 cc/h). In 100% of cases, the Sedaconda ACD-S® device could be placed in the standard position without clinically relevant respiratory repercussions ( Supplementary Table 2 ). The maximum doses administered during the evaluation period averaged 5 cc/h. Second, sedation administration is dynamic over time and must be based on close multimodal monitoring ( 14 ). In the specific case of neurocritically ill patients, the concept of a vulnerable brain ( 15 ) must be considered, which necessitates more precise individualization of sedation. The incorporation of the density spectral array ( 16 ) can be very useful for more rigorous refining and adapting to the prior presence of brain damage (baseline activity). Other potentially useful tools in this same area include the estimation of the individualized optimal BIS™( 17 ) as well as the integration of multimodal parameters such as brain tissue oxygen partial pressure (PbtO₂), the pressure reactivity index (PRx), the mean flow index (Mx), or cerebral microdialysis. Finally, another major drawback in monitoring is the lack of validated tools for detecting nociception in critically ill, deeply sedated patients ( 18 ). DISCUSSION To our knowledge, NEURO-CONDA is the first randomized clinical trial evaluating early inhaled isoflurane sedation in neurocritical patients undergoing invasive ICP monitoring. Unlike previous reports in which inhaled sedation was introduced as a late switch strategy, our study specifically addresses the acute and most vulnerable phase of brain injury. In this context, early isoflurane sedation achieved consistent deep sedation while maintaining ICP and CPP stability, without an increased need for vasopressor support. These findings provide prospective data to inform the safety profile of inhaled sedation in a population traditionally considered at high risk for cerebral hemodynamic instability. The first noteworthy bibliographic reference appears in 2012, when Bösel et al. ( 19 ) published a study that included 19 patients undergoing MV and diagnosed with neurocritical conditions (subarachnoid hemorrhage (SAH), intracranial hemorrhage, and ischemic stroke) who underwent a switch from intravenous to inhaled sedation. They concluded that the increase in ICP values was not clinically relevant, although MAP and CPP did decrease. These findings are interesting because hypotension secondary to sedation can compromise cerebral perfusion. In our study, the need for vasopressor support did not show significant differences between groups, and even the ICP and CPP values over the days showed a better profile in the experimental group. Isoflurane is known to induce dose-dependent cerebral vasodilatation ( 20 ). However, in our cohort ICP remained stable throughout the observation period, suggesting that the relatively low concentrations used for ICU sedatives may limit clinically relevant intracranial effects when strict multimodal monitoring is applied. This hypothesis corresponds with the cerebral vascular resistance values, which remained within normal ranges in both groups. An additional noteworthy finding from neuromonitoring was the decrease in ICP observed in the isoflurane-treated group, which reached statistical significance compared to the group undergoing intravenous sedation at 48 hours (p = 0.049) and 72 hours (p = 0.029) (see Table 2 ). The observed reduction in ICP at 48 and 72 hours raises the hypothesis that sustained exposure to low-dose isoflurane may induce adaptive cerebrovascular responses. In patients with preserved autoregulation, compensatory vasoconstrictive mechanisms may offset vasodilatory effects, maintaining intracranial stability. Confirmation of this hypothesis requires future studies incorporating dynamic autoregulation monitoring (PRx, Mx) ( 17 ). Furthermore, although approximately half of the sample showed an alteration in the ICP waveform morphology, the possible secondary increase in cerebral blood flow did not translate into an increase in ICP values. This could indicate that the hemodynamic effect of isoflurane was limited, or that sufficient compensatory mechanisms existed to prevent a significant clinical impact on ICP. Finally, it is possible that the patients' overall clinical context, along with the applied neurocritical management strategy, contributes to maintaining cerebral hemodynamic stability, minimizing any potential impact of isoflurane on ICP. Taken together, these factors could explain why, despite the vasodilatory effect described in the literature ( 21 – 23 ), this effect in our study was not significant in terms of decreasing resistance or increasing ICP. To date, only a limited number of clinical studies ( 24 , 25 ) have evaluated the use of isoflurane sedation in neurocritical ill patients. Preclinical studies ( 28 , 29 ), including experimental models of SAH, suggest that isoflurane may exert anti-inflammatory effects and reduce the incidence of CSD. In our cohort, the TBI subgroup, representing the majority of patients, showed results consistent with the overall population, with no evidence of ICP increase or CPP deterioration. Although the sample size was small (n = 17), these findings are noteworthy, as previous studies specifically evaluating early isoflurane sedation in neurocritical TBI patients are lacking. Sevoflurane has also been explored in neurocritical care as an inhaled alternative to intravenous agents. However, differences in pharmacokinetics and pharmacodynamics between sevoflurane and isoflurane should be considered. Furthermore, isoflurane is the only volatile agent authorized for use in ICUs ( 30 ). Regarding nociception monitoring, an interesting finding of our study is that most patients presented NOL® values < 10. Incorporating objective nociception monitoring in states of deep sedation, where behavioral scales are not valid, could allow for a reduction in opioid exposure regardless of the type of sedation. Few studies to date validate its use in the ICU (12,31). LIMITATIONS This study has several limitations. First, its small sample size and single-center design, as it is a pilot study, limits its statistical power. Second, the open-label design may introduce clinical management bias, although the use of monitored endpoints partially mitigates this effect. Finally, it was not designed to assess long-term clinical outcomes such as delirium, duration of MV, or functional recovery; therefore, no conclusions can be drawn regarding neurological prognosis. It is important to note that our cohort did not include patients with SAH since our hospital is not a designated center for this condition. Therefore, these results should be interpreted as physiological safety rather than evidence of clinical superiority. CONCLUSIONS In this randomized pilot trial, early inhaled sedation with isoflurane was feasible and associated with a safety profile comparable to that of conventional intravenous sedation in neurocritically ill patients undergoing invasive neuromonitoring. Our findings suggest that, with prior experience, strict multimodal monitoring, and appropriate patient selection, inhaled sedation can be used from early stages without compromising neurological control. This approach may facilitate more predictable neurological wake-up assessments and potentially reduce complications associated with prolonged intravenous sedation. Larger, prospective, randomized studies are needed to confirm these findings and evaluate the impact of inhaled sedation on both ICU outcomes and medium- to long-term neurological prognosis. Declarations Ethics approval and consent to participate The study was approved by the Research Ethics Committee for Medicinal Products of our center (CEIm 2024.011) and the Spanish Agency for Medicines and Health Products (AEMPS -CTIS 2024-512077-27-00) and was conducted in accordance with the principles of the Declaration of Helsinki. Given the clinical status of the included patients, informed consent was obtained from their legal representatives. Consent for publication Not applicable Competing interests The authors declare that they have no competing interests. Funding No specific funding was received for this study. Author Contribution C.M.-G. conceived and designed the study.All authors contributed to data collection.All authors analyzed and interpreted the data.C.M.-G. contributed to methodology and supervision.M.V.-R. drafted the manuscript.M.V.-R. and J.M.S. prepared the figures.C.M.-G. critically revised the manuscript for important intellectual content.All authors read and approved the final manuscript and agree to be accountable for all aspects of the work. Acknowledgements Not applicable Data Availability The datasets used and analysed during the current study are available from the corresponding author on reasonable request.All data generated or analysed during this study are included in this published article and its supplementary information files. References Oddo M, Crippa IA, Mehta S, Menon D, Payen JF, Taccone FS, et al. Optimizing sedation in patients with acute brain injury. Crit Care diciembre de. 2016;20(1):128. 10.1186/s13054-016-1294-5 . 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Supplementary Files SUPPLEMENTARYMATERIALNEUROCONDARANDOMIZEDPILOTTRIAL.pdf TABLE1NEUROCONDARANDOMIZEDPILOTTRIAL.docx TABLE2NEUROCONDARANDOMIZEDPILOTTRIAL.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 08 Apr, 2026 Reviews received at journal 07 Apr, 2026 Reviews received at journal 05 Apr, 2026 Reviews received at journal 24 Mar, 2026 Reviewers agreed at journal 24 Mar, 2026 Reviewers agreed at journal 24 Mar, 2026 Reviewers agreed at journal 24 Mar, 2026 Reviewers invited by journal 24 Mar, 2026 Editor assigned by journal 20 Mar, 2026 Submission checks completed at journal 20 Mar, 2026 First submitted to journal 17 Mar, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Murcia-Gubianas","email":"data:image/png;base64,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","orcid":"","institution":"Hospital Universitari de Girona Doctor Josep Trueta","correspondingAuthor":true,"prefix":"","firstName":"Cristina","middleName":"","lastName":"Murcia-Gubianas","suffix":""},{"id":611593203,"identity":"492c86af-5768-4dbe-aa1e-c51a27a09a60","order_by":1,"name":"Marina Vilà-Rivas","email":"","orcid":"","institution":"Hospital Universitari de Girona Doctor Josep Trueta","correspondingAuthor":false,"prefix":"","firstName":"Marina","middleName":"","lastName":"Vilà-Rivas","suffix":""},{"id":611593206,"identity":"78bcbf84-61f7-412a-a0ae-7934ba160084","order_by":2,"name":"Laia Tarré Ferré","email":"","orcid":"","institution":"Hospital Universitari de Girona Doctor Josep Trueta","correspondingAuthor":false,"prefix":"","firstName":"Laia","middleName":"Tarré","lastName":"Ferré","suffix":""},{"id":611593208,"identity":"9a12c7ad-b3b9-4fdb-b089-6c203ce0f83c","order_by":3,"name":"Cristina Fuster Bertolin","email":"","orcid":"","institution":"Hospital Universitari de Girona Doctor Josep Trueta","correspondingAuthor":false,"prefix":"","firstName":"Cristina","middleName":"Fuster","lastName":"Bertolin","suffix":""},{"id":611593210,"identity":"de4fd9a8-e7ea-49da-92f3-cfacbd880a99","order_by":4,"name":"Patricia Sebastián Cernuda","email":"","orcid":"","institution":"Hospital Universitari de Girona Doctor Josep Trueta","correspondingAuthor":false,"prefix":"","firstName":"Patricia","middleName":"Sebastián","lastName":"Cernuda","suffix":""},{"id":611593213,"identity":"08458204-d4ab-422b-afb1-3ce213504b36","order_by":5,"name":"María Luisa Palomanes Espadalé","email":"","orcid":"","institution":"Hospital Universitari de Girona Doctor Josep Trueta","correspondingAuthor":false,"prefix":"","firstName":"María","middleName":"Luisa Palomanes","lastName":"Espadalé","suffix":""},{"id":611593216,"identity":"4c858c91-5017-4854-8140-8f35d2e7fc37","order_by":6,"name":"Joan Martínez Sancho","email":"","orcid":"","institution":"Institut d'Investigació Biomèdica de Girona","correspondingAuthor":false,"prefix":"","firstName":"Joan","middleName":"Martínez","lastName":"Sancho","suffix":""},{"id":611593218,"identity":"e7717bc0-ff6d-449e-b186-70e78af9a556","order_by":7,"name":"Carol Lorencio","email":"","orcid":"","institution":"Hospital Universitari de Girona Doctor Josep Trueta","correspondingAuthor":false,"prefix":"","firstName":"Carol","middleName":"","lastName":"Lorencio","suffix":""}],"badges":[],"createdAt":"2026-03-17 14:53:36","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9150218/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9150218/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":105566456,"identity":"1100b18c-bbc7-40e8-8afe-dd5e8b2fa95e","added_by":"auto","created_at":"2026-03-27 12:56:27","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":611525,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"FIGURE1NEUROCONDARANDOMIZEDPILOTTRIAL.png","url":"https://assets-eu.researchsquare.com/files/rs-9150218/v1/f6c4c6682b721dc1820f87d9.png"},{"id":105477384,"identity":"5d35467f-cddf-43b5-b097-bce395f1878c","added_by":"auto","created_at":"2026-03-26 13:07:06","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":317115,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"FIGURE2NEUROCONDARANDOMIZEDPILOTTRIAL.png","url":"https://assets-eu.researchsquare.com/files/rs-9150218/v1/e864f22f50046ae5031ddf0c.png"},{"id":105566859,"identity":"7fae7c9f-611e-4127-9ee4-6f69f2ad0f28","added_by":"auto","created_at":"2026-03-27 12:57:34","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":340597,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"FIGURE3NEUROCONDARANDOMIZEDPILOTTRIAL.png","url":"https://assets-eu.researchsquare.com/files/rs-9150218/v1/b6b3925de1261464e8066d74.png"},{"id":105570229,"identity":"bd82ec3a-10d7-41fb-977b-c2544966e0ce","added_by":"auto","created_at":"2026-03-27 13:15:34","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1881427,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9150218/v1/e03e2d6b-b51f-4166-9e54-bf7d812b3edb.pdf"},{"id":105477386,"identity":"52d650a4-eb7d-4842-aa06-b8538789d725","added_by":"auto","created_at":"2026-03-26 13:07:06","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":2333174,"visible":true,"origin":"","legend":"","description":"","filename":"SUPPLEMENTARYMATERIALNEUROCONDARANDOMIZEDPILOTTRIAL.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9150218/v1/3867b3487cc679c1b2943d21.pdf"},{"id":105477385,"identity":"cb5842f8-ad81-4097-9117-4fef14faae9e","added_by":"auto","created_at":"2026-03-26 13:07:06","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":186360,"visible":true,"origin":"","legend":"","description":"","filename":"TABLE1NEUROCONDARANDOMIZEDPILOTTRIAL.docx","url":"https://assets-eu.researchsquare.com/files/rs-9150218/v1/279507d395eb172c00edeada.docx"},{"id":105567077,"identity":"b8219fd5-2a8d-4b87-b75f-36c3cc6b705d","added_by":"auto","created_at":"2026-03-27 12:58:14","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":363658,"visible":true,"origin":"","legend":"","description":"","filename":"TABLE2NEUROCONDARANDOMIZEDPILOTTRIAL.docx","url":"https://assets-eu.researchsquare.com/files/rs-9150218/v1/beea4a32fe0b556aa8d4fd69.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Early inhaled isoflurane sedation in neurocritical patients with invasive intracranial pressure monitoring: The NEURO-CONDA randomized pilot trial","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eSedation and analgesia are essential components of the management of critically ill patients, allowing for the control of pain, anxiety, and agitation, as well as adequate adaptation to mechanical ventilation (MV). In neurocritically ill patients, sedation acquires additional complexity, as it must contribute to the control of intracranial pressure (ICP), preserve cerebral perfusion, decrease cerebral metabolic demand, and prevent secondary insults that could worsen the primary brain injury, such as the onset of seizures or cortical spreading depression (CSD) (\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Traditionally, intravenous sedation with propofol or benzodiazepines has been the predominant strategy in intensive care units (ICUs). However, prolonged administration is associated with several limitations, including metabolite accumulation, development of tolerance and tachyphylaxis, prolonged times to awakening, an increased risk of delirium, risk of hypertriglyceridemia, and propofol-related infusion syndrome (PRIS). These drawbacks have driven the search for alternative strategies. Inhalation sedation with isoflurane, widely used in surgical settings, has recently been introduced in ICUs, primarily in Europe (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Its pharmacodynamic and pharmacokinetic characteristics could offer significant advantages in the sedation of patients with acute brain injury. These include minimal renal and hepatic metabolism, shorter time to cognitive recovery, the absence of tachyphylaxis, tolerance, and withdrawal, the ability to promote spontaneous ventilation by facilitating respiratory drive, the potential opioid-sparing and muscle-relaxant effect, and other neuroprotective properties under investigation (anticonvulsant, preconditioning to cerebral hypoxia) (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Despite this, its use to date has been limited, mainly due to concerns about a possible increase in ICP and a decrease in cerebral perfusion pressure (CPP) secondary to its cerebral and systemic vasodilatory effects, respectively (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Consequently, scientific evidence for the use of isoflurane in neurocritically ill patients is scarce.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and population\u003c/h2\u003e \u003cp\u003eThis is a phase IV, randomized, open-label, parallel-group pilot trial that included neurocritical patients with traumatic brain injury (TBI), stroke and intracranial hemorrhage. The recruitment period spanned from May 2024 to October 2025. Patients underwent an inclusion process followed by randomization, and each enrolled patient was assigned to one of two treatment arms (allocation ratio 1:1): a control group receiving propofol or an experimental group receiving isoflurane via the Sedaconda ACD-S\u0026reg; device (Sedana Medical). Data were collected at six time points (0, 1 12, 24, 48 and 72 hours). The study was approved by the Research Ethics Committee for Medicinal Products of our center (CEIm 2024.011) and the Spanish Agency for Medicines and Health Products (AEMPS -CTIS 2024-512077-27-00) and was conducted in accordance with the principles of the Declaration of Helsinki. Given the clinical status of the included patients, informed consent was obtained from their legal representatives. Patients over 18 years who, due to their clinical condition and the criteria of their attending physician, required ICP monitoring and whose ICP value was within the normal range (\u0026lt;\u0026thinsp;22 mmHg) were included. Patients with intracranial hypertension, initial values of regional cerebral oxygen saturation (rSO2)\u0026thinsp;\u0026lt;\u0026thinsp;50%, severe hypoxemia (pO2\u0026thinsp;\u0026lt;\u0026thinsp;60mmHg), high inspiratory oxygen fraction (FiO2) requirements (\u0026gt;\u0026thinsp;0.6) and/or high positive end-expiratory pressure (PEEP) values (\u0026gt;\u0026thinsp;10cmH2O), shock with vasoactive support with norepinephrine\u0026thinsp;\u0026gt;\u0026thinsp;0.5 mcg/kg/min and/or lactate\u0026thinsp;\u0026gt;\u0026thinsp;2.5mmol/L, pregnant patients, patients with any contraindication to isoflurane administration, patients at the end of life or admitted for donation purposes, and those with refusal of informed consent by family member/legal representative were excluded.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eObjectives\u003c/h3\u003e\n\u003cp\u003eThe primary objective was to evaluate the efficacy and safety of isoflurane compared to propofol. Efficacy was defined as the sedative\u0026rsquo;s ability to achieve the target level of sedation. Safety was defined by the percentage of serious adverse drug reactions (ADRs) detected in each group: increased intracranial pressure (ICP)\u0026thinsp;\u0026gt;\u0026thinsp;25 mmHg for \u0026gt;\u0026thinsp;5 minutes, ICP\u0026thinsp;\u0026gt;\u0026thinsp;22 mmHg for 30 minutes or unresponsive to standard treatment, cerebral perfusion pressure (CPP)\u0026thinsp;\u0026lt;\u0026thinsp;60 mmHg requiring vasopressor support\u0026thinsp;\u0026gt;\u0026thinsp;20% of usual doses, or rSO2\u0026thinsp;\u0026lt;\u0026thinsp;50% for 30 minutes or a decrease\u0026thinsp;\u0026gt;\u0026thinsp;20% from baseline. These criteria were used to discontinue the sedative therapy under study. Secondary objectives were to assess analgesic status using data provided by NOL\u0026reg; (Medasense), record various complementary neuromonitoring parameters, and perform exhaustive monitoring of respiratory and hemodynamic parameters as well as the need for vasoactive support throughout the various study cut-off points.\u003c/p\u003e\n\u003ch3\u003eDemographic and systemic variables\u003c/h3\u003e\n\u003cp\u003eBaseline variables collected included demographic data, comorbidity (Charlson Comorbidity Index (CCI)), and severity (Simplified Acute Physiology Score (SAPS II)), as well as hospital admission characteristics (days of MV, length of stay, and mortality in the ICU and hospital), neurological diagnosis at admission, and initial Glasgow Coma Scale (GCS) score. In addition, vital signs, vasopressor doses, laboratory and respiratory variables were recorded at each cutoff point during the study period.\u003c/p\u003e\n\u003ch3\u003eMonitoring of sedation and nociception\u003c/h3\u003e\n\u003cp\u003eIn all patients, the degree of sedation was monitored using the Bispectral Index System (BIS\u0026trade;, Medtronic) and the Richmond Agitation-Sedation Scale (RASS), both standard monitoring methods used in cases of deep sedation in the ICU. For patients sedated with isoflurane, the level of expired gas was also monitored using a dedicated gas analyzer (Phillips). Nociception was assessed using the Nociception Level Index (NOL\u0026reg;) device with the PMD200 platform (Medasense). In patients requiring neuromuscular blockade, the Train of Four (TOF\u0026reg;- Phillips NMT module) was used, although subsequent analysis was not performed because only two patients required it. The presence of subsequent delirium was not monitored because the Confusion Assessment Method in the ICU (CAM-ICU) scale is not validated in neurocritically ill patients (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003ch3\u003eNeuromonitoring\u003c/h3\u003e\n\u003cp\u003eNeuromonitoring included continuous ICP measurement using a parenchymal sensor (Raumedic) and calculation of CPP (CPP\u0026thinsp;=\u0026thinsp;Mean Arterial Pressure - ICP). Additionally, rSO2 was monitored using an INVOS 7100 monitor with bifrontal near-infrared spectroscopy (NIRS) technology (Medtronic), as well as various cerebral blood flow parameters assessed by transcranial Doppler (TCD) and optic nerve sheath diameter (ONSD) (GE Healthcare).\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis and sample size calculation\u003c/h2\u003e \u003cp\u003eThe statistical analysis was conducted according to the intention-to-treat principle and included all randomized patients according to their assigned group, regardless of the strategy ultimately received or any potential protocol deviations. The distribution of continuous variables was evaluated through graphical inspection and the Shapiro-Wilk test. Variables with an approximately normal distribution were described as mean and standard deviation, whereas those not normally distributed were expressed as median and interquartile range. Categorical variables were summarized as absolute frequencies and percentages. Baseline comparability between the inhaled sedation group with isoflurane and the conventional intravenous sedation group with propofol was evaluated using the Student's t-test for independent samples or the Mann-Whitney U test as appropriate, and using the chi-square test or Fisher's exact test for categorical variables. Given the pilot nature of the study, these comparisons were considered descriptive and no adjustments for multiplicity were performed. An exploratory analysis was performed in the subpopulation of patients with traumatic brain injury, replicating the main analytical strategy. These results were considered descriptive given the limitation of the sample size. All statistical tests were two-sided and a value of less than 0.05 was considered statistically significant. Statistical analyzes were performed using RStudio statistical software, version 4.5.2. Given the design of the study, a formal sample size calculation was not required (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). However, general rules for determining an appropriate sample size for a pilot study have been described in the scientific literature. For two-group studies, it is recommended to recruit between 24 and 40 patients in total (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Therefore, with 15 patients per group, we meet these general recommendations.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eStudy population\u003c/h2\u003e \u003cp\u003eThirty patients were included, reaching the sample size planned for the pilot study (Fig.\u0026nbsp;1). Demographic, clinical, and severity characteristics are shown in \u003cb\u003eTable\u0026nbsp;1\u003c/b\u003e, revealing statistically comparable groups. The process resulted in a balanced distribution of patients with traumatic brain injury (TBI), thus classifying them as a comparable, homogeneous subpopulation.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eEfficacy and safety\u003c/h2\u003e \u003cp\u003eThe sedation target set by the attending physician during the study period was deep sedation. Efficacy was 100%, with no differences in RASS and BIS\u0026trade; values obtained according to the sedative (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e2\u003c/span\u003e, \u003cb\u003eFig.\u0026nbsp;2)\u003c/b\u003e. Exhaled gas values measured by the analyzer ranged from 0.2 to 0.5%. Neuromonitoring safety parameters including ICP and CPP, remained stable throughout the study period in both groups. Lower ICP values were detected at 48 and 72 hours, and higher CPP values were observed at 72 hours in the isoflurane study group (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e2\u003c/span\u003e, \u003cb\u003eFig.\u0026nbsp;3\u003c/b\u003e). The required norepinephrine doses were not statistically different. Furthermore, no patients experienced serious ADRs, nor were any hepatic (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) or renal (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e) related to sedation recorded during the study period. Finally, ICU and hospital mortality rates were similar.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eAnalgesia and other parameters\u003c/h2\u003e \u003cp\u003eAccording to the established interpretation ranges, NOL\u0026reg; values\u0026thinsp;\u0026lt;\u0026thinsp;10 are associated with overanalgesia, values between 10 and 25 with adequate analgesia, and values\u0026thinsp;\u0026gt;\u0026thinsp;25 with underanalgesia (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). At almost all of the analyzed cut-off points, more than 70% of patients presented NOL\u0026reg; values\u0026thinsp;\u0026lt;\u0026thinsp;10, with no differences between groups (\u003cb\u003eSupplementary Table\u0026nbsp;1\u003c/b\u003e). Additional monitoring using NIRS and DTT was available for all patients (\u003cb\u003eSupplementary Table\u0026nbsp;2\u003c/b\u003e). The ICP waveform morphology showed a similar distribution between groups, with adequate compliance in 17 patients and impaired compliance in 12 (1 missing value). The analytical evaluation and respiratory parameters are detailed in \u003cb\u003eSupplementary Tables\u0026nbsp;3 and 4.\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eSubanalysis in TBI\u003c/h2\u003e \u003cp\u003eIn the subgroup of patients with TBI (n\u0026thinsp;=\u0026thinsp;17), baseline characteristics were comparable between both groups (\u003cb\u003eSupplementary Table\u0026nbsp;5\u003c/b\u003e). Sedation efficacy was 100% throughout the study period (\u003cb\u003eSupplementary Table\u0026nbsp;6\u003c/b\u003e), and no significant differences were found in any of the variables studied (\u003cb\u003eSupplementary Tables\u0026nbsp;6 and 7\u003c/b\u003e). \u003cb\u003eSupplementary Fig.\u0026nbsp;1\u003c/b\u003e shows the evolution of ICP values over the study period in both groups. Neurological follow-up was available at 6 months in this subgroup using the Glasgow Outcome Scale\u0026ndash;Extended (GOSE) (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e) in 10 patients. The distribution of scores is specified in \u003cb\u003eSupplementary Fig.\u0026nbsp;2\u003c/b\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003ePRACTICAL APPROACH\u003c/h2\u003e \u003cp\u003eFirst, we believe that administering inhaled sedation requires a learning curve for the entire treatment team through the application of standardized protocols. An interesting finding, likely resulting from prior experience, is that the initial isoflurane doses required averaged 1.8 cc/h, lower than the standard (3 cc/h). In 100% of cases, the Sedaconda ACD-S\u0026reg; device could be placed in the standard position without clinically relevant respiratory repercussions (\u003cb\u003eSupplementary Table\u0026nbsp;2\u003c/b\u003e). The maximum doses administered during the evaluation period averaged 5 cc/h. Second, sedation administration is dynamic over time and must be based on close multimodal monitoring (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). In the specific case of neurocritically ill patients, the concept of a vulnerable brain (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e) must be considered, which necessitates more precise individualization of sedation. The incorporation of the density spectral array (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e) can be very useful for more rigorous refining and adapting to the prior presence of brain damage (baseline activity). Other potentially useful tools in this same area include the estimation of the individualized optimal BIS\u0026trade;(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e) as well as the integration of multimodal parameters such as brain tissue oxygen partial pressure (PbtO₂), the pressure reactivity index (PRx), the mean flow index (Mx), or cerebral microdialysis. Finally, another major drawback in monitoring is the lack of validated tools for detecting nociception in critically ill, deeply sedated patients (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eTo our knowledge, NEURO-CONDA is the first randomized clinical trial evaluating early inhaled isoflurane sedation in neurocritical patients undergoing invasive ICP monitoring. Unlike previous reports in which inhaled sedation was introduced as a late switch strategy, our study specifically addresses the acute and most vulnerable phase of brain injury. In this context, early isoflurane sedation achieved consistent deep sedation while maintaining ICP and CPP stability, without an increased need for vasopressor support. These findings provide prospective data to inform the safety profile of inhaled sedation in a population traditionally considered at high risk for cerebral hemodynamic instability. The first noteworthy bibliographic reference appears in 2012, when \u003cem\u003eB\u0026ouml;sel et al.\u003c/em\u003e (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e) published a study that included 19 patients undergoing MV and diagnosed with neurocritical conditions (subarachnoid hemorrhage (SAH), intracranial hemorrhage, and ischemic stroke) who underwent a switch from intravenous to inhaled sedation. They concluded that the increase in ICP values was not clinically relevant, although MAP and CPP did decrease. These findings are interesting because hypotension secondary to sedation can compromise cerebral perfusion. In our study, the need for vasopressor support did not show significant differences between groups, and even the ICP and CPP values over the days showed a better profile in the experimental group. Isoflurane is known to induce dose-dependent cerebral vasodilatation (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). However, in our cohort ICP remained stable throughout the observation period, suggesting that the relatively low concentrations used for ICU sedatives may limit clinically relevant intracranial effects when strict multimodal monitoring is applied. This hypothesis corresponds with the cerebral vascular resistance values, which remained within normal ranges in both groups. An additional noteworthy finding from neuromonitoring was the decrease in ICP observed in the isoflurane-treated group, which reached statistical significance compared to the group undergoing intravenous sedation at 48 hours (p\u0026thinsp;=\u0026thinsp;0.049) and 72 hours (p\u0026thinsp;=\u0026thinsp;0.029) (see Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The observed reduction in ICP at 48 and 72 hours raises the hypothesis that sustained exposure to low-dose isoflurane may induce adaptive cerebrovascular responses. In patients with preserved autoregulation, compensatory vasoconstrictive mechanisms may offset vasodilatory effects, maintaining intracranial stability. Confirmation of this hypothesis requires future studies incorporating dynamic autoregulation monitoring (PRx, Mx) (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Furthermore, although approximately half of the sample showed an alteration in the ICP waveform morphology, the possible secondary increase in cerebral blood flow did not translate into an increase in ICP values. This could indicate that the hemodynamic effect of isoflurane was limited, or that sufficient compensatory mechanisms existed to prevent a significant clinical impact on ICP. Finally, it is possible that the patients' overall clinical context, along with the applied neurocritical management strategy, contributes to maintaining cerebral hemodynamic stability, minimizing any potential impact of isoflurane on ICP. Taken together, these factors could explain why, despite the vasodilatory effect described in the literature (\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e), this effect in our study was not significant in terms of decreasing resistance or increasing ICP. To date, only a limited number of clinical studies (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e) have evaluated the use of isoflurane sedation in neurocritical ill patients. Preclinical studies (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e), including experimental models of SAH, suggest that isoflurane may exert anti-inflammatory effects and reduce the incidence of CSD. In our cohort, the TBI subgroup, representing the majority of patients, showed results consistent with the overall population, with no evidence of ICP increase or CPP deterioration. Although the sample size was small (n\u0026thinsp;=\u0026thinsp;17), these findings are noteworthy, as previous studies specifically evaluating early isoflurane sedation in neurocritical TBI patients are lacking.\u003c/p\u003e \u003cp\u003e Sevoflurane has also been explored in neurocritical care as an inhaled alternative to intravenous agents. However, differences in pharmacokinetics and pharmacodynamics between sevoflurane and isoflurane should be considered. Furthermore, isoflurane is the only volatile agent authorized for use in ICUs (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eRegarding nociception monitoring, an interesting finding of our study is that most patients presented NOL\u0026reg; values\u0026thinsp;\u0026lt;\u0026thinsp;10. Incorporating objective nociception monitoring in states of deep sedation, where behavioral scales are not valid, could allow for a reduction in opioid exposure regardless of the type of sedation. Few studies to date validate its use in the ICU (12,31).\u003c/p\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eLIMITATIONS\u003c/h2\u003e \u003cp\u003eThis study has several limitations. First, its small sample size and single-center design, as it is a pilot study, limits its statistical power. Second, the open-label design may introduce clinical management bias, although the use of monitored endpoints partially mitigates this effect. Finally, it was not designed to assess long-term clinical outcomes such as delirium, duration of MV, or functional recovery; therefore, no conclusions can be drawn regarding neurological prognosis. It is important to note that our cohort did not include patients with SAH since our hospital is not a designated center for this condition. Therefore, these results should be interpreted as physiological safety rather than evidence of clinical superiority.\u003c/p\u003e \u003c/div\u003e"},{"header":"CONCLUSIONS","content":"\u003cp\u003eIn this randomized pilot trial, early inhaled sedation with isoflurane was feasible and associated with a safety profile comparable to that of conventional intravenous sedation in neurocritically ill patients undergoing invasive neuromonitoring. Our findings suggest that, with prior experience, strict multimodal monitoring, and appropriate patient selection, inhaled sedation can be used from early stages without compromising neurological control. This approach may facilitate more predictable neurological wake-up assessments and potentially reduce complications associated with prolonged intravenous sedation. Larger, prospective, randomized studies are needed to confirm these findings and evaluate the impact of inhaled sedation on both ICU outcomes and medium- to long-term neurological prognosis.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e \u003cp\u003eThe study was approved by the Research Ethics Committee for Medicinal Products of our center (CEIm 2024.011) and the Spanish Agency for Medicines and Health Products (AEMPS -CTIS 2024-512077-27-00) and was conducted in accordance with the principles of the Declaration of Helsinki. Given the clinical status of the included patients, informed consent was obtained from their legal representatives.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent for publication\u003c/strong\u003e \u003cp\u003eNot applicable\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eCompeting interests\u003c/h2\u003e \u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eNo specific funding was received for this study.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eC.M.-G. conceived and designed the study.All authors contributed to data collection.All authors analyzed and interpreted the data.C.M.-G. contributed to methodology and supervision.M.V.-R. drafted the manuscript.M.V.-R. and J.M.S. prepared the figures.C.M.-G. critically revised the manuscript for important intellectual content.All authors read and approved the final manuscript and agree to be accountable for all aspects of the work.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003eNot applicable\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets used and analysed during the current study are available from the corresponding author on reasonable request.All data generated or analysed during this study are included in this published article and its supplementary information files.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eOddo M, Crippa IA, Mehta S, Menon D, Payen JF, Taccone FS, et al. 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Disponible en: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://cima.aemps.es/cima/pdfs/es/ft/86293/FT_86293.html.pdf\u003c/span\u003e\u003cspan address=\"https://cima.aemps.es/cima/pdfs/es/ft/86293/FT_86293.html.pdf\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBonvecchio E, Vailati D, Mura FD, Marino G. Nociception level index variations in ICU: curarized vs non-curarized patients \u0026mdash; a pilot study. J Anesth Analg Crit Care 20 de agosto de. 2024;4(1):57. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s44158-024-00193-z\u003c/span\u003e\u003cspan address=\"10.1186/s44158-024-00193-z\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"critical-care","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cric","sideBox":"Learn more about [Critical Care](http://ccforum.biomedcentral.com/)","snPcode":"13054","submissionUrl":"https://submission.nature.com/new-submission/13054/3","title":"Critical Care","twitterHandle":"@Crit_Care","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-9150218/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9150218/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Purpose:\nEvidence regarding inhaled sedation in neurocritically ill patients remains limited, mainly due to concerns about potential increases in intracranial pressure (ICP). We aimed to evaluate the efficacy and safety of isoflurane compared with propofol in invasively monitored neurocritical patients.\n\nMethods:\nNEURO-CONDA is a phase IV, randomized, open-label, parallel-group pilot trial conducted in a tertiary ICU (May 2024–October 2025). Adult neurocritical patients requiring ICP monitoring and without intracranial hypertension were randomized to receive either propofol or isoflurane. The primary endpoints were efficacy (assessed with RASS and BIS™) and safety, defined as the occurrence of serious adverse drug reactions (ADRs), including sustained ICP elevation or cerebral perfusion pressure (CPP) \u003c60 mmHg requiring increased vasopressor support. Nociception (NOL®) and other systemic parameters were recorded for up to 72 hours. Analyses were performed according to the intention-to-treat principle.\n\nResults:\nThirty patients were included (15 per group), with comparable baseline characteristics; 17 had traumatic brain injury (TBI). Sedation efficacy was 100% in both groups. No serious ADRs occurred. ICP and CPP remained stable throughout the study period and were not increased in the isoflurane group at any time point. Vasopressor requirements, ICU length of stay, and mortality were similar between groups. \n\nConclusions:\nIn this randomized pilot trial, early sedation with isoflurane was feasible and achieved reliable deep sedation without compromising intracranial or cerebral perfusion parameters in invasively monitored neurocritical patients. Larger randomized studies are warranted to confirm these findings and assess long-term neurological outcomes.","manuscriptTitle":"Early inhaled isoflurane sedation in neurocritical patients with invasive intracranial pressure monitoring: The NEURO-CONDA randomized pilot trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-26 13:07:01","doi":"10.21203/rs.3.rs-9150218/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-08T05:38:24+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-07T09:41:07+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-05T06:06:01+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-24T19:59:19+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"80598395678724550884865088129341050434","date":"2026-03-24T18:33:11+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"315961266650721984925031638693391078540","date":"2026-03-24T16:52:43+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"151541966105071984443083484478981176718","date":"2026-03-24T14:25:33+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-24T12:53:37+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-20T04:51:44+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-20T04:50:44+00:00","index":"","fulltext":""},{"type":"submitted","content":"Critical Care","date":"2026-03-17T14:48:30+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"critical-care","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cric","sideBox":"Learn more about [Critical Care](http://ccforum.biomedcentral.com/)","snPcode":"13054","submissionUrl":"https://submission.nature.com/new-submission/13054/3","title":"Critical Care","twitterHandle":"@Crit_Care","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1e346678-fa1d-4158-8451-e22813e79437","owner":[],"postedDate":"March 26th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-15T07:11:24+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-26 13:07:01","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9150218","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9150218","identity":"rs-9150218","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}