Gustavo Balanza Villegas

All Publications

• Development and prospective validation of postoperative pain prediction from preoperative EHR data using attention-based set embeddings. NPJ digital medicine Liu, R., Gutiérrez, R., Mather, R. V., Stone, T. A., Santa Cruz Mercado, L. A., Bharadwaj, K., Johnson, J., Das, P., Balanza, G., Uwanaka, E., Sydloski, J., Chen, A., Hagood, M., Bittner, E. A., Purdon, P. L. 2023; 6 (1): 209

  Abstract

  Preoperative knowledge of expected postoperative pain can help guide perioperative pain management and focus interventions on patients with the greatest risk of acute pain. However, current methods for predicting postoperative pain require patient and clinician input or laborious manual chart review and often do not achieve sufficient performance. We use routinely collected electronic health record data from a multicenter dataset of 234,274 adult non-cardiac surgical patients to develop a machine learning method which predicts maximum pain scores on the day of surgery and four subsequent days and validate this method in a prospective cohort. Our method, POPS, is fully automated and relies only on data available prior to surgery, allowing application in all patients scheduled for or considering surgery. Here we report that POPS achieves state-of-the-art performance and outperforms clinician predictions on all postoperative days when predicting maximum pain on the 0-10 NRS in prospective validation, though with degraded calibration. POPS is interpretable, identifying comorbidities that significantly contribute to postoperative pain based on patient-specific context, which can assist clinicians in mitigating cases of acute pain.

  View details for DOI 10.1038/s41746-023-00947-z

  View details for PubMedID 37973817

  View details for PubMedCentralID 8369227

• Differential cortical network engagement during states of un/consciousness in humans. Neuron Zelmann, R., Paulk, A. C., Tian, F., Balanza Villegas, G. A., Dezha Peralta, J., Crocker, B., Cosgrove, G. R., Richardson, R. M., Williams, Z. M., Dougherty, D. D., Purdon, P. L., Cash, S. S. 2023

  Abstract

  What happens in the human brain when we are unconscious? Despite substantial work, we are still unsure which brain regions are involved and how they are impacted when consciousness is disrupted. Using intracranial recordings and direct electrical stimulation, we mapped global, network, and regional involvement during wake vs. arousable unconsciousness (sleep) vs. non-arousable unconsciousness (propofol-induced general anesthesia). Information integration and complex processing we`re reduced, while variability increased in any type of unconscious state. These changes were more pronounced during anesthesia than sleep and involved different cortical engagement. During sleep, changes were mostly uniformly distributed across the brain, whereas during anesthesia, the prefrontal cortex was the most disrupted, suggesting that the lack of arousability during anesthesia results not from just altered overall physiology but from a disconnection between the prefrontal and other brain areas. These findings provide direct evidence for different neural dynamics during loss of consciousness compared with loss of arousability.

  View details for DOI 10.1016/j.neuron.2023.08.007

  View details for PubMedID 37659409

• Association of Intraoperative Opioid Administration With Postoperative Pain and Opioid Use. JAMA surgery Santa Cruz Mercado, L. A., Liu, R., Bharadwaj, K. M., Johnson, J. J., Gutierrez, R., Das, P., Balanza, G., Deng, H., Pandit, A., Stone, T. A., Macdonald, T., Horgan, C., Tou, S. L., Houle, T. T., Bittner, E. A., Purdon, P. L. 2023; 158 (8): 854-864

  Abstract

  Opioids administered to treat postsurgical pain are a major contributor to the opioid crisis, leading to chronic use in a considerable proportion of patients. Initiatives promoting opioid-free or opioid-sparing modalities of perioperative pain management have led to reduced opioid administration in the operating room, but this reduction could have unforeseen detrimental effects in terms of postoperative pain outcomes, as the relationship between intraoperative opioid usage and later opioid requirements is not well understood.To characterize the association between intraoperative opioid usage and postoperative pain and opioid requirements.This retrospective cohort study evaluated electronic health record data from a quaternary care academic medical center (Massachusetts General Hospital) for adult patients who underwent noncardiac surgery with general anesthesia from April 2016 to March 2020. Patients who underwent cesarean surgery, received regional anesthesia, received opioids other than fentanyl or hydromorphone, were admitted to the intensive care unit, or who died intraoperatively were excluded. Statistical models were fitted on the propensity weighted data set to characterize the effect of intraoperative opioid exposures on primary and secondary outcomes. Data were analyzed from December 2021 to October 2022.Intraoperative fentanyl and intraoperative hydromorphone average effect site concentration estimated using pharmacokinetic/pharmacodynamic models.The primary study outcomes were the maximal pain score during the postanesthesia care unit (PACU) stay and the cumulative opioid dose, quantified in morphine milligram equivalents (MME), administered during the PACU stay. Medium- and long-term outcomes associated with pain and opioid dependence were also evaluated.The study cohort included a total of 61 249 individuals undergoing surgery (mean [SD] age, 55.44 [17.08] years; 32 778 [53.5%] female). Increased intraoperative fentanyl and intraoperative hydromorphone were both associated with reduced maximum pain scores in the PACU. Both exposures were also associated with a reduced probability and reduced total dosage of opioid administration in the PACU. In particular, increased fentanyl administration was associated with lower frequency of uncontrolled pain; a decrease in new chronic pain diagnoses reported at 3 months; fewer opioid prescriptions at 30, 90, and 180 days; and decreased new persistent opioid use, without significant increases in adverse effects.Contrary to prevailing trends, reduced opioid administration during surgery may have the unintended outcome of increasing postoperative pain and opioid consumption. Conversely, improvements in long-term outcomes might be achieved by optimizing opioid administration during surgery.

  View details for DOI 10.1001/jamasurg.2023.2009

  View details for PubMedID 37314800

  View details for PubMedCentralID PMC10267849

• A Narrative Review Illustrating the Clinical Utility of Electroencephalogram-Guided Anesthesia Care in Children ANESTHESIA AND ANALGESIA Bong, C., Balanza, G. A., Khoo, C., Tan, J., Desel, T., Purdon, P. 2023; 137 (1): 108-123

  Abstract

  The major therapeutic end points of general anesthesia include hypnosis, amnesia, and immobility. There is a complex relationship between general anesthesia, responsiveness, hemodynamic stability, and reaction to noxious stimuli. This complexity is compounded in pediatric anesthesia, where clinicians manage children from a wide range of ages, developmental stages, and body sizes, with their concomitant differences in physiology and pharmacology. This renders anesthetic requirements difficult to predict based solely on a child's age, body weight, and vital signs. Electroencephalogram (EEG) monitoring provides a window into children's brain states and may be useful in guiding clinical anesthesia management. However, many clinicians are unfamiliar with EEG monitoring in children. Young children's EEGs differ substantially from those of older children and adults, and there is a lack of evidence-based guidance on how and when to use the EEG for anesthesia care in children. This narrative review begins by summarizing what is known about EEG monitoring in pediatric anesthesia care. A key knowledge gap in the literature relates to a lack of practical information illustrating the utility of the EEG in clinical management. To address this gap, this narrative review illustrates how the EEG spectrogram can be used to visualize, in real time, brain responses to anesthetic drugs in relation to hemodynamic stability, surgical stimulation, and other interventions such as cardiopulmonary bypass. This review discusses anesthetic management principles in a variety of clinical scenarios, including infants, children with altered conscious levels, children with atypical neurodevelopment, children with hemodynamic instability, children undergoing total intravenous anesthesia, and those undergoing cardiopulmonary bypass. Each scenario is accompanied by practical illustrations of how the EEG can be visualized to help titrate anesthetic dosage to avoid undersedation or oversedation when patients experience hypotension or other physiological challenges, when surgical stimulation increases, and when a child's anesthetic requirements are otherwise less predictable. Overall, this review illustrates how well-established clinical management principles in children can be significantly complemented by the addition of EEG monitoring, thus enabling personalized anesthesia care to enhance patient safety and experience.

  View details for DOI 10.1213/ANE.0000000000006267

  View details for Web of Science ID 001012135200017

  View details for PubMedID 36729437

• Association of Intraoperative Opioid Administration With Postoperative Pain and Opioid Use JAMA SURGERY Mercado, L. A., Liu, R., Bharadwaj, K. M., Johnson, J. J., Gutierrez, R., Das, P., Balanza, G., Deng, H., Pandit, A., Stone, T. D., Macdonald, T., Horgan, C., Tou, S., Houle, T. T., Bittner, E. A., Purdon, P. L. 2023

  View details for DOI 10.1001/jamasurg.2023.2009

  View details for Web of Science ID 001012129000006

• Characterizing brain dynamics during ketamine-induced dissociation and subsequent interactions with propofol using human intracranial neurophysiology. Nature communications Tian, F., Lewis, L. D., Zhou, D. W., Balanza, G. A., Paulk, A. C., Zelmann, R., Peled, N., Soper, D., Santa Cruz Mercado, L. A., Peterfreund, R. A., Aglio, L. S., Eskandar, E. N., Cosgrove, G. R., Williams, Z. M., Richardson, R. M., Brown, E. N., Akeju, O., Cash, S. S., Purdon, P. L. 2023; 14 (1): 1748

  Abstract

  Ketamine produces antidepressant effects in patients with treatment-resistant depression, but its usefulness is limited by its psychotropic side effects. Ketamine is thought to act via NMDA receptors and HCN1 channels to produce brain oscillations that are related to these effects. Using human intracranial recordings, we found that ketamine produces gamma oscillations in prefrontal cortex and hippocampus, structures previously implicated in ketamine's antidepressant effects, and a 3 Hz oscillation in posteromedial cortex, previously proposed as a mechanism for its dissociative effects. We analyzed oscillatory changes after subsequent propofol administration, whose GABAergic activity antagonizes ketamine's NMDA-mediated disinhibition, alongside a shared HCN1 inhibitory effect, to identify dynamics attributable to NMDA-mediated disinhibition versus HCN1 inhibition. Our results suggest that ketamine engages different neural circuits in distinct frequency-dependent patterns of activity to produce its antidepressant and dissociative sensory effects. These insights may help guide the development of brain dynamic biomarkers and novel therapeutics for depression.

  View details for DOI 10.1038/s41467-023-37463-3

  View details for PubMedID 36991011

  View details for PubMedCentralID PMC10060225

• Sevoflurane requirements during electroencephalogram (EEG)-guided vs standard anesthesia Care in Children: A randomized controlled trial. Journal of clinical anesthesia Long, M. H., Lim, E. H., Balanza, G. A., Allen, J. C., Purdon, P. L., Bong, C. L. 2022; 81: 110913

  Abstract

  Intra-operative electroencephalographic (EEG) monitoring utilizing the spectrogram allows visualization of children's brain response during anesthesia and may complement routine cardiorespiratory monitoring to facilitate titration of anesthetic doses. We aimed to determine if EEG-guided anesthesia will result in lower sevoflurane requirements, lower incidence of burst suppression and improved emergence characteristics in children undergoing routine general anesthesia, compared to standard care.Randomized controlled trial.Tertiary pediatric hospital.200 children aged 1 to 6 years, ASA 1 or 2, undergoing routine sevoflurane anesthesia for minor surgery lasting 30 to 240 min.Children were randomized to either EEG-guided anesthesia (EEG-G) or standard care (SC). EEG-G group had sevoflurane titrated to maintain continuous slow/delta oscillations on the raw EEG and spectrogram, aiming to avoid burst suppression and, as far as possible, maintain a patient state index (PSI) between 25 and50. SC group received standard anesthesia care and the anesthesia teams were blinded to EEG waveforms.The primary outcomes were the average end-tidal sevoflurane concentration during induction and maintenance of anesthesia. Secondary outcomes include incidence and duration of intra-operative burst suppression and Pediatric Anesthesia Emergence Delirium (PAED) scores.The EEG-G group received lower end-tidal sevoflurane concentrations during induction [4.80% vs 5.67%, -0.88% (-1.45, -0.31) p = 0.003] and maintenance of anesthesia [2.23% vs 2.38%, -0.15% (-0.25, -0.05) p = 0.005], and had a lower incidence of burst suppression [3.1% vs 10.9%, p = 0.044] compared to the SC group. PAED scores were similar between groups. Children <2 years old required higher average end-tidal sevoflurane concentrations, regardless of group.EEG-guided anesthesia care reduces sevoflurane requirements in children undergoing general anesthesia, possibly lowering the incidence of burst suppression, without altering emergence characteristics. EEG monitoring allows direct visualization of brain responses in real time and allows clearer appreciation of varying sevoflurane requirements in children of different ages.

  View details for DOI 10.1016/j.jclinane.2022.110913

  View details for PubMedID 35772250

• An electroencephalogram biomarker of fentanyl drug effects. PNAS nexus Balanza, G. A., Bharadwaj, K. M., Mullen, A. C., Beck, A. M., Work, E. C., McGovern, F. J., Houle, T. T., Eric, T. P., Purdon, P. L. 2022; 1 (4): pgac158

  Abstract

  Opioid drugs influence multiple brain circuits in parallel to produce analgesia as well as side effects, including respiratory depression. At present, we do not have real-time clinical biomarkers of these brain effects. Here, we describe the results of an experiment to characterize the electroencephalographic signatures of fentanyl in humans. We find that increasing concentrations of fentanyl induce a frontal theta band (4 to 8 Hz) signature distinct from slow-delta oscillations related to sleep and sedation. We also report that respiratory depression, quantified by decline in an index of instantaneous minute ventilation, occurs at ≈1700-fold lower concentrations than those that produce sedation as measured by reaction time. The electroencephalogram biomarker we describe could facilitate real-time monitoring of opioid drug effects and enable more precise and personalized opioid administration.

  View details for DOI 10.1093/pnasnexus/pgac158

  View details for PubMedID 36329725

  View details for PubMedCentralID PMC9615126