Intensive care for extreme prematurity--moving beyond gestational age.

BACKGROUND: Decisions regarding whether to administer intensive care to extremely premature infants are often based on gestational age alone. However, other factors also affect the prognosis for these patients. METHODS: We prospectively studied a cohort of 4446 infants born at 22 to 25 weeks\u27 gestation (determined on the basis of the best obstetrical estimate) in the Neonatal Research Network of the National Institute of Child Health and Human Development to relate risk factors assessable at or before birth to the likelihood of survival, survival without profound neurodevelopmental impairment, and survival without neurodevelopmental impairment at a corrected age of 18 to 22 months. RESULTS: Among study infants, 3702 (83%) received intensive care in the form of mechanical ventilation. Among the 4192 study infants (94%) for whom outcomes were determined at 18 to 22 months, 49% died, 61% died or had profound impairment, and 73% died or had impairment. In multivariable analyses of infants who received intensive care, exposure to antenatal corticosteroids, female sex, singleton birth, and higher birth weight (per each 100-g increment) were each associated with reductions in the risk of death and the risk of death or profound or any neurodevelopmental impairment; these reductions were similar to those associated with a 1-week increase in gestational age. At the same estimated likelihood of a favorable outcome, girls were less likely than boys to receive intensive care. The outcomes for infants who underwent ventilation were better predicted with the use of the above factors than with use of gestational age alone. CONCLUSIONS: The likelihood of a favorable outcome with intensive care can be better estimated by consideration of four factors in addition to gestational age: sex, exposure or nonexposure to antenatal corticosteroids, whether single or multiple birth, and birth weight. (ClinicalTrials.gov numbers, NCT00063063 [ClinicalTrials.gov] and NCT00009633 [ClinicalTrials.gov].)

Advantages of Bayesian monitoring methods in deciding whether and when to stop a clinical trial: an example of a neonatal cooling trial.

BackgroundDecisions to stop randomized trials are often based on traditional P value thresholds and are often unconvincing to clinicians. To familiarize clinical investigators with the application and advantages of Bayesian monitoring methods, we illustrate the steps of Bayesian interim analysis using a recent major trial that was stopped based on frequentist analysis of safety and futility.MethodsWe conducted Bayesian reanalysis of a factorial trial in newborn infants with hypoxic-ischemic encephalopathy that was designed to investigate whether outcomes would be improved by deeper (32 °C) or longer cooling (120 h), as compared with those achieved by standard whole body cooling (33.5 °C for 72 h). Using prior trial data, we developed neutral and enthusiastic prior probabilities for the effect on predischarge mortality, defined stopping guidelines for a clinically meaningful effect, and derived posterior probabilities for predischarge mortality.ResultsBayesian relative risk estimates for predischarge mortality were closer to 1.0 than were frequentist estimates. Posterior probabilities suggested increased predischarge mortality (relative risk > 1.0) for the three intervention groups; two crossed the Bayesian futility threshold.ConclusionsBayesian analysis incorporating previous trial results and different pre-existing opinions can help interpret accruing data and facilitate informed stopping decisions that are likely to be meaningful and convincing to clinicians, meta-analysts, and guideline developers.Trial registrationClinicalTrials.gov NCT01192776 . Registered on 31 August 2010

Operator-Schmidt decompositions and the Fourier transform, with applications to the operator-Schmidt numbers of unitaries

The operator-Schmidt decomposition is useful in quantum information theory for quantifying the nonlocality of bipartite unitary operations. We construct a family of unitary operators on C^n tensor C^n whose operator-Schmidt decompositions are computed using the discrete Fourier transform. As a corollary, we produce unitaries on C^3 tensor C^3 with operator-Schmidt number S for every S in {1,...,9}. This corollary was unexpected, since it contradicted reasonable conjectures of Nielsen et al [Phys. Rev. A 67 (2003) 052301] based on intuition from a striking result in the two-qubit case. By the results of Dur, Vidal, and Cirac [Phys. Rev. Lett. 89 (2002) 057901 quant-ph/0112124], who also considered the two-qubit case, our result implies that there are nine equivalence classes of unitaries on C^3 tensor C^3 which are probabilistically interconvertible by (stochastic) local operations and classical communication. As another corollary, a prescription is produced for constructing maximally-entangled operators from biunimodular functions. Reversing tact, we state a generalized operator-Schmidt decomposition of the quantum Fourier transform considered as an operator C^M_1 tensor C^M_2 --> C^N_1 tensor C^N_2, with M_1 x M_2 = N_1 x N_2. This decomposition shows (by Nielsen's bound) that the communication cost of the QFT remains maximal when a net transfer of qudits is permitted. In an appendix, a canonical procedure is given for removing basis-dependence for results and proofs depending on the "magic basis" introduced in [S. Hill and W. Wootters, "Entanglement of a pair of quantum bits," Phys Rev. Lett 78 (1997) 5022-5025, quant-ph/9703041 (and quant-ph/9709029)].Comment: More formal version of my talk at the Simons Conference on Quantum and Reversible Computation at Stony Brook May 31, 2003. The talk slides and audio are available at http://www.physics.sunysb.edu/itp/conf/simons-qcomputation.html. Fixed typos and minor cosmetic

Hospital-Level Nicu Capacity, Utilization, and 30-Day Outcomes in Texas

IMPORTANCE: Risk-adjusted neonatal intensive care unit (NICU) utilization and outcomes vary markedly across regions and hospitals. The causes of this variation are poorly understood. OBJECTIVE: to assess the association of hospital-level NICU bed capacity with utilization and outcomes in newborn cohorts with differing levels of health risk. DESIGN, SETTING, AND PARTICIPANTS: This population-based retrospective cohort study included all Medicaid-insured live births in Texas from 2010 to 2014 using linked vital records and maternal and newborn claims data. Participants were Medicaid-insured singleton live births (LBs) with birth weights of at least 400 g and gestational ages between 22 and 44 weeks. Newborns were grouped into 3 cohorts: very low birth weight (VLBW; \u3c1500 \u3eg), late preterm (LPT; 34-36 weeks\u27 gestation), and nonpreterm newborns (NPT; ≥37 weeks\u27 gestation). Data analysis was conducted from January 2022 to October 2023. EXPOSURE: Hospital NICU capacity measured as reported NICU beds/100 LBs, adjusted (ie, allocated) for transfers. MAIN OUTCOMES AND MEASURES: NICU admissions and special care days; inpatient mortality and 30-day postdischarge adverse events (ie, mortality, emergency department visit, admission, observation stay). RESULTS: The overall cohort of 874 280 single LBs included 9938 VLBW (5054 [50.9%] female; mean [SD] birth weight, 1028.9 [289.6] g; mean [SD] gestational age, 27.6 [2.6] wk), 63 160 LPT (33 684 [53.3%] female; mean [SD] birth weight, 2664.0 [409.4] g; mean [SD] gestational age, 35.4 [0.8] wk), and 801 182 NPT (407 977 [50.9%] female; mean [SD] birth weight, 3318.7 [383.4] g; mean [SD] gestational age, 38.9 [1.0] wk) LBs. Median (IQR) NICU capacity was 0.84 (0.57-1.30) allocated beds/100 LB/year. For VLBW newborns, NICU capacity was not associated with the risk of NICU admission or number of special care days. For LPT newborns, birth in hospitals with the highest compared with the lowest category of capacity was associated with a 17% higher risk of NICU admission (adjusted risk ratio [aRR], 1.17; 95% CI, 1.01-1.33). For NPT newborns, risk of NICU admission was 55% higher (aRR, 1.55; 95% CI, 1.22-1.97) in the highest- vs the lowest-capacity hospitals. The number of special care days for LPT and NPT newborns was 21% (aRR, 1.21; 95% CI,1.08-1.36) and 37% (aRR, 1.37; 95% CI, 1.08-1.74) higher in the highest vs lowest capacity hospitals, respectively. Among LPT and NPT newborns, NICU capacity was associated with higher inpatient mortality and 30-day postdischarge adverse events. CONCLUSIONS AND RELEVANCE: In this cohort study of Medicaid-insured newborns in Texas, greater hospital NICU bed supply was associated with increased NICU utilization in newborns born LPT and NPT. Higher capacity was not associated with lower risk of adverse events. These findings raise important questions about how the NICU is used for newborns with lower risk

In-hospital outcomes and 30-day readmission rates among ischemic and hemorrhagic stroke patients with delirium

OBJECTIVE: Delirium is associated with poor outcomes among critically ill patients. However, it is not well characterized among patients with ischemic or hemorrhagic stroke (IS and HS). We provide the population-level frequency of in-hospital delirium and assess its association with in-hospital outcomes and with 30-day readmission among IS and HS patients. METHODS: We analyzed Nationwide in-hospital and readmission data for years 2010-2015 and identified stroke patients using ICD-9 codes. Delirium was identified using validated algorithms. Outcomes were in-hospital mortality, length of stay, unfavorable discharge disposition, and 30-day readmission. We used survey design logistic regression methods to provide national estimates of proportions and 95% confidence intervals (CI) for delirium, and odds ratios (OR) for association between delirium and poor outcomes. RESULTS: We identified 3,107,437 stroke discharges of whom 7.45% were coded to have delirium. This proportion significantly increased between 2010 (6.3%) and 2015 (8.7%) (aOR, 95% CI: 1.04, 1.03-1.05). Delirium proportion was higher among HS patients (ICH: 10.0%, SAH: 9.8%) as compared to IS patients (7.0%). Delirious stroke patients had higher in-hospital mortality (12.3% vs. 7.8%), longer in-hospital stay (11.6 days vs. 7.3 days) and a significantly greater adjusted risk of 30-day-readmission (16.7%) as compared to those without delirium (12.2%) (aRR, 95% CI: 1.13, 1.11-1.15). Upon readmission, patients with delirium at initial admission continued to have a longer length of stay (7.7 days vs. 6.6 days) and a higher in-hospital mortality (9.3% vs. 6.4%). CONCLUSION: Delirium identified through claims data in stroke patients is independently associated with poor in-hospital outcomes both at index admission and readmission. Identification and management of delirium among stroke patients provides an opportunity to improve outcomes

Outcomes of safety and effectiveness in a multicenter randomized, controlled trial of whole-body hypothermia for neonatal hypoxic-ischemic encephalopathy.

BACKGROUND: Whole-body hypothermia reduced the frequency of death or moderate/severe disabilities in neonates with hypoxic-ischemic encephalopathy in a randomized, controlled multicenter trial. OBJECTIVE: Our goal was to evaluate outcomes of safety and effectiveness of hypothermia in infants up to 18 to 22 months of age. DESIGN/METHODS: A priori outcomes were evaluated between hypothermia (n = 102) and control (n = 106) groups. RESULTS: Encephalopathy attributable to causes other than hypoxia-ischemia at birth was not noted. Inotropic support (hypothermia, 59% of infants; control, 56% of infants) was similar during the 72-hour study intervention period in both groups. Need for blood transfusions (hypothermia, 24%; control, 24%), platelet transfusions (hypothermia, 20%; control, 12%), and volume expanders (hypothermia, 54%; control, 49%) was similar in the 2 groups. Among infants with persistent pulmonary hypertension (hypothermia, 25%; control, 22%), nitric-oxide use (hypothermia, 68%; control, 57%) and placement on extracorporeal membrane oxygenation (hypothermia, 4%; control, 9%) was similar between the 2 groups. Non-central nervous system organ dysfunctions occurred with similar frequency in the hypothermia (74%) and control (73%) groups. Rehospitalization occurred among 27% of the infants in the hypothermia group and 42% of infants in the control group. At 18 months, the hypothermia group had 24 deaths, 19 severe disabilities, and 2 moderate disabilities, whereas the control group had 38 deaths, 25 severe disabilities, and 1 moderate disability. Growth parameters were similar between survivors. No adverse outcomes were noted among infants receiving hypothermia with transient reduction of temperature below a target of 33.5 degrees C at initiation of cooling. There was a trend in reduction of frequency of all outcomes in the hypothermia group compared with the control group in both moderate and severe encephalopathy categories. CONCLUSIONS: Although not powered to test these secondary outcomes, whole-body hypothermia in infants with encephalopathy was safe and was associated with a consistent trend for decreasing frequency of each of the components of disability

Automated Large Vessel Occlusion Detection Software and Thrombectomy Treatment Times: a Cluster Randomized Clinical Trial

IMPORTANCE: The benefit of endovascular stroke therapy (EVT) in large vessel occlusion (LVO) ischemic stroke is highly time dependent. Process improvements to accelerate in-hospital workflows are critical. OBJECTIVE: to determine whether automated computed tomography (CT) angiogram interpretation coupled with secure group messaging can improve in-hospital EVT workflows. DESIGN, SETTING, AND PARTICIPANTS: This cluster randomized stepped-wedge clinical trial took place from January 1, 2021, through February 27, 2022, at 4 comprehensive stroke centers (CSCs) in the greater Houston, Texas, area. All 443 participants with LVO stroke who presented through the emergency department were treated with EVT at the 4 CSCs. Exclusion criteria included patients presenting as transfers from an outside hospital (n = 158), in-hospital stroke (n = 39), and patients treated with EVT through randomization in a large core clinical trial (n = 3). INTERVENTION: Artificial intelligence (AI)-enabled automated LVO detection from CT angiogram coupled with secure messaging was activated at the 4 CSCs in a random-stepped fashion. Once activated, clinicians and radiologists received real-time alerts to their mobile phones notifying them of possible LVO within minutes of CT imaging completion. MAIN OUTCOMES AND MEASURES: Primary outcome was the effect of AI-enabled LVO detection on door-to-groin (DTG) time and was measured using a mixed-effects linear regression model, which included a random effect for cluster (CSC) and a fixed effect for exposure status (pre-AI vs post-AI). Secondary outcomes included time from hospital arrival to intravenous tissue plasminogen activator (IV tPA) bolus in eligible patients, time from initiation of CT scan to start of EVT, and hospital length of stay. In exploratory analysis, the study team evaluated the impact of AI implementation on 90-day modified Rankin Scale disability outcomes. RESULTS: Among 243 patients who met inclusion criteria, 140 were treated during the unexposed period and 103 during the exposed period. Median age for the complete cohort was 70 (IQR, 58-79) years and 122 were female (50%). Median National Institutes of Health Stroke Scale score at presentation was 17 (IQR, 11-22) and the median DTG preexposure was 100 (IQR, 81-116) minutes. In mixed-effects linear regression, implementation of the AI algorithm was associated with a reduction in DTG time by 11.2 minutes (95% CI, -18.22 to -4.2). Time from CT scan initiation to EVT start fell by 9.8 minutes (95% CI, -16.9 to -2.6). There were no differences in IV tPA treatment times nor hospital length of stay. In multivariable logistic regression adjusted for age, National Institutes of Health Stroke scale score, and the Alberta Stroke Program Early CT Score, there was no difference in likelihood of functional independence (modified Rankin Scale score, 0-2; odds ratio, 1.3; 95% CI, 0.42-4.0). CONCLUSIONS AND RELEVANCE: Automated LVO detection coupled with secure mobile phone application-based communication improved in-hospital acute ischemic stroke workflows. Software implementation was associated with clinically meaningful reductions in EVT treatment times. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05838456

Effect of Depth and Duration of Cooling on Death or Disability at Age 18 Months Among Neonates With Hypoxic-Ischemic Encephalopathy: A Randomized Clinical Trial

Importance Hypothermia for 72 hours at 33.5°C for neonatal hypoxic-ischemic encephalopathy reduces death or disability, but rates continue to be high. Objective To determine if cooling for 120 hours or to a temperature of 32.0°C reduces death or disability at age 18 months in infants with hypoxic-ischemic encephalopathy. Design, Setting, and Participants Randomized 2 × 2 factorial clinical trial in neonates (≥36 weeks’ gestation) with hypoxic-ischemic encephalopathy at 18 US centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network between October 2010 and January 2016. Interventions A total of 364 neonates were randomly assigned to 4 hypothermia groups: 33.5°C for 72 hours (n = 95), 32.0°C for 72 hours (n = 90), 33.5°C for 120 hours (n = 96), or 32.0°C for 120 hours (n = 83). Main Outcomes and Measures The primary outcome was death or moderate or severe disability at 18 to 22 months of age adjusted for center and level of encephalopathy. Severe disability included any of Bayley Scales of Infant Development III cognitive score less than 70, Gross Motor Function Classification System (GMFCS) level of 3 to 5, or blindness or hearing loss despite amplification. Moderate disability was defined as a cognitive score of 70 to 84 and either GMFCS level 2, active seizures, or hearing with amplification. Results The trial was stopped for safety and futility in November 2013 after 364 of the planned 726 infants were enrolled. Among 347 infants (95%) with primary outcome data (mean age at follow-up, 20.7 [SD, 3.5] months; 42% female), death or disability occurred in 56 of 176 (31.8%) cooled for 72 hours and 54 of 171 (31.6%) cooled for 120 hours (adjusted risk ratio, 0.92 [95% CI, 0.68-1.25]; adjusted absolute risk difference, −1.0% [95% CI, −10.2% to 8.1%]) and in 59 of 185 (31.9%) cooled to 33.5°C and 51 of 162 (31.5%) cooled to 32.0°C (adjusted risk ratio, 0.92 [95% CI, 0.68-1.26]; adjusted absolute risk difference, −3.1% [95% CI, −12.3% to 6.1%]). A significant interaction between longer and deeper cooling was observed (P = .048), with primary outcome rates of 29.3% at 33.5°C for 72 hours, 34.5% at 32.0°C for 72 hours, 34.4% at 33.5°C for 120 hours, and 28.2% at 32.0°C for 120 hours. Conclusions and Relevance Among term neonates with moderate or severe hypoxic-ischemic encephalopathy, cooling for longer than 72 hours, cooling to lower than 33.5°C, or both did not reduce death or moderate or severe disability at 18 months of age. However, the trial may be underpowered, and an interaction was found between longer and deeper cooling. These results support the current regimen of cooling for 72 hours at 33.5°C

Effect of Therapeutic Hypothermia Initiated After 6 Hours of Age on Death or Disability Among Newborns With Hypoxic-Ischemic Encephalopathy: A Randomized Clinical Trial

Importance: Hypothermia initiated at less than 6 hours after birth reduces death or disability for infants with hypoxic-ischemic encephalopathy at 36 weeks' or later gestation. To our knowledge, hypothermia trials have not been performed in infants presenting after 6 hours. Objective: To estimate the probability that hypothermia initiated at 6 to 24 hours after birth reduces the risk of death or disability at 18 months among infants with hypoxic-ischemic encephalopathy. Design, Setting, and Participants: A randomized clinical trial was conducted between April 2008 and June 2016 among infants at 36 weeks' or later gestation with moderate or severe hypoxic-ischemic encephalopathy enrolled at 6 to 24 hours after birth. Twenty-one US Neonatal Research Network centers participated. Bayesian analyses were prespecified given the anticipated limited sample size. Interventions: Targeted esophageal temperature was used in 168 infants. Eighty-three hypothermic infants were maintained at 33.5°C (acceptable range, 33°C-34°C) for 96 hours and then rewarmed. Eighty-five noncooled infants were maintained at 37.0°C (acceptable range, 36.5°C-37.3°C). Main Outcomes and Measures: The composite of death or disability (moderate or severe) at 18 to 22 months adjusted for level of encephalopathy and age at randomization. Results: Hypothermic and noncooled infants were term (mean [SD], 39 [2] and 39 [1] weeks' gestation, respectively), and 47 of 83 (57%) and 55 of 85 (65%) were male, respectively. Both groups were acidemic at birth, predominantly transferred to the treating center with moderate encephalopathy, and were randomized at a mean (SD) of 16 (5) and 15 (5) hours for hypothermic and noncooled groups, respectively. The primary outcome occurred in 19 of 78 hypothermic infants (24.4%) and 22 of 79 noncooled infants (27.9%) (absolute difference, 3.5%; 95% CI, -1% to 17%). Bayesian analysis using a neutral prior indicated a 76% posterior probability of reduced death or disability with hypothermia relative to the noncooled group (adjusted posterior risk ratio, 0.86; 95% credible interval, 0.58-1.29). The probability that death or disability in cooled infants was at least 1%, 2%, or 3% less than noncooled infants was 71%, 64%, and 56%, respectively. Conclusions and Relevance: Among term infants with hypoxic-ischemic encephalopathy, hypothermia initiated at 6 to 24 hours after birth compared with noncooling resulted in a 76% probability of any reduction in death or disability, and a 64% probability of at least 2% less death or disability at 18 to 22 months. Hypothermia initiated at 6 to 24 hours after birth may have benefit but there is uncertainty in its effectiveness