Targeting placental growth factor/neuropilin 1 pathway inhibits growth and spread of medulloblastoma.

Medulloblastoma is the most common pediatric malignant brain tumor. Although current therapies improve survival, these regimens are highly toxic and are associated with significant morbidity. Here, we report that placental growth factor (PlGF) is expressed in the majority of medulloblastomas, independent of their subtype. Moreover, high expression of PlGF receptor neuropilin 1 (Nrp1) correlates with poor overall survival in patients. We demonstrate that PlGF and Nrp1 are required for the growth and spread of medulloblastoma: PlGF/Nrp1 blockade results in direct antitumor effects in vivo, resulting in medulloblastoma regression, decreased metastasis, and increased mouse survival. We reveal that PlGF is produced in the cerebellar stroma via tumor-derived Sonic hedgehog (Shh) and show that PlGF acts through Nrp1-and not vascular endothelial growth factor receptor 1-to promote tumor cell survival. This critical tumor-stroma interaction-mediated by Shh, PlGF, and Nrp1 across medulloblastoma subtypes-supports the development of therapies targeting PlGF/Nrp1 pathway.

Case Studies Using the Electroencephalogram to Monitor Anesthesia-Induced Brain States in Children.

For this child, at this particular moment, how much anesthesia should I give? Determining the drug requirements of a specific patient is a fundamental problem in medicine. Our current approach uses population-based pharmacological models to establish dosing. However, individual patients, and children in particular, may respond to drugs differently. In anesthesiology, we have the advantage that we can monitor our patients in real time and titrate drugs to the desired effect. Examples include blood pressure management or muscle relaxation. Although the brain is the primary site of action for sedative-hypnotic drugs, the brain is not routinely monitored during general anesthesia or sedation, a fact that would surprise many patients. One reason for this is that, until recently, physiologically principled approaches for anesthetic brain monitoring have not been articulated. In the past few years, our knowledge of anesthetic brain mechanisms has developed rapidly. We now know that anesthetic drug effects are clearly visible in the electroencephalogram (EEG) of adults and reflect underlying anesthetic pharmacology and brain mechanisms. Most recently, similar effects have been characterized in children. In this article, we describe how EEG monitoring could be used to guide anesthetic management in pediatric patients. We review previous evidence and present multiple case studies showing how drug-specific and dose-dependent EEG signatures seen in adults are visible in children and infants, including those with neurological disorders. We propose that the EEG can be used in the anesthetic care of children to enable anesthesiologists to better assess the drug requirements of individual patients in real time and improve patient safety and experience.

Do-Not-Resuscitate Status Is Associated With Increased Mortality But Not Morbidity.

BACKGROUND: Do-not-resuscitate (DNR) orders instruct medical personnel to forego cardiopulmonary resuscitation in the event of cardiopulmonary arrest, but they do not preclude surgical management. Several studies have reported that DNR status is an independent predictor of 30-day mortality; however, the etiology of increased mortality remains unclear. We hypothesized that DNR patients would demonstrate increased postoperative mortality, but not morbidity, relative to non-DNR patients undergoing the same procedures. METHODS: Using the American College of Surgeons National Surgical Quality Improvement Program database for 2007-2013, we performed a retrospective analysis to compare DNR and non-DNR cohorts matched by the most common procedures performed in DNR patients. We employed univariable and multivariable logistic regression to characterize patterns of care in the perioperative period as well as identify independent risk factors for increased mortality and assess for the presence of "failure to rescue." RESULTS: The most common procedures performed on DNR patients were emergent and centered on immediate symptom relief. When adjusting for preoperative factors, DNR patients were still found to have increased incidence of postoperative mortality (odds ratio 2.54 [2.29-2.82], P < .001) but not postoperative morbidity at 30 days. In addition, cardiopulmonary resuscitative measures and unplanned intubation were found to be less frequent in the DNR cohort. CONCLUSIONS: These findings suggest that increased mortality is the result of adherence to goals of care rather than "failure to rescue."

A Case Report of Tension Hydrothorax Incited by Bowel Perforation.

We report the case of a 34-year-old man who developed cardiac arrest due to tension hydrothorax from colonic perforation. Tension hydrothorax, an entity characterized by pleural effusion leading to mediastinal compression, has not been reported in association with intraabdominal inflammation. Our patient developed respiratory insufficiency after repair of colonic perforation, followed by respiratory failure and cardiac arrest. Transthoracic echocardiography provided rapid diagnosis during decompensation and prompted a lifesaving thoracostomy. Clinicians should consider tension hydrothorax as a rare cause of hemodynamic collapse, even in the absence of liver failure, and use bedside tools like transthoracic echocardiography to facilitate diagnosis and intervention.

Escalating Care on Labor and Delivery.

Maternal morbidity and mortality are rising due in part to the rising prevalence of chronic illness, socioeconomic and racial disparities, and advanced maternal age. Prevention of maternal adverse outcomes requires prompt escalation of care to facilities with appropriate capabilities including intensive care services. The development of obstetrical-specific risk assessment tools and protocolized care for the most common causes of maternal intensive care unit (ICU) admission has helped to reduce preventable complications. However, significant work remains to address barriers to the escalation of maternal care and minimize delays in appropriate management.

Rapid Expansion of the Airway Response Team to Meet the Needs of the COVID-19 Pandemic.

INTRODUCTION: The COVID-19 pandemic has brought unprecedented numbers of patients with acute respiratory distress to medical centers. Hospital systems require rapid adaptation to respond to the increased demand for airway management while ensuring high quality patient care and provider safety. There is limited literature detailing successful system-level approaches to adapt to the surge of COVID-19 patients requiring airway management. METHODS: A deliberate system-level approach was used to expand a preexisting airway response service. Through a needs analysis (taking into account both existing resources and anticipated demands), we established priorities and solutions for the airway management challenges encountered during the pandemic. RESULTS: During our COVID-19 surge (March 10, 2020, through May 26, 2020), there were 619 airway consults, and the COVID airway response team (CART) performed 341 intubations. Despite a 4-fold increase in intubations during the surge, there was no increase in cardiac arrests or surgical airways and no documented COVID-19 infections among the CART. CONCLUSIONS: Our system-level approach successfully met the sudden escalation in demand in airway management incurred by the COVID-19 surge. The approach that addressed staffing needs prioritized provider protection and enhanced quality and safety monitoring may be adaptable to other institutions.

An examination of sedation requirements and practices for mechanically ventilated critically ill patients with COVID-19.

PURPOSE: Preliminary reports suggest that critically ill patients with coronavirus disease 2019 (COVID-19) infection requiring mechanical ventilation may have markedly increased sedation needs compared with critically ill, mechanically ventilated patients without COVID-19. We conducted a study to examine sedative use for this patient population within multiple intensive care units (ICUs) of a large academic medical center. METHODS: A retrospective, single-center cohort study of sedation practices for critically ill patients with COVID-19 during the first 10 days of mechanical ventilation was conducted in 8 ICUs at Massachusetts General Hospital, Boston, MA. The study population was a sequential cohort of 86 critically ill, mechanically ventilated patients with COVID-19. Data characterizing the sedative medications, doses, drug combinations, and duration of administration were collected daily and compared to published recommendations for sedation of critically ill patients without COVID-19. The associations between drug doses, number of drugs administered, baseline patient characteristics, and inflammatory markers were investigated. RESULTS: Among the study cohort, propofol and hydromorphone were the most common initial drug combination, with these medications being used on a given day in up to 100% and 88% of patients, respectively. The doses of sedative and analgesic infusions increased for patients over the first 10 days, reaching or exceeding the upper limits of published dosage guidelines for propofol (48% of patients), dexmedetomidine (29%), midazolam (7.7%), ketamine (32%), and hydromorphone (38%). The number of sedative and analgesic agents simultaneously administered increased over time for each patient, with more than 50% of patients requiring 3 or more agents by day 2. Compared with patients requiring 3 or fewer agents, patients requiring more than 3 agents were of younger age, had an increased body mass index, had increased serum ferritin and lactate dehydrogenase concentrations, had a lower Pao2:Fio2 (ratio of arterial partial pressure of oxygen to fraction of inspired oxygen), and were more likely to receive neuromuscular blockade. CONCLUSION: Our study confirmed the clinical impression of elevated sedative use in critically ill, mechanically ventilated patients with COVID-19 relative to guideline-recommended sedation practices in other critically ill populations.

Postoperative outcomes in patients with a do-not-resuscitate (DNR) order undergoing elective procedures.

STUDY OBJECTIVE: Do-not-resuscitate (DNR) status has been shown to be an independent risk factor for mortality in the post-operative period. Patients with DNR orders often undergo elective surgeries to alleviate symptoms and improve quality of life, but there are limited data on outcomes for informed decision making. DESIGN: Retrospective cohort study. SETTING: A multi-institutional setting including operating room, postoperative recovery area, inpatient wards, and the intensive care unit. PATIENTS: A total of 566 patients with a DNR status and 316,431 patients without a DNR status undergoing elective procedures using the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) from 2012. INTERVENTIONS: Patients undergoing elective surgical procedures. MEASUREMENTS: We analyzed the risk-adjusted 30-day morbidity and mortality outcomes for the matched DNR and non-DNR cohorts undergoing elective surgeries. MAIN RESULTS: DNR patients had significantly increased odds of 30-day mortality (OR 2.51 [1.55-4.05], p < 0.001) compared with non-DNR patients. In the DNR versus non-DNR cohort there was no significant difference in the occurrence of a number of 30-day complications, the rate of resuscitative measures undertaken, including cardiac arrest requiring CPR, reintubation, or return to the OR. The most common complications in both DNR and non-DNR patients undergoing elective procedures were transfusion, urinary tract infection, reoperation, and sepsis. Finally, the DNR patients had a significantly increased total length of hospital stay (7.65 ±â€¯9.55 vs. 6.87 ±â€¯9.21 days, p = 0.002). CONCLUSIONS: DNR patients, as compared with non-DNR patients, have increased post-operative mortality but not morbidity, which may arise from unmeasured severity of illness or transition to comfort care in accordance with a patient's wishes. The informed consent process for elective surgeries in this patient population should include a discussion of acceptable operative risk.

Age-Dependent Changes in the Propofol-Induced Electroencephalogram in Children With Autism Spectrum Disorder.

Patients with autism spectrum disorder (ASD) often require sedation or general anesthesia. ASD is thought to arise from deficits in GABAergic signaling leading to abnormal neurodevelopment. We sought to investigate differences in how ASD patients respond to the GABAergic drug propofol by comparing the propofol-induced electroencephalogram (EEG) of ASD and neurotypical (NT) patients. This investigation was a prospective observational study. Continuous 4-channel frontal EEG was recorded during routine anesthetic care of patients undergoing endoscopic procedures between July 1, 2014 and May 1, 2016. Study patients were defined as those with previously diagnosed ASD by DSM-V criteria, aged 2-30 years old. NT patients were defined as those lacking neurological or psychiatric abnormalities, aged 2-30 years old. The primary outcome was changes in propofol-induced alpha (8-13 Hz) and slow (0.1-1 Hz) oscillation power by age. A post hoc analysis was performed to characterize incidence of burst suppression during propofol anesthesia. The primary risk factor of interest was a prior diagnosis of ASD. Outcomes were compared between ASD and NT patients using Bayesian methods. Compared to NT patients, slow oscillation power was initially higher in ASD patients (17.05 vs. 14.20 dB at 2.33 years), but progressively declined with age (11.56 vs. 13.95 dB at 22.5 years). Frontal alpha power was initially lower in ASD patients (17.65 vs. 18.86 dB at 5.42 years) and continued to decline with age (6.37 vs. 11.89 dB at 22.5 years). The incidence of burst suppression was significantly higher in ASD vs. NT patients (23.0% vs. 12.2%, p < 0.01) despite reduced total propofol dosing in ASD patients. Ultimately, we found that ASD patients respond differently to propofol compared to NT patients. A similar pattern of decreased alpha power and increased sensitivity to burst suppression develops in older NT adults; one interpretation of our data could be that ASD patients undergo a form of accelerated neuronal aging in adolescence. Our results suggest that investigations of the propofol-induced EEG in ASD patients may enable insights into the underlying differences in neural circuitry of ASD and yield safer practices for managing patients with ASD.

Dexmedetomidine promotes biomimetic non-rapid eye movement stage 3 sleep in humans: A pilot study.

OBJECTIVES: Sleep, which comprises of rapid eye movement (REM) and non-REM stages 1-3 (N1-N3), is a natural occurring state of decreased arousal that is crucial for normal cardiovascular, immune and cognitive function. The principal sedative drugs produce electroencephalogram beta oscillations, which have been associated with neurocognitive dysfunction. Pharmacological induction of altered arousal states that neurophysiologically approximate natural sleep, termed biomimetic sleep, may eliminate drug-induced neurocognitive dysfunction. METHODS: We performed a prospective, single-site, three-arm, randomized-controlled, crossover polysomnography pilot study (n = 10) comparing natural, intravenous dexmedetomidine- (1-µg/kg over 10 min [n = 7] or 0.5-µg/kg over 10 min [n = 3]), and zolpidem-induced sleep in healthy volunteers. Sleep quality and psychomotor performance were assessed with polysomnography and the psychomotor vigilance test, respectively. Sleep quality questionnaires were also administered. RESULTS: We found that dexmedetomidine promoted N3 sleep in a dose dependent manner, and did not impair performance on the psychomotor vigilance test. In contrast, zolpidem extended release was associated with decreased theta (∼5-8 Hz; N2 and N3) and increased beta oscillations (∼13-25 Hz; N2 and REM). Zolpidem extended release was also associated with increased lapses on the psychomotor vigilance test. No serious adverse events occurred. CONCLUSIONS: Pharmacological induction of biomimetic N3 sleep with psychomotor sparing benefits is feasible. SIGNIFICANCE: These results suggest that α2a adrenergic agonists may be developed as a new class of sleep enhancing medications with neurocognitive sparing benefits.