Ravulizumab in Atypical Hemolytic Uremic Syndrome: An Analysis of 2-Year Efficacy and Safety Outcomes in 2 Phase 3 Trials.

Rationale & Objective: Atypical hemolytic uremic syndrome (aHUS) is a rare form of thrombotic microangiopathy (TMA) caused by complement dysregulation. Ravulizumab is a C5i approved for the treatment of aHUS. This analysis assessed long-term outcomes of ravulizumab in adults and pediatric patients with aHUS. Study Design: This analysis reports 2-year data from 2 phase 3, single-arm studies. Setting & Participants: One study included C5i-naïve adults (NCT02949128), and the other included 2 cohorts of pediatric patients (C5i-naïve and those who switched to ravulizumab from eculizumab [pediatric switch patients]; NCT03131219). Exposure: Patients received intravenous ravulizumab every 4-8 weeks, with the dose depending on body weight. Outcomes: The primary endpoint in the studies of C5i-naïve patients was complete TMA response, which consisted of platelet count normalization, lactate dehydrogenase normalization, and ≥25% improvement in serum creatinine concentrations from baseline, at 2 consecutive assessments ≥4 weeks apart. Analytical Approach: All analyses used descriptive statistics. No formal statistical comparisons were performed. Results: In total, 86 and 92 patients were included in efficacy and safety analyses, respectively. Complete TMA response rates over 2 years were 61% and 90% in C5i-naïve adults and pediatric patients, respectively. The median increase in estimated glomerular filtration rate from baseline was maintained over 2 years in C5i-naïve adults (35 mL/min/1.73 m2) and pediatric patients (82.5 mL/min/1.73 m2). Most adverse events and serious adverse events occurred during the first 26 weeks. No meningococcal infections were reported. Improvement in the Functional Assessment of Chronic Illness Therapy - Fatigue score achieved by 26 weeks was maintained over 2 years. Limitations: Limitations were the small sample of pediatric switch patients and limited availability of genetic data. Conclusions: Long-term treatment with ravulizumab is well tolerated and associated with improved hematologic and renal parameters and quality of life in adults and pediatric patients with aHUS.

This research tested a drug called ravulizumab for the treatment of atypical hemolytic uremic syndrome (aHUS). aHUS is a rare disease that causes clots in tiny blood vessels. This can damage the kidneys and other organs. We analyzed data from 2 clinical trials in which children and adults with aHUS received ravulizumab through a tube placed in a vein (intravenous line). They received ravulizumab every 4-8 weeks depending on their weight. We found that treating patients for 2 years with ravulizumab was associated with improved blood health, kidney function, and quality of life and was well tolerated. These results support ravulizumab as a long-term treatment for people with aHUS.

Closed-loop control of anesthetic state in nonhuman primates.

Research in human volunteers and surgical patients has shown that unconsciousness under general anesthesia can be reliably tracked using real-time electroencephalogram processing. Hence, a closed-loop anesthesia delivery (CLAD) system that maintains precisely specified levels of unconsciousness is feasible and would greatly aid intraoperative patient management. The US Federal Drug Administration has approved no CLAD system for human use due partly to a lack of testing in appropriate animal models. To address this key roadblock, we implement a nonhuman primate (NHP) CLAD system that controls the level of unconsciousness using the anesthetic propofol. The key system components are a local field potential (LFP) recording system; propofol pharmacokinetics and pharmacodynamic models; the control variable (LFP power between 20 and 30 Hz), a programmable infusion system and a linear quadratic integral controller. Our CLAD system accurately controlled the level of unconsciousness along two different 125-min dynamic target trajectories for 18 h and 45 min in nine experiments in two NHPs. System performance measures were comparable or superior to those in previous CLAD reports. We demonstrate that an NHP CLAD system can reliably and accurately control in real-time unconsciousness maintained by anesthesia. Our findings establish critical steps for CLAD systems' design and testing prior to human testing.

Perioperative Electroencephalogram Spectral Dynamics Related to Postoperative Delirium in Older Patients.

BACKGROUND: Intraoperative electroencephalography (EEG) signatures related to the development of postoperative delirium (POD) in older patients are frequently studied. However, a broad analysis of the EEG dynamics including preoperative, postinduction, intraoperative and postoperative scenarios and its correlation to POD development is still lacking. We explored the relationship between perioperative EEG spectra-derived parameters and POD development, aiming to ascertain the diagnostic utility of these parameters to detect patients developing POD. METHODS: Patients aged ≥65 years undergoing elective surgeries that were expected to last more than 60 minutes were included in this prospective, observational single center study (Biomarker Development for Postoperative Cognitive Impairment [BioCog] study). Frontal EEGs were recorded, starting before induction of anesthesia and lasting until recovery of consciousness. EEG data were analyzed based on raw EEG files and downloaded excel data files. We performed multitaper spectral analyses of relevant EEG epochs and further used multitaper spectral estimate to calculate a corresponding spectral parameter. POD assessments were performed twice daily up to the seventh postoperative day. Our primary aim was to analyze the relation between the perioperative spectral edge frequency (SEF) and the development of POD. RESULTS: Of the 237 included patients, 41 (17%) patients developed POD. The preoperative EEG in POD patients was associated with lower values in both SEF (POD 13.1 ± 4.6 Hz versus no postoperative delirium [NoPOD] 17.4 ± 6.9 Hz; P = .002) and corresponding γ-band power (POD -24.33 ± 2.8 dB versus NoPOD -17.9 ± 4.81 dB), as well as reduced postinduction absolute α-band power (POD -7.37 ± 4.52 dB versus NoPOD -5 ± 5.03 dB). The ratio of SEF from the preoperative to postinduction state (SEF ratio) was ~1 in POD patients, whereas NoPOD patients showed a SEF ratio >1, thus indicating a slowing of EEG with loss of unconscious. Preoperative SEF, preoperative γ-band power, and SEF ratio were independently associated with POD (P = .025; odds ratio [OR] = 0.892, 95% confidence interval [CI], 0.808-0.986; P = .029; OR = 0.568, 95% CI, 0.342-0.944; and P = .009; OR = 0.108, 95% CI, 0.021-0.568, respectively). CONCLUSIONS: Lower preoperative SEF, absence of slowing in EEG while transitioning from preoperative state to unconscious state, and lower EEG power in relevant frequency bands in both these states are related to POD development. These findings may suggest an underlying pathophysiology and might be used as EEG-based marker for early identification of patients at risk to develop POD.

A hidden Markov model reliably characterizes ketamine-induced spectral dynamics in macaque local field potentials and human electroencephalograms.

Ketamine is an NMDA receptor antagonist commonly used to maintain general anesthesia. At anesthetic doses, ketamine causes high power gamma (25-50 Hz) oscillations alternating with slow-delta (0.1-4 Hz) oscillations. These dynamics are readily observed in local field potentials (LFPs) of non-human primates (NHPs) and electroencephalogram (EEG) recordings from human subjects. However, a detailed statistical analysis of these dynamics has not been reported. We characterize ketamine's neural dynamics using a hidden Markov model (HMM). The HMM observations are sequences of spectral power in seven canonical frequency bands between 0 to 50 Hz, where power is averaged within each band and scaled between 0 and 1. We model the observations as realizations of multivariate beta probability distributions that depend on a discrete-valued latent state process whose state transitions obey Markov dynamics. Using an expectation-maximization algorithm, we fit this beta-HMM to LFP recordings from 2 NHPs, and separately, to EEG recordings from 9 human subjects who received anesthetic doses of ketamine. Our beta-HMM framework provides a useful tool for experimental data analysis. Together, the estimated beta-HMM parameters and optimal state trajectory revealed an alternating pattern of states characterized primarily by gamma and slow-delta activities. The mean duration of the gamma activity was 2.2s([1.7,2.8]s) and 1.2s([0.9,1.5]s) for the two NHPs, and 2.5s([1.7,3.6]s) for the human subjects. The mean duration of the slow-delta activity was 1.6s([1.2,2.0]s) and 1.0s([0.8,1.2]s) for the two NHPs, and 1.8s([1.3,2.4]s) for the human subjects. Our characterizations of the alternating gamma slow-delta activities revealed five sub-states that show regular sequential transitions. These quantitative insights can inform the development of rhythm-generating neuronal circuit models that give mechanistic insights into this phenomenon and how ketamine produces altered states of arousal.

Machine learning of EEG spectra classifies unconsciousness during GABAergic anesthesia.

In current anesthesiology practice, anesthesiologists infer the state of unconsciousness without directly monitoring the brain. Drug- and patient-specific electroencephalographic (EEG) signatures of anesthesia-induced unconsciousness have been identified previously. We applied machine learning approaches to construct classification models for real-time tracking of unconscious state during anesthesia-induced unconsciousness. We used cross-validation to select and train the best performing models using 33,159 2s segments of EEG data recorded from 7 healthy volunteers who received increasing infusions of propofol while responding to stimuli to directly assess unconsciousness. Cross-validated models of unconsciousness performed very well when tested on 13,929 2s EEG segments from 3 left-out volunteers collected under the same conditions (median volunteer AUCs 0.99-0.99). Models showed strong generalization when tested on a cohort of 27 surgical patients receiving solely propofol collected in a separate clinical dataset under different circumstances and using different hardware (median patient AUCs 0.95-0.98), with model predictions corresponding with actions taken by the anesthesiologist during the cases. Performance was also strong for 17 patients receiving sevoflurane (alone or in addition to propofol) (median AUCs 0.88-0.92). These results indicate that EEG spectral features can predict unconsciousness, even when tested on a different anesthetic that acts with a similar neural mechanism. With high performance predictions of unconsciousness, we can accurately monitor anesthetic state, and this approach may be used to engineer infusion pumps to intelligibly respond to patients' neural activity.

Personalized Connectome Mapping to Guide Targeted Therapy and Promote Recovery of Consciousness in the Intensive Care Unit.

There are currently no therapies proven to promote early recovery of consciousness in patients with severe brain injuries in the intensive care unit (ICU). For patients whose families face time-sensitive, life-or-death decisions, treatments that promote recovery of consciousness are needed to reduce the likelihood of premature withdrawal of life-sustaining therapy, facilitate autonomous self-expression, and increase access to rehabilitative care. Here, we present the Connectome-based Clinical Trial Platform (CCTP), a new paradigm for developing and testing targeted therapies that promote early recovery of consciousness in the ICU. We report the protocol for STIMPACT (Stimulant Therapy Targeted to Individualized Connectivity Maps to Promote ReACTivation of Consciousness), a CCTP-based trial in which intravenous methylphenidate will be used for targeted stimulation of dopaminergic circuits within the subcortical ascending arousal network (ClinicalTrials.gov NCT03814356). The scientific premise of the CCTP and the STIMPACT trial is that personalized brain network mapping in the ICU can identify patients whose connectomes are amenable to neuromodulation. Phase 1 of the STIMPACT trial is an open-label, safety and dose-finding study in 22 patients with disorders of consciousness caused by acute severe traumatic brain injury. Patients in Phase 1 will receive escalating daily doses (0.5-2.0 mg/kg) of intravenous methylphenidate over a 4-day period and will undergo resting-state functional magnetic resonance imaging and electroencephalography to evaluate the drug's pharmacodynamic properties. The primary outcome measure for Phase 1 relates to safety: the number of drug-related adverse events at each dose. Secondary outcome measures pertain to pharmacokinetics and pharmacodynamics: (1) time to maximal serum concentration; (2) serum half-life; (3) effect of the highest tolerated dose on resting-state functional MRI biomarkers of connectivity; and (4) effect of each dose on EEG biomarkers of cerebral cortical function. Predetermined safety and pharmacodynamic criteria must be fulfilled in Phase 1 to proceed to Phase 2A. Pharmacokinetic data from Phase 1 will also inform the study design of Phase 2A, where we will test the hypothesis that personalized connectome maps predict therapeutic responses to intravenous methylphenidate. Likewise, findings from Phase 2A will inform the design of Phase 2B, where we plan to enroll patients based on their personalized connectome maps. By selecting patients for clinical trials based on a principled, mechanistic assessment of their neuroanatomic potential for a therapeutic response, the CCTP paradigm and the STIMPACT trial have the potential to transform the therapeutic landscape in the ICU and improve outcomes for patients with severe brain injuries.

Constructing a control-ready model of EEG signal during general anesthesia in humans.

Significant effort toward the automation of general anesthesia has been made in the past decade. One open challenge is in the development of control-ready patient models for closed-loop anesthesia delivery. Standard depth-of-anesthesia tracking does not readily capture inter-individual differences in response to anesthetics, especially those due to age, and does not aim to predict a relationship between a control input (infused anesthetic dose) and system state (commonly, a function of electroencephalography (EEG) signal). In this work, we developed a control-ready patient model for closed-loop propofol-induced anesthesia using data recorded during a clinical study of EEG during general anesthesia in ten healthy volunteers. We used principal component analysis to identify the low-dimensional state-space in which EEG signal evolves during anesthesia delivery. We parameterized the response of the EEG signal to changes in propofol target-site concentration using logistic models. We note that inter-individual differences in anesthetic sensitivity may be captured by varying a constant cofactor of the predicted effect-site concentration. We linked the EEG dose-response with the control input using a pharmacokinetic model. Finally, we present a simple nonlinear model predictive control in silico demonstration of how such a closed-loop system would work.

A simulation-based comparative analysis of PID and LQG control for closed-loop anesthesia delivery.

Closed loop anesthesia delivery (CLAD) systems can help anesthesiologists efficiently achieve and maintain desired anesthetic depth over an extended period of time. A typical CLAD system would use an anesthetic marker, calculated from physiological signals, as real-time feedback to adjust anesthetic dosage towards achieving a desired set-point of the marker. Since control strategies for CLAD vary across the systems reported in recent literature, a comparative analysis of common control strategies can be useful. For a nonlinear plant model based on well-established models of compartmental pharmacokinetics and sigmoid-Emax pharmacodynamics, we numerically analyze the set-point tracking performance of three output-feedback linear control strategies: proportional-integral-derivative (PID) control, linear quadratic Gaussian (LQG) control, and an LQG with integral action (ILQG). Specifically, we numerically simulate multiple CLAD sessions for the scenario where the plant model parameters are unavailable for a patient and the controller is designed based on a nominal model and controller gains are held constant throughout a session. Based on the numerical analyses performed here, conditioned on our choice of model and controllers, we infer that in terms of accuracy and bias PID control performs better than ILQG which in turn performs better than LQG. In the case of noisy observations, ILQG can be tuned to provide a smoother infusion rate while achieving comparable steady state response with respect to PID. The numerical analysis framework and findings reported here can help CLAD developers in their choice of control strategies. This paper may also serve as a tutorial paper for teaching control theory for CLAD.

Cognitive Impairment Is Associated with Absolute Intraoperative Frontal α-Band Power but Not with Baseline α-Band Power: A Pilot Study.

BACKGROUND: Cognitive abilities decline with aging, leading to a higher risk for the development of postoperative delirium or postoperative neurocognitive disorders after general anesthesia. Since frontal α-band power is known to be highly correlated with cognitive function in general, we hypothesized that preoperative cognitive impairment is associated with lower baseline and intraoperative frontal α-band power in older adults. METHODS: Patients aged ≥65 years undergoing elective surgery were included in this prospective observational study. Cognitive function was assessed on the day before surgery using six age-sensitive cognitive tests. Scores on those tests were entered into a principal component analysis to calculate a composite "g score" of global cognitive ability. Patient groups were dichotomized into a lower cognitive group (LC) reaching the lower 1/3 of "g scores" and a normal cognitive group (NC) consisting of the upper 2/3 of "g scores." Continuous pre- and intraoperative frontal electroencephalograms (EEGs) were recorded. EEG spectra were analyzed at baseline, before start of anesthesia medication, and during a stable intraoperative period. Significant differences in band power between the NC and LC groups were computed by using a frequency domain (δ 0.5-3 Hz, θ 4-7 Hz, α 8-12 Hz, ß 13-30 Hz)-based bootstrapping algorithm. RESULTS: Of 38 included patients (mean age 72 years), 24 patients were in the NC group, and 14 patients had lower cognitive abilities (LC). Intraoperative α-band power was significantly reduced in the LC group compared to the NC group (NC -1.6 [-4.48/1.17] dB vs. LC -6.0 [-9.02/-2.64] dB), and intraoperative α-band power was positively correlated with "g score" (Spearman correlation: r = 0.381; p = 0.018). Baseline EEG power did not show any associations with "g." CONCLUSIONS: Preoperative cognitive impairment in older adults is associated with intraoperative absolute frontal α-band power, but not baseline α-band power.

A hidden semi-Markov model for estimating burst suppression EEG.

Burst suppression is an electroencephalogram (EEG) pattern associated with profoundly inactivated brain states characterized by cerebral metabolic depression. This pattern is distinguished by short-duration band-limited electrical activity (bursts) interspersed between relatively near-isoelectric periods (suppressions). Prior work in neurophysiology suggests that burst and suppression segments are respectively associated with consumption and regeneration of adenosine triphosphate resource in cortical networks. This indicates that once a suppression (or, burst) segment begins, the propensity to switch out of the state gradually increases with duration spent in the state. Prior EEG monitoring frameworks that track the brain state during burst suppression by tracking the estimated fraction of time spent in suppression, relative to bursts, do not incorporate this information. In this work, we incorporate this information within a hidden semi-Markov model (HSMM) wherein two states (burst & suppression) stochastically switch between each other using sojourn-time dependent transition probabilities. We demonstrate the HSMM's utility in analyzing clinical data by estimating the state probabilities, the optimal state sequence, and the brain's metabolic activation level characterized by parameters governing sojourn-time dependence in transition probabilities. The HSMM-based approach proposed here provides a novel statistical framework that advances the state-of-the-art in analyzing burst suppression EEG.

A state-space model for dynamic functional connectivity.

Dynamic functional connectivity (DFC) analysis involves measuring correlated neural activity over time across multiple brain regions. Significant regional correlations among neural signals, such as those obtained from resting-state functional magnetic resonance imaging (fMRI), may represent neural circuits associated with rest. The conventional approach of estimating the correlation dynamics as a sequence of static correlations from sliding time-windows has statistical limitations. To address this issue, we propose a multivariate stochastic volatility model for estimating DFC inspired by recent work in econometrics research. This model assumes a state-space framework where the correlation dynamics of a multivariate normal observation sequence is governed by a positive-definite matrix-variate latent process. Using this statistical model within a sequential Bayesian estimation framework, we use blood oxygenation level dependent activity from multiple brain regions to estimate posterior distributions on the correlation trajectory. We demonstrate the utility of this DFC estimation framework by analyzing its performance on simulated data, and by estimating correlation dynamics in resting state fMRI data from a patient with a disorder of consciousness (DoC). Our work advances the state-of-the-art in DFC analysis and its principled use in DoC biomarker exploration.

A Smoother State Space Multitaper Spectrogram.

A recent work (Kim et al. 2018) has reported a novel statistical modeling framework, the State-Space Multitaper (SSMT) method, to estimate time-varying spectral representation of non-stationary time series data. It combines the strengths of the multitaper spectral (MT) analysis paradigm with that of state-space (SS) models. In this current work, we explore a variant of the original SSMT framework by imposing a smoothness promoting SS model to generate smoother estimates of power spectral densities for non-stationary data. Specifically, we assume that the continuous processes giving rise to observations in the frequencies of interest follow multiple independent Integrated Wiener Processes (IWP). We use both synthetic data and electroencephalography (EEG) data collected from a human subject under anesthesia to compare the IWP- SSMT with the SSMT method and demonstrate the former's utility in yielding smoother descriptions of underlying processes. The original SSMT and IWP-SSMT can co-exist as a part of a model selection toolkit for nonstationary time series data.

Pharmacodynamic modeling of propofol-induced general anesthesia in young adults.

Target controlled infusion (TCI) of intraveneous anesthetics can assist clinical practitioners to provide improved care for General Anesthesia (GA). Pharmacokinetic/Pharmacodynamic (PK/PD) models help in relating the anesthetic drug infusion to observed brain activity inferred from electroencephalogram (EEG) signals. The parameters in popular population PK/PD models for propofol-induced GA (Marsh and Schnider models) are either verified based on proprietary functions of the EEG signal which are difficult to correlate with the neurophysiological models of anesthesia, or the marker itself needs to be estimated simultaneously with the PD model. Both these factors make these existing paradigms challenging to apply in real-time context where a patient-specific tuning of parameters is desired. In this work, we propose a simpler EEG marker from frequency domain description of EEG and develop two corresponding PK/PD modeling approaches which differ in whether they use existing population-level PK models (approach 1) or not (approach 2). We use a simple deterministic parameter estimation approach to identify the unknown PK/PD model parameters from an existing human EEG data-set. We infer that both approaches 1 and 2 yield similar and reasonably good fits to the marker data. This work can be useful in developing patient-specific TCI strategies to induce GA.