Factors Influencing Willingness to Participate in Clinical Studies in Pediatric Anesthesia (FILIPPA): A vignette-based, structured interview study.

BACKGROUND: Informed consent is a relevant backdrop for conducting clinical trials, particularly those involving children. While several factors are known to influence the willingness to consent to pediatric anesthesia studies, the influence of study design on consenting behavior is unknown. AIMS: To quantify the impact of study complexity on willingness to consent to pediatric anesthesia studies. METHODS: We conducted a vignette-based interview study by presenting three hypothetical studies to 106 parents or legal guardians whose children were scheduled to undergo anesthesia. These studies differed in level of complexity and included an example of a prospective observational study, a randomized controlled trial, and a phase-II-pharmacological study. Primary outcome was the willingness to consent, using a 5-point Likert scale ranging from "absolutely consent" to "absolutely decline". Secondary outcomes were the effects of child-related (such as sex, age, previous anesthesia, research exposure) and proxy-related factors. RESULTS: Response probabilities for "absolute consent" were 90.9% [95% CI 85.3-96.5] for the observational study, 48.6% [95% CI 38.3-58.9] for the randomized controlled trial, and 32.7% [95% CI 23.9-41.6] for the phase-II-pharmacological study. Response probabilities for "absolutely decline" were 1.6% [95% CI 0.3-2.8], 14.4% [95% CI 8.3-20.5], and 24.7% [95% CI 16.6-32.7], respectively. Significant effects were found for previous research exposure (OR = 0.486 [95% CI 0.256-0.923], p = .027), older age (OR = 0.963 [95% CI 0.927-0.999], p = .045) and the gender of the parent or legal guardian, as mothers were less willing to consent (OR = 0.234 [95% CI 0.107-0.512], p < .001). CONCLUSIONS: Willingness to consent decreased with increasing level of study complexity. When conducting more complex studies, greater efforts need to be made to increase the enrollment of pediatric patients.

Characteristics and Outcomes of Obstetric Sepsis by Three Sets of Clinical Diagnostic Criteria: A Retrospective Study.

OBJECTIVE: Pregnancy-related mortality in the United States is the highest of all developed nations with a reported rate of 17 deaths per 100,000 live births in 2014 to 2017. Sepsis-related mortality is a major component of pregnancy-related mortality. Similar to nonpregnancy-related sepsis, the criteria for pregnancy-related sepsis are evolving. The purposes of this study were to compare three criteria for sepsis (Sepsis-2, Sepsis-3, California Maternal Quality Care Collaborative [CMQCC]) with one another and to determine patient outcomes using those three sets of criteria. STUDY DESIGN: Using the electronic medical record, we obtained granular data on all patients at University of Michigan Medical Center from July 10, 2009 to September 4, 2019 with suspected sepsis (blood cultures and administration of antibiotics) during pregnancy until the 42nd postpartum day. Agreement between the three criteria were assessed with kappa and shown by a Venn diagram. Groups were compared using standardized differences and chi square, rank sum, or independent t-tests. RESULTS: Of the 228 patients having sepsis by any criteria, 191 (83%) patients met the criteria for Sepsis-2, 131 (57%) for Sepsis-3, and 62 (27%) met criteria according to CMQCC. Agreement between the three criteria ranged from kappa = 0.13 (95% confidence interval [CI]: 0.09, 0.18) to kappa = 0.31 (95% CI: 0.23, 0.39). Patients who met CMQCC criteria tended to have more comorbidities and higher APACHE II (Acute Physiology And Chronic Health Evaluation) scores. Mortality (by 90 days) among the groups was low with 10 (4%) patients dying. Patients meeting criteria for CMQCC sepsis had higher mortality than the non-CMQCC patients with sepsis (10 vs. 2%, standardized difference = 0.31, p = 0.027). CONCLUSION: The agreement among Sepsis-2, Sepsis-3, and CMQCC diagnostic criteria is weak. CMQCC criteria identifies patients with sepsis at higher risk of death. KEY POINTS: · Agreements (kappa) between the three criteria are poor.. · CMQCC sepsis patients have more comorbidities.. · Endometritis was the most common cause of sepsis.. · CMQCC mortality was 10%; non-CMQCC mortality was 2%..

Evaluation of the non-invasive Temple Touch Pro temperature monitoring system compared with oesophageal temperature in paediatric anaesthesia (PETER PAN): A prospective observational study.

BACKGROUND: Monitoring peri-operative body temperature in children is currently mainly achieved through invasive devices. The Temple Touch Pro Temperature Monitoring System estimates core temperature noninvasively based on heat flux thermometry. OBJECTIVE: To investigate the agreement of this noninvasive sensor against standard oesophageal core temperature. DESIGN: A prospective observational study. SETTING: University hospital recruiting between April and July 2021. PATIENTS: One hundred children (32 girls) aged 6 years or younger scheduled for noncardiac surgery, resulting in 6766 data pairs. Exclusion criteria were contraindication for the insertion of an oesophageal temperature probe, and procedures in which one of the measurement methods would interfere with the surgical field. MAIN OUTCOME MEASURES: Primary outcome was the agreement analysis by a Bland-Altman comparison with multiple measurements. Posthoc, we performed another agreement analysis after exclusion of a statistically determined equilibration time. Secondary outcomes were the temperature differences over time and subgroup analysis of hypothermic, normothermic and hyperthermic temperature ranges, age, sex and sensor's side by type III analysis of variance. Further, we correlated the sonographically determined depth of the artery with trueness. RESULTS: The mean difference was -0.07°C (95% CI -0.15 to +0.05) with limits of agreement of -1.00 and +0.85°C. After adjusting for an equilibration time of 13 min, the mean difference improved to -0.04°C (95% CI -0.08 to +0.01) with limits of agreement of -0.68 and +0.60°C. Concordance correlation coefficient was 0.83 (95% CI 0.82 to 0.84). Differences between the skin sensor and oesophageal reference increased over time by -0.05°C per hour. Subgroup analysis showed no clinically relevant differences. Depth of artery negatively correlated with trueness by 0.03°C per millimetre. CONCLUSIONS: Although the Temple Touch Pro sensor showed acceptable accuracy after allowing for an equilibration time, it still needs further investigation for routine use in children. This particularly affects accuracy in hypothermic ranges, imprecise positioning and applicability in children with immature or vulnerable skin. TRIAL REGISTRATION: German Clinical Trials Register, identifier: DRKS00024703.

Guedel oropharyngeal airway: The validation of facial landmark-distances to estimate sizing in children - Visualisation by magnetic resonance imaging (GUEDEL-I): A prospective observational study.

OBJECTIVE: To validate the ERC-recommended facial landmark-distance for oropharyngeal airway sizing in children. METHODS: We conducted a prospective observational study in anaesthetised, spontaneously breathing children ≤12 years undergoing cranial MRI. Oropharyngeal airways were inserted following the distance from the maxillary incisors to the mandibular angle. Primary outcome was the rate of properly sized oropharyngeal airways on MRI, defined as the distal end positioned within 10 mm from the epiglottis without contacting it. Secondary outcomes were the occurrence of tongue protrusion, oropharyngeal airways clinical efficacy, and related adverse events. Furthermore, we calculated probabilities for the estimation of proper size when considering five facial landmark-distances and optimal rules based on biometric parameters. RESULTS: In 94 children with a mean (SD) age of 4.7 (±3) years, 47.9% [95%-CI 38%-57.9%] oropharyngeal airways were properly sized, while 23.4% [95%-CI 15.9%-33%] were undersized, and 28.7% [95%-CI 20.5%-38.7%] oversized. Tongue protrusion occurred in 59.1% [95%-CI 38.2%-77.2%] of undersized and 15.6% [95%-CI 7.6%-29.2%] of properly sized oropharyngeal airways. No oropharyngeal airway required replacement. Comparing probabilities for five landmark-distances, "maxillary incisors to the angle of the mandible" proved superior for proper sizing at 41.2% [95%-CI 32%-51.7%]. The best-fit formula was "22.43 + 17.54 × log(weight[kg])" with a probability of 61.7% [95%-CI 51.5%-70.9%]. CONCLUSION: Although the facial landmark-distance "maxillary incisors to the angle of the mandible" does not reliably predict oropharyngeal airway size, no clinical problems have been encountered. Since it can be considered the least inaccurate facial landmark-distance, it can serve as an approximation, but the efficacy of oropharyngeal airways should be evaluated clinically. REGISTERED CLINICAL TRIAL: German Clinical Trials Register; DRKS00025918.

Comparison of static and rolling logistic regression models on predicting invasive mechanical ventilation or death from COVID-19-A retrospective, multicentre study.

INTRODUCTION: COVID-19 virus has undergone mutations, and the introduction of vaccines and effective treatments have changed its clinical severity. We hypothesized that models that evolve may better predict invasive mechanical ventilation or death than do static models. METHODS: This retrospective study of adult patients with COVID-19 from six Michigan hospitals analysed 20 demographic, comorbid, vital sign and laboratory factors, one derived factor and nine factors representing changes in vital signs or laboratory values with time for their ability to predict death or invasive mechanical ventilation within the next 4, 8 or 24 h. Static logistic regression was constructed on the initial 300 patients and tested on the remaining 6741 patients. Rolling logistic regression was similarly constructed on the initial 300 patients, but then new patients were added, and older patients removed. Each new construction model was subsequently tested on the next patient. Static and rolling models were compared with receiver operator characteristic and precision-recall curves. RESULTS: Of the 7041 patients, 534 (7.6%) required invasive mechanical ventilation or died within 14 days of arrival. Rolling models improved discrimination (0.865 ± 0.010, 0.856 ± 0.007 and 0.843 ± 0.005 for the 4, 8 and 24-h models, respectively; all p < 0.001 compared with the static logistic regressions with 0.827 ± 0.011, 0.794 ± 0.012 and 0.735 ± 0.012, respectively). Similarly, the areas under the precision-recall curves improved from 0.006, 0.010 and 0.021 with the static models to 0.030, 0.045 and 0.076 for the 4-, 8- and 24-h rolling models, respectively, all p < 0.001. CONCLUSION: Rolling models with contemporaneous data maintained better metrics of performance than static models, which used older data.

Modeling iatrogenic intraoperative hyperthermia from external warming in children: A pooled analysis from two prospective observational studies.

BACKGROUND: Maintenance of normothermia is an important quality metric in pediatric anesthesia. While inadvertent hypothermia is effectively prevented by forced-air warming, this therapeutic approach can lead to iatrogenic hyperthermia in young children. AIMS: To estimate the influence of external warming by forced air on the development of intraoperative hyperthermia in anesthetized children aged 6 years or younger. METHODS: We pooled data from two previous clinical studies. Primary outcome was the course of core temperature over time analyzed by a quadratic regression model. Secondary outcomes were the incidence of hyperthermia (body core temperature >38°C), the probability of hyperthermia over the duration of warming in relation to age and surface-area-to-weight ratio, respectively, analyzed by multiple logistic regression models. The influence of baseline temperature on hyperthermia was estimated using a Cox proportional hazards model. RESULTS: Two hundred children (55 female) with a median age of 2.1 [1st -3rd quartile 1-4.2] years were analyzed. Mean temperature increased by 0.43°C after 1 h, 0.64°C after 2 h, and reached a peak of 0.66°C at 147 min. Overall, 33 children were hyperthermic at at least one measurement point. The odds ratios of hyperthermia were 1.14 (95%-CI: 1.07-1.22) or 1.13 (95%-CI: 1.06-1.21) for every 10 min of warming therapy in a model with age or surface-area-to weight ratio (ceteris paribus), respectively. Odds ratio was 1.33 (95%-CI: 1.07-1.71) for a decrease of 1 year in age and 1.63 (95%-CI: 0.93-2.83) for an increase of 0.01 in the surface-to-weight-area ratio (ceteris paribus). An increase of 0.1°C in baseline temperature increased the hazard of becoming hyperthermic by a factor of 1.33 (95%-CI: 1.23-1.43). CONCLUSIONS: In children, external warming by forced-air needs to be closely monitored and adjusted in a timely manner to avoid iatrogenic hyperthermia especially during long procedures, in young age, higher surface-area-to-weight ratio, and higher baseline temperature.

Upregulated influenza A viral entry factors and enhanced interferon-alpha response in the nasal epithelium of pregnant rats.

Despite the increased severity of influenza A infection in pregnancy, knowledge about the expression of cell entry factors for influenza A virus (IAV) and the innate immune response in the nasal epithelium, the primary portal of viral entry, is limited. Here, we compared the expression of IAV cell entry factors and the status of the innate immune response in the nasal epithelium of pregnant vs. non-pregnant female rats. IAV cell entry factors - sialic acid [SA] α-2,3- and α-2,6-linked glycans for avian and human IAV, respectively - were detected and quantified with lectin-based immunoblotting and flow cytometry. Baseline frequencies of innate immune cell phenotypes in single cell suspensions of the nasal epithelium were studied with flow cytometry. Subsequently, the magnitude of interferon and cytokine responses was studied with ELISA and cytokine arrays after intranasal resiquimod, a Toll-like receptor 7/8 agonist that mimics IAV infection. We noted substantially increased expression of cell entry factors for both avian and human IAV in the nasal epithelium during pregnancy. Assessment of the innate immune state of the nasal epithelium during pregnancy revealed two previously unreported features: (i) increased presence of tissue-resident plasmacytoid dendritic cells, and (ii) markedly enhanced release of interferon-α but not of the other interferons or cytokines 2 h after intranasal resiquimod. Collectively, our findings challenge the conventional notion of pregnancy-induced immunosuppression as a cause for severe influenza A disease and suggest the need for focused studies on viral tropism during pregnancy to better understand the proximate cause for the observed immunopathology.

Retrospective study evaluating telehealth antenatal anesthesia consults for high-risk obstetric patients.

BACKGROUND: Telehealth has gained popularity, particularly in the COVID-19 era. The use of telehealth is now being applied to preoperative evaluation clinics in an effort to overcome barriers to antenatal anesthesia assessment of high-risk obstetrical patients. OBJECTIVES: The objective of this study is to determine if the quality of antenatal anesthesia telehealth consults of high-risk obstetric patients is comparable to in-person encounters. This is determined by assessing if telehealth consults are feasible and meet the standards of care, as well as the level of patient satisfaction and ease of use as reported by providers. STUDY DESIGN: This retrospective study assessed patients prior to delivery who completed a video-telehealth anesthesia consultation (51 cases) from November 1st, 2019 to November 30th, 2020 and all of those for patients receiving an in-person anesthesia consultation (171 controls) from November 2017 through October 2019. Our primary hypothesis was that telehealth and in-person consultations would not result in different standards of care. The primary outcome was an indicator of meeting the standard of care, and the difference in proportions between the telehealth and in-person consultation was tested by Fisher's exact test. Our secondary hypotheses were that patients reported high levels of satisfaction and could use telehealth easily and providers could use the platform easily. Secondary outcomes were assessed by using the Consultation and Relational Empathy (CARE) and the Telehealth Usability Questionnaire (TUQ) surveys, respectively. RESULTS: For the primary outcome, 94.1% (48/51) of telehealth and 89.5% (153/171) of in-person visits met the standard of care, indicating no significant difference between groups (p-value = .4204). The CARE score was 46 [41,50] {median [interquartile range]}, (p-value < .0001), indicating patient satisfaction with telehealth. The use-average scores on the TUQ for the patient and provider were 6.67 [6.33, 7] and 6 [5.33, 7] respectively, indicating great system usability. CONCLUSION: This study demonstrates no significant difference in the standard of care between in-person and telehealth visits. Furthermore, telehealth consultation was feasible and associated with high patient satisfaction and platform usability. Preoperative consultation of high-risk obstetric patients using telehealth visits should be routinely considered in clinical practice.Condensation: There is no significant difference in the standard of care between in-person and telehealth antenatal anesthesia consultations, and patients report high satisfaction and platform usability.Telehealth is gaining popularity, but its role in antenatal anesthesia consultation of high risk obstetrical patients has not yet been defined with respect to standard of care, patient satisfaction, and platform usability.There was no significant difference in standard of care between in-person and telehealth antenatal anesthesia consultations, and patients reported high satisfaction and platform usability.Telehealth should be considered as an alternative to in-person antenatal anesthesia consultation of high risk obstetrical patients. It is a particularly attractive alternative to in-person consultation due to cost-savings, increased patient accessibility, and ease of use.

Difficulty in Advancing Flexible Epidural Catheters When Establishing Labor Analgesia: An Observational Open-Label Randomized Trial.

BACKGROUND: While flexible epidural catheters reduce the risk of paresthesia and intravascular cannulation, they may be more challenging to advance beyond the tip of a Tuohy needle. This may increase placement time, number of attempts, and possibly complications when establishing labor analgesia. This study investigated the ability to advance flexible epidural catheters through different epidural needles from 2 commonly used, commercially available, epidural kits. METHODS: We hypothesized that the multiorifice wire-reinforced polyamide nylon blend epidural catheters will have a higher rate of successful first attempt insertion than the single-end hole wire-reinforced polyurethane catheters for the establishment of labor analgesia. The primary outcome was a difference in proportions of failure to advance the epidural catheter between the 2 epidural kits and was tested by a χ2 test. Two-hundred forty epidural kits were collected (n = 120/group) for 240 laboring patients requesting epidural analgesia in this open-label clinical trial from November 2018 to September 2019. Two-week time intervals were randomized for the exclusive use of 1 of the 2 kits in this study, where all patients received labor analgesia through either the flexible epidural catheter "A" or the flexible epidural catheter "B." Engineering properties of the equipment used were then determined. RESULTS: Flexible epidural catheter "A," the single-end hole wire-reinforced polyurethane catheter, did not advance at the first attempt in 15% (n = 18 of 120) of the parturients compared to 0.8% (n = 1 of 120) of the catheter "B," the multiorifice wire-reinforced polyamide nylon blend epidural catheter (P < .0001). Twenty-five additional epidural needle manipulations were recorded in the laboring patients who received catheter "A," while 1 epidural needle manipulation was recorded in the parturients who received catheter "B" (P < .0001). Bending stiffness of the epidural catheters used from kit "B" was twice the bending stiffness of the catheters used from kit "A" (bending stiffness catheters "A" 0.64 ± 0.04 N·mm2 versus bending stiffness catheters "B" 1.28 ± 0.20 N·mm2, P = .0038), and the angle formed by the needle and the epidural catheter from kit "A" was less acute than the angle formed from kit "B" (kit "A" 14.17 ± 1.72° versus kit "B" 21.83 ± 1.33°, P = .0036), with a mean difference of 7.66° between the 2 kits' angles. CONCLUSIONS: The incidence of an inability to advance single-end hole wire-reinforced polyurethane catheter was higher compared to the use of multiorifice wire-reinforced polyamide nylon blend epidural catheter. Variation of morphological features of epidural needles and catheters may play a critical role in determining the successful establishment of labor epidural analgesia.

Sugammadex Administration in Pregnant Women: A Case Series of Maternal and Fetal Outcomes.

Sugammadex, given its high affinity for amino-steroid neuromuscular blockers, offers rapid and reliable neuromuscular blockade reversal, making it a popular reversal agent. This characteristic can be very useful in pregnant women, where incomplete reversal can have poor maternal and fetal outcomes. However, its use antenatally in pregnancy is controversial given concerns for progesterone binding, a hormone that is crucial for maintenance of pregnancy. This case series presents obstetric and fetal outcomes in 25 pregnant women who received sugammadex during the antenatal period, thus highlighting the need for further research into the safety of sugammadex during pregnancy.

Clinically applicable approach for predicting mechanical ventilation in patients with COVID-19.

BACKGROUND: Patients with coronavirus disease 2019 (COVID-19) requiring mechanical ventilation have high mortality and resource utilisation. The ability to predict which patients may require mechanical ventilation allows increased acuity of care and targeted interventions to potentially mitigate deterioration. METHODS: We included hospitalised patients with COVID-19 in this single-centre retrospective observational study. Our primary outcome was mechanical ventilation or death within 24 h. As clinical decompensation is more recognisable, but less modifiable, as the prediction window shrinks, we also assessed 4, 8, and 48 h prediction windows. Model features included demographic information, laboratory results, comorbidities, medication administration, and vital signs. We created a Random Forest model, and assessed performance using 10-fold cross-validation. The model was compared with models derived from generalised estimating equations using discrimination. RESULTS: Ninety-three (23%) of 398 patients required mechanical ventilation or died within 14 days of admission. The Random Forest model predicted pending mechanical ventilation with good discrimination (C-statistic=0.858; 95% confidence interval, 0.841-0.874), which is comparable with the discrimination of the generalised estimating equation regression. Vitals sign data including SpO2/FiO2 ratio (Random Forest Feature Importance Z-score=8.56), ventilatory frequency (5.97), and heart rate (5.87) had the highest predictive utility. In our highest-risk cohort, the number of patients needed to identify a single new case was 3.2, and for our second quintile it was 5.0. CONCLUSION: Machine learning techniques can be leveraged to improve the ability to predict which patients with COVID-19 are likely to require mechanical ventilation, identifying unrecognised bellwethers and providing insight into the constellation of accompanying signs of respiratory failure in COVID-19.

Risk of Major Complications After Perioperative Norepinephrine Infusion Through Peripheral Intravenous Lines in a Multicenter Study.

BACKGROUND: Continuous infusions of norepinephrine to treat perioperative hypotension are typically administered through a central venous line rather than a peripheral venous catheter to avoid the risk of localized tissue necrosis in case of drug extravasation. There is limited literature to estimate the risk of skin necrosis when peripheral norepinephrine is used to counteract anesthesia-associated hypotension in elective surgical cases. This study aimed to estimate the rate of occurrence of drug-related adverse effects, including skin necrosis requiring surgical management when norepinephrine peripheral extravasation occurs. METHODS: This retrospective cohort study used the perioperative databases of the University Hospitals in Amsterdam and Utrecht, the Netherlands, to identify surgical patients who received norepinephrine peripheral intravenous infusions (20 µg/mL) between 2012 and 2016. The risk of drug-related adverse effects, including skin necrosis, was estimated. Particular care was taken to identify patients who needed plastic surgical or medical attention secondary to extravasation of dilute, peripheral norepinephrine. RESULTS: A total of 14,385 patients who received norepinephrine peripheral continuous infusions were identified. Drug extravasation was observed in 5 patients (5/14,385 = 0.035%). The 95% confidence interval (CI) for infusion extravasation was 0.011%-0.081%, indicating an estimated risk of 1-8 events per every 10,000 patients. There were zero related complications requiring surgical or medical intervention, resulting in a 95% CI of 0%-0.021% and indicating a risk of approximately 0-2 events per 10,000 patients. CONCLUSIONS: In the current database analysis, no significant association was found between the use of peripheral intravenous norepinephrine infusions and adverse events.

Case report of amniotic fluid embolism coagulopathy following abortion; use of viscoelastic point-of-care analysis.

BACKGROUND: Amniotic fluid embolism (AFE) is a rare, life threatening obstetric complication, often associated with severe coagulopathy. Induced abortions are extremely safe procedures however complications including AFE can occur. CASE PRESENTATION: A 29-year-old previously healthy woman, gravida 1 para 0, presented for a scheduled second trimester induced abortion via dilation and evacuation at 22-weeks gestation. The case was complicated by a suspected AFE with associated profound coagulopathy. Viscoelastic point-of-care coagulation analysis was used to successfully and swiftly guide management of her coagulopathy. CONCLUSION: AFE can occur in the setting of induced abortion. This case report suggests viscoelastic point-of-care coagulation analyzers may aid in the management of pregnancy-related coagulopathy by providing faster coagulation assessment than laboratory testing, and facilitating timely, targeted management of coagulopathy.

Sacral anatomical interspace landmark for lumbar puncture in pregnancy: A randomized trial.

OBJECTIVE: To determine whether the sacral anatomical interspace landmark (SAIL) technique is more accurate than the classic intercristal line (ICL) technique in pregnant patients and to assess the percentage of clinical determinations above the third lumbar vertebra. METHODS: In this prospective, randomized, open-label trial, there were 110 singleton pregnant patients with gestational age greater than 37 weeks included. Selection procedure was a convenience sample of pregnant patients who presented for office visits or vaginal or cesarean delivery between March 15 and July 31, 2018, at a single-center obstetric tertiary care university hospital. Both techniques were evaluated by 2 physicians independently assessing each method. Before data collection, we hypothesized that the SAIL technique would be more accurate than the ICL technique in determining the L4-L5 interspace, and that the SAIL technique would produce more estimations below the third lumbar vertebra than the ICL technique. Therefore, the primary outcome was accuracy in identifying the L4-L5 lumbar interspace with SAIL vs ICL. The secondary outcome was difference in clinical assessments above the third lumbar vertebra. Both outcomes were measured via ultrasonography. RESULTS: Patients were 31 ± 5 years of age (mean ± SD) and had body mass index of 31.8 ± 5.7 kg/m2 and gestational age of 38.8 ± 1.1 weeks. A total of 110 patients were analyzed. SAIL correctly identified the L4-L5 interspace 49% of the time vs 8% using ICL (p < 0.0001). Estimations above L3 were 1% for SAIL vs 31% for ICL (p < 0.0001). CONCLUSIONS: Our study shows improved accuracy in identifying intervertebral space using the SAIL technique; this may prevent direct mechanical trauma to the conus medullaris when lumbar punctures are performed in pregnancy. CLINICALTRIALSGOV IDENTIFIER: NCT03433612.

Maternal Noninfectious Fever Enhances Cell Proliferation and Microglial Activation in the Neonatal Rat Dentate Gyrus.

BACKGROUND: Fever and increased maternal interleukin-6 (IL-6) plasma levels in labor are associated with an increased risk of adverse events in offspring, including neonatal seizures, cerebral palsy, and low intelligence scores at school age. However, the neural changes in the neonate that might mediate the adverse effects of maternal noninfectious fever are not fully characterized. This study was designed to test the hypothesis that induced maternal noninfectious fever alters neonatal neural progenitor cell proliferation and enhances microglial activation in the rat dentate gyrus of the hippocampus. METHODS: Systemic vehicle or IL-6 was given 3 times to near-term pregnant rats (n = 7/group) every 90 minutes, and maternal core temperature was recorded. Neonatal brains were processed and analyzed for dentate gyrus cell proliferation (using Ki-67, n = 10/group, and glial fibrillary acidic protein, n = 6/group) and resident microglia activation (using ionized calcium-binding adaptor protein-1 [Iba-1], n = 6/group). In separate studies, the authors assessed microglia proliferation using Ki-67/Iba-1 costaining (n = 5/group). RESULTS: Compared to controls, exposure to IL-6 resulted in significant maternal temperature increase [mean temperature difference 0.558°C (95% CI, 0.417-0.698; P < .0001)]. Following maternal IL-6, Ki-67 cell proliferation in the dentate gyrus was 55 % higher in neonates whose mother received IL-6 (38.8 ± 9.2) compared with those that received vehicle (25.1 ± 7.8); mean difference 13.7 (95% CI, 5.68-21.71); (P = .0021). Glial fibrillary acidic protein cell proliferation was 40% higher in the neonatal dentate gyrus whose mother received IL-6 when compared to controls (713 ± 85.52 vs 500 ± 115); mean difference 212 (95% CI, 82.2-343.4); (P = .004). Resident microglial activation was 90% higher in the dentate gyrus of neonates whose mother received IL-6 when compared to controls (71.8 ± 9.3 vs 37.8 ± 5.95); mean Iba-1 in stained cells was significantly different between IL-6 and vehicle groups 34 (95% CI, 23.94-44.05); (P < .0001). Proliferating microglia, determined by the colocalization of Ki-67 and Iba-1, were not different in the vehicle (8.8 % ± 3.19 %) and the IL-6 (5.6% ± 2.3%) groups (mean difference 3.2% (95% CI, -0.8-7.25) (P = .1063). CONCLUSIONS: IL-6 is sufficient to induce maternal systemic temperature increases in near-term pregnant rats as well as neuronal, glial, and neuroinflammatory changes in the dentate gyrus of the neonatal hippocampus. These alterations might disrupt fetal neurodevelopment during a vulnerable period.

Increasing Role of Maternal Immune Activation in Neurodevelopmental Disorders.

The earliest stages of development are critically sensitive to environmental insults. An unfortunately timed stress on the developing brain can have dramatic consequences for the neurodevelopment and future mental health of the individual. In particular, infection of the mother during pregnancy has been correlated with increased risk of psychiatric and neurodevelopmental disorders. Evidence suggests that maternal immune activation, independently from the infection itself, can be responsible for the outcome in the offspring. This recognition has resulted in expanding study designs from epidemiologic correlations to the search for a causal relationship between activation of the maternal immune system and cognitive consequences for the offspring. However, this causality analysis remained limited in humans until recent work that longitudinally linked specific markers of maternal inflammation during pregnancy with alterations of the newborn brain and cognitive development of toddlers. This focused narrative review compares and discusses the results of these recent studies and places them into the broader landscape of maternal immune activation literature. New data point, in particular, to the association between the levels of interleukin 6 (IL-6) and modifications of the offspring's salience network and subsequent cognitive impairments. This article further emphasizes the need to carefully control for potential confounders in studying the effects of maternal immune activation on the neonatal brain as well as the under-investigated consequences of intra-partum fever on offspring neurodevelopment.

Noninfectious Fever in the Near-Term Pregnant Rat Induces Fetal Brain Inflammation: A Model for the Consequences of Epidural-Associated Maternal Fever.

BACKGROUND: Women laboring with epidural analgesia experience fever much more frequently than do women who chose other forms of analgesia, and maternal intrapartum fever is associated with numerous adverse consequences, including brain injury in the fetus. We developed a model of noninfectious inflammatory fever in the near-term pregnant rat to simulate the pathophysiology of epidural-associated fever and hypothesized that it would produce fetal brain inflammation. METHODS: Twenty-four pregnant Sprague-Dawley rats were studied at 20 days gestation (term: 22 days). Dams were treated by injection of rat recombinant interleukin (IL)-6 or vehicle at 90-minute intervals, and temperature was monitored every 30 minutes. Eight hours after the first treatment, dams were delivered of fetuses and then killed. Maternal IL-6 was measured at delivery. Fetal brains (n = 24) were processed and stained for ED-1/CD68, a marker for activated microglia, and cell counts in the lateral septal and hippocampal brain regions were measured. Fetal brains were also stained for cyclooxygenase-2 (COX-2), a downstream marker of neuroinflammation. Eight fetal brains were further analyzed for quantitative forebrain COX-2 by Western blotting compared to a ß-actin standard. Maternal temperature and IL-6 levels were compared between treatments, as were cell counts, COX-2 staining, and COX-2 levels by Mann-Whitney U test, repeated-measures analysis of variance, or Fisher exact test, as appropriate. RESULTS: Injection of rat IL-6 at 90-minute intervals produced an elevation of maternal temperature compared to vehicle (P < .0001). IL-6 levels were elevated to clinically relevant levels at delivery in IL-6 compared to vehicle-treated animals (mean ± standard deviation: 923 ± 97 vs 143 ± 94 pg/mL, P = .0006). ED-1-stained cells were present in significantly higher numbers in fetal brains from IL-6 compared to saline-treated dams (median [interquartile range]: caudal hippocampus, 99 [94-104] and 64 [57-68], respectively, P = .002; lateral septum, 102 [96-111] and 68 [65-69], respectively, P = .002), as well as COX-2 immunostaining (lateral septum, 22 [20-26] and 17 [15-18], respectively, P = .005; dorsal hippocampus, 27 [22-32] and 16 [14-19], respectively, P = .013) and quantitative COX-2 Western blotting activity (mean ± standard error of the mean: vehicle, 0% of ß-actin intensity versus IL-6, 41.5% ± 24%, P < .001). CONCLUSIONS: Noninfectious inflammatory fever is inducible in the near-term pregnant rat by injection of IL-6 at levels comparable to those observed during human epidural labor analgesia. Maternal IL-6 injection causes neuroinflammation in the fetus.

Association between Intrapartum Magnesium Administration and the Incidence of Maternal Fever: A Retrospective Cross-sectional Study.

BACKGROUND: Intrapartum maternal fever is associated with several adverse neonatal outcomes. Intrapartum fever can be infectious or inflammatory in etiology. Increases in interleukin 6 and other inflammatory markers are associated with maternal fever. Magnesium has been shown to attenuate interleukin 6-mediated fever in animal models. We hypothesized that parturients exposed to intrapartum magnesium would have a lower incidence of fever than nonexposed parturients. METHODS: In this study, electronic medical record data from all deliveries at Northwestern Memorial Hospital (Chicago, Illinois) between 2007 and 2014 were evaluated. The primary outcome was intrapartum fever (temperature at or higher than 38.0°C). Factors associated with the development of maternal fever were evaluated using a multivariable logistic regression model. Propensity score matching was used to reduce potential bias from nonrandom selection of magnesium administration. RESULTS: Of the 58,541 women who met inclusion criteria, 5,924 (10.1%) developed intrapartum fever. Febrile parturients were more likely to be nulliparous, have used neuraxial analgesia, and have been delivered via cesarean section. The incidence of fever was lower in women exposed to magnesium (6.0%) than those who were not (10.2%). In multivariable logistic regression, women exposed to magnesium were less likely to develop a fever (adjusted odds ratio = 0.42 [95% CI, 0.31 to 0.58]). After propensity matching (N = 959 per group), the odds ratio of developing fever was lower in women who received magnesium therapy (odds ratio = 0.68 [95% CI, 0.48 to 0.98]). CONCLUSIONS: Magnesium may play a protective role against the development of intrapartum fever. Future work should further explore the association between magnesium dosing and the incidence of maternal fever.