Impact of severity and age with variable definitions of bronchopulmonary dysplasia on neurodevelopmental outcomes.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is associated with neurodevelopmental impairment (NDI). METHODS: To compare the ability of NICHD 2001 and Jensen 2019 definitions of BPD and respiratory support at 40 weeks postmenstrual age (PMA) to predict NDI, a retrospective study (1/2010-12/2020) was conducted in infants with gestational age <32 weeks and birth weight <1500 g. The primary outcome measure was NDI at 18-24 months corrected age. RESULTS: Of 1119 infants, 227 (20.7%) met the inclusion criteria and had adequate follow-up data. Multivariate regression analysis showed that the NICHD 2001 definition was not predictive of NDI. Infants with Grade 2 or 3 BPD (Jensen 2019) had 4.75 (95% CI: 1.282-17.563) times greater odds of having NDI than infants without BPD. Infants requiring respiratory support at 40 weeks PMA had 4.95 (95% CI: 1.490-16.47) times greater odds of having NDI. Receiver operating characteristic curves demonstrated that the 2 definitions of BPD and the need for respiratory support at 40 weeks PMA were similar in their ability to predict NDI. CONCLUSION: There is no significant difference in the ability of the NICHD 2001 and Jensen 2019 BPD definitions, as well as the need for respiratory support at 40 weeks, for predicting NDI. IMPACT STATEMENT: Current bronchopulmonary dysplasia (BPD) definitions may not effectively predict neurodevelopmental impairment (NDI) in preterm infants. Grades 2/3 BPD (Jensen 2019 criteria) significantly associate with NDI. Infants requiring respiratory support at 40 weeks post-menstrual age (PMA) have 5 times higher odds of NDI than those on room air at 40 weeks PMA. The NICHD 2001, Jensen 2019 definitions, and the requirement for respiratory support at 40 weeks PMA, do not differ in their ability to predict NDI. Future studies should include multiple centers, with level III-IV NICUs, catering to socioeconomic, culturally, and racially diverse populations.

Integrative Pharmacology in the Treatment of Substance Use Disorders.

The detrimental physical, mental, and socioeconomic effects of substance use disorders (SUDs) have been apparent to the medical community for decades. However, it has become increasingly urgent in recent years to develop novel pharmacotherapies to treat SUDs. Currently, practitioners typically rely on monotherapy. Monotherapy has been shown to be superior to no treatment at all for most substance classes. However, many randomized controlled trials (RCTs) have revealed that monotherapy leads to poorer outcomes when compared with combination treatment in all specialties of medicine. The results of RCTs suggest that monotherapy frequently fails since multiple dysregulated pathways, enzymes, neurotransmitters, and receptors are involved in the pathophysiology of SUDs. As such, research is urgently needed to determine how various neurobiological mechanisms can be targeted by novel combination treatments to create increasingly specific yet exceedingly comprehensive approaches to SUD treatment. This article aims to review the neurobiology that integrates many pathophysiologic mechanisms and discuss integrative pharmacology developments that may ultimately improve clinical outcomes for patients with SUDs. Many neurobiological mechanisms are known to be involved in SUDs including dopaminergic, nicotinic, N-methyl-D-aspartate (NMDA), and kynurenic acid (KYNA) mechanisms. Emerging evidence indicates that KYNA, a tryptophan metabolite, modulates all these major pathophysiologic mechanisms. Therefore, achieving KYNA homeostasis by harmonizing integrative pathophysiology and pharmacology could prove to be a better therapeutic approach for SUDs. We propose KYNA-NMDA-α7nAChRcentric pathophysiology, the "conductor of the orchestra," as a novel approach to treat many SUDs concurrently. KYNA-NMDA-α7nAChR pathophysiology may be the "command center" of neuropsychiatry. To date, extant RCTs have shown equivocal findings across comparison conditions, possibly because investigators targeted single pathophysiologic mechanisms, hit wrong targets in underlying pathophysiologic mechanisms, and tested inadequate monotherapy treatment. We provide examples of potential combination treatments that simultaneously target multiple pathophysiologic mechanisms in addition to KYNA. Kynurenine pathway metabolism demonstrates the greatest potential as a target for neuropsychiatric diseases. The investigational medications with the most evidence include memantine, galantamine, and N-acetylcysteine. Future RCTs are warranted with novel combination treatments for SUDs. Multicenter RCTs with integrative pharmacology offer a promising, potentially fruitful avenue to develop novel therapeutics for the treatment of SUDs.

Surge of Midazolam Use in the Midst of Lorazepam Shortage.

BACKGROUND: Lorazepam is a widely prescribed benzodiazepine that is used to manage anxiety, insomnia, and status epilepticus and is used for pre-anesthetic care as well as several off-label indications including aggression, alcohol withdrawal, panic disorder, chemotherapy-associated anticipatory nausea, and catatonia. Recent increases in demand, manufacturing changes, and quality control issues have resulted in a shortage of injectable and oral lorazepam, prompting clinicians to use alternatives. One such alternative is midazolam, a drug that has been used primarily in the intensive care unit and anesthesia settings. PROCEDURES: This article examines the significant pharmacologic differences between lorazepam and midazolam. In addition, this article provides dosage guidelines based on the current scientific knowledge and recommendations for conversion equivalencies. RESULTS: The clinical preference for lorazepam can be attributed to its simpler metabolism with no active metabolites, better suitability for patients with less severe hepatic and renal impairment, less risk of adverse reactions, fewer drug-drug interactions, and greater desirability for special populations. In periods of shortages, midazolam has been shown to be effective for a number of off-label uses. To manage conditions that have not been extensively studied, clinicians may opt to use conversion equivalencies, with the caveat that guidelines may vary greatly between institutions and online sources; therefore, it would be best to start low and titrate slowly. CONCLUSIONS: Our goal is to aid clinicians in safely and effectively prescribing midazolam during the shortage of injectable lorazepam so that patients are provided the same effects and benefits.

Paper Charts: A Continued Barrier to Psychiatric Care in the Midst of a Broken and Fragmented Mental Health System.

ABSTRACT: The use of electronic medical records (EMRs) has increased dramatically over the last 15 years. However, psychiatry has lagged. EMRs are not being used by many mental health professionals. There are many reasons, including financial burden, lack of technological support, stigma, disaggregation of upfront costs, indirect benefits, and concerns about privacy and Health Insurance Portability and Accountability Act compliance. Obtaining paper records is a lengthy process, making continuity of care and emergency care challenging. Even when records are made available, it is common for information to be incomplete. The objective of this article is to highlight how the continued use of paper charts may decrease the quality and timeliness of psychiatric care provided and to discuss the psychiatry-specific issues created by EMRs. A case illustrating the disruption of care by continued use of paper charts in psychiatric facilities is presented. The growing use of EMR creates new challenges that affect psychiatry in ways other fields are not affected. These challenges include confidentiality issues, the frequent change/spectrum of diagnoses, determining how much information should be recorded in a note, and what the implications are of the information recorded. This article will discuss the use of EMRs in psychiatry, as well as encourage medical students and residents to take a deeper dive into psychiatry-specific issues regarding the use of EMR. EMR use may have a profound impact on our patient outcomes, health care delivery system, shorter inpatient stay, as well as reduce health care costs.

Brain Histopathology of Adult Decedents After Extracorporeal Membrane Oxygenation.

OBJECTIVE: To test the hypothesis that brain injury is more common and varied in patients receiving extracorporeal membrane oxygenation (ECMO) than radiographically observed, we described neuropathology findings of ECMO decedents and associated clinical factors from 3 institutions. METHODS: We conducted a retrospective multicenter observational study of brain autopsies from adult ECMO recipients. Pathology findings were examined for correlation with demographics, clinical data, ECMO characteristics, and outcomes. RESULTS: Forty-three decedents (n = 13 female, median age 47 years) received autopsies after undergoing ECMO for acute respiratory distress syndrome (n = 14), cardiogenic shock (n = 14), and cardiac arrest (n = 15). Median duration of ECMO was 140 hours, most decedents (n = 40) received anticoagulants; 60% (n = 26) underwent venoarterial ECMO, and 40% (n = 17) underwent venovenous ECMO. Neuropathology was found in 35 decedents (81%), including microhemorrhages (37%), macrohemorrhages (35%), infarctions (47%), and hypoxic-ischemic brain injury (n = 17, 40%). Most pathology occurred in frontal neocortices (n = 43 occurrences), basal ganglia (n = 33), and cerebellum (n = 26). Decedents with hemorrhage were older (median age 57 vs 38 years, p = 0.01); those with hypoxic brain injury had higher Sequential Organ Failure Assessment scores (8.0 vs 2.0, p = 0.04); and those with infarction had lower peak Paco2 (53 vs 61 mm Hg, p = 0.04). Six of 9 patients with normal neuroimaging results were found to have pathology on autopsy. The majority underwent withdrawal of life-sustaining therapy (n = 32, 74%), and 2 of 8 patients with normal brain autopsy underwent withdrawal of life-sustaining therapy for suspected neurologic injury. CONCLUSION: Neuropathological findings after ECMO are common, varied, and associated with various clinical factors. Further study on underlying mechanisms is warranted and may guide ECMO management.

Towards detection of brain injury using multimodal non-invasive neuromonitoring in adults undergoing extracorporeal membrane oxygenation.

Extracorporeal membrane oxygenation (ECMO) is a form of cardiopulmonary bypass that provides life-saving support to critically ill patients whose illness is progressing despite maximal conventional support. Use in adults is expanding, however neurological injuries are common. Currently, the existing brain imaging tools are a snapshot in time and require high-risk patient transport. Here we assess the feasibility of measuring diffuse correlation spectroscopy, transcranial Doppler ultrasound, electroencephalography, and auditory brainstem responses at the bedside, and developing a cerebral autoregulation metric. We report preliminary results from two patients, demonstrating feasibility and laying the foundation for future studies monitoring neurological health during ECMO.