Conservative versus liberal oxygenation targets in critically ill children (Oxy-PICU): a UK multicentre, open, parallel-group, randomised clinical trial.

BACKGROUND: The optimal target for systemic oxygenation in critically ill children is unknown. Liberal oxygenation is widely practiced, but has been associated with harm in paediatric patients. We aimed to evaluate whether conservative oxygenation would reduce duration of organ support or incidence of death compared to standard care. METHODS: Oxy-PICU was a pragmatic, multicentre, open-label, randomised controlled trial in 15 UK paediatric intensive care units (PICUs). Children admitted as an emergency, who were older than 38 weeks corrected gestational age and younger than 16 years receiving invasive ventilation and supplemental oxygen were randomly allocated in a 1:1 ratio via a concealed, central, web-based randomisation system to conservative peripheral oxygen saturations ([SpO2] 88-92%) or liberal (SpO2 >94%) targets. The primary outcome was the duration of organ support at 30 days following random allocation, a rank-based endpoint with death either on or before day 30 as the worst outcome (a score equating to 31 days of organ support), with survivors assigned a score between 1 and 30 depending on the number of calendar days of organ support received. The primary effect estimate was the probabilistic index, a value greater than 0·5 indicating more than 50% probability that conservative oxygenation is superior to liberal oxygenation for a randomly selected patient. All participants in whom consent was available were included in the intention-to-treat analysis. The completed study was registered with the ISRCTN registry (ISRCTN92103439). FINDINGS: Between Sept 1, 2020, and May 15, 2022, 2040 children were randomly allocated to conservative or liberal oxygenation groups. Consent was available for 1872 (92%) of 2040 children. The conservative oxygenation group comprised 939 children (528 [57%] of 927 were female and 399 [43%] of 927 were male) and the liberal oxygenation group included 933 children (511 [56%] of 920 were female and 409 [45%] of 920 were male). Duration of organ support or death in the first 30 days was significantly lower in the conservative oxygenation group (probabilistic index 0·53, 95% CI 0·50-0·55; p=0·04 Wilcoxon rank-sum test, adjusted odds ratio 0·84 [95% CI 0·72-0·99]). Prespecified adverse events were reported in 24 (3%) of 939 patients in the conservative oxygenation group and 36 (4%) of 933 patients in the liberal oxygenation group. INTERPRETATION: Among invasively ventilated children who were admitted as an emergency to a PICU receiving supplemental oxygen, a conservative oxygenation target resulted in a small, but significant, greater probability of a better outcome in terms of duration of organ support at 30 days or death when compared with a liberal oxygenation target. Widespread adoption of a conservative oxygenation saturation target (SpO2 88-92%) could help improve outcomes and reduce costs for the sickest children admitted to PICUs. FUNDING: UK National Institute for Health and Care Research Health Technology Assessment Programme.

Randomization to a Liberal Versus Conservative Oxygenation Target: Redox Responses in Critically Ill Children.

RATIONALE: Optimal systemic oxygenation targets in pediatric critical illness are unknown. A U-shaped relationship exists between blood oxygen levels and PICU mortality. Redox stress or iatrogenic injury from intensive treatments are potential mechanisms of harm from hyperoxia. OBJECTIVES: To measure biomarkers of oxidative status in children admitted to PICU and randomized to conservative (oxygen-hemoglobin saturation [Sp o2 ] 88-92%) versus liberal (Sp o2 > 94%) peripheral oxygenation targets. DESIGN: Mechanistic substudy nested within the Oxygen in PICU (Oxy-PICU) pilot randomized feasibility clinical trial ( ClinicalTrials.gov : NCT03040570). SETTING: Three U.K. mixed medical and surgical PICUs in university hospitals. PATIENTS: Seventy-five eligible patients randomized to the Oxy-PICU randomized feasibility clinical trial. INTERVENTIONS: Randomization to a conservative (Sp o2 88-92%) versus liberal (Sp o2 > 94%) peripheral oxygenation target. MEASUREMENTS AND MAIN RESULTS: Blood and urine samples were collected at two timepoints: less than 24 hours and up to 72 hours from randomization in trial participants (March 2017 to July 2017). Plasma was analyzed for markers of ischemic/oxidative response, namely thiobarbituric acid-reactive substances (TBARS; lipid peroxidation marker) and ischemia-modified albumin (protein oxidation marker). Total urinary nitrate/nitrite was measured as a marker of reactive oxygen and nitrogen species (RONS). Blood hypoxia-inducible factor (HIF)-1a messenger RNA (mRNA) expression (hypoxia response gene) was measured by reverse transcription- polymerase chain reaction. Total urinary nitrate/nitrite levels were greater in the liberal compared with conservative oxygenation group at 72 hours (median difference 32.6 µmol/mmol of creatinine [95% CI 13.7-93.6]; p < 0.002, Mann-Whitney test). HIF-1a mRNA expression was increased in the conservative group compared with liberal in less than 24-hour samples (6.0-fold [95% CI 1.3-24.0]; p = 0.032). There were no significant differences in TBARS or ischemia-modified albumin. CONCLUSIONS: On comparing liberal with conservative oxygenation targets, we show, first, significant redox response (increase in urinary markers of RONS), but no changes in markers of lipid or protein oxidation. We also show what appears to be an early hypoxic response (increase in HIF-1a gene expression) in subjects exposed to conservative rather than liberal oxygenation targets.

Protocol for a Randomized Multiple Center Trial of Conservative Versus Liberal Oxygenation Targets in Critically Ill Children (Oxy-PICU): Oxygen in Pediatric Intensive Care.

OBJECTIVES: Oxygen administration is a fundamental part of pediatric critical care, with supplemental oxygen offered to nearly every acutely unwell child. However, optimal targets for systemic oxygenation are unknown. Oxy-PICU aims to evaluate the clinical effectiveness and cost-effectiveness of a conservative peripheral oxygen saturation (Sp o2 ) target of 88-92% compared with a liberal target of more than 94%. DESIGN: Pragmatic, open, multiple-center, parallel group randomized control trial with integrated economic evaluation. SETTING: Fifteen PICUs across England, Wales, and Scotland. PATIENTS: Infants and children age more than 38 week-corrected gestational age to 16 years who are accepted to a participating PICU as an unplanned admission and receiving invasive mechanical ventilation with supplemental oxygen for abnormal gas exchange. INTERVENTION: Adjustment of ventilation and inspired oxygen settings to achieve an Sp o2 target of 88-92% during invasive mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: Randomization is 1:1 to a liberal Sp o2 target of more than 94% or a conservative Sp o2 target of 88-92% (inclusive), using minimization with a random component. Minimization will be performed on: age, site, primary reason for admission, and severity of abnormality of gas exchange. Due to the emergency nature of the treatment, approaching patients for written informed consent will be deferred to after randomization. The primary clinical outcome is a composite of death and days of organ support at 30 days. Baseline demographics and clinical status will be recorded as well as daily measures of oxygenation and organ support, and discharge outcomes. This trial received Health Research Authority approval on December 23, 2019 (reference: 272768), including a favorable ethical opinion from the East of England-Cambridge South Research Ethics Committee (reference number: 19/EE/0362). Trial findings will be disseminated in national and international conferences and peer-reviewed journals.

Psychological impact of working in paediatric intensive care. A UK-wide prevalence study.

OBJECTIVE: To determine the prevalence of work-related psychological distress in staff working in UK paediatric intensive care units (PICU). DESIGN: Online (Qualtrics) staff questionnaire, conducted April to May 2018. SETTING: Staff working in 29 PICUs and 10 PICU transport services were invited to participate. PARTICIPANTS: 1656 staff completed the survey: 1194 nurses, 270 physicians and 192 others. 234 (14%) respondents were male. Median age was 35 (IQR 28-44). MAIN OUTCOME MEASURES: The Moral Distress Scale-Revised (MDS-R) was used to look at moral distress, the abbreviated Maslach Burnout Inventory to examine the depersonalisation and emotional exhaustion domains of burnout, and the Trauma Screening Questionnaire (TSQ) to assess risk of post-traumatic stress disorder (PTSD). RESULTS: 435/1194 (36%) nurses, 48/270 (18%) physicians and 19/192 (10%) other staff scored above the study threshold for moral distress (≥90 on MDS-R) (χ2 test, p<0.00001). 594/1194 (50%) nurses, 99/270 (37%) physicians and 86/192 (45%) other staff had high burnout scores (χ2 test, p=0.0004). 366/1194 (31%) nurses, 42/270 (16%) physicians and 21/192 (11%) other staff scored at risk for PTSD (χ2 test, p<0.00001). Junior nurses were at highest risk of moral distress and PTSD, and junior doctors of burnout. Larger unit size was associated with higher MDS-R, burnout and TSQ scores. CONCLUSIONS: These results suggest that UK PICU staff are experiencing work-related distress. Further studies are needed to understand causation and to develop strategies for prevention and treatment.

Conservative versus liberal oxygenation targets in critically ill children: the randomised multiple-centre pilot Oxy-PICU trial.

BACKGROUND: Oxygen saturation monitoring for children receiving respiratory support is standard worldwide. No randomised clinical trials have compared peripheral oxygen saturation (SpO2) targets for critically ill children. The harm of interventions to raise SpO2 to > 94% may exceed their benefits. METHODS: We undertook an open, parallel-group randomised trial of children > 38 weeks completed gestation and < 16 years of age receiving invasive or non-invasive respiratory support and supplemental oxygen who were admitted urgently to one of three paediatric intensive care units. A 'research without prior consent' approach was employed. Children were randomly assigned to a liberal oxygenation group (SpO2 targets > 94%) or a conservative oxygenation group (SpO2 = 88-92% inclusive). Outcomes were measures of feasibility: recruitment rate, protocol adherence and acceptability, between-group separation of SpO2 and safety. The Oxy-PICU trial was registered before recruitment: ClinicalTrials.gov identifier NCT03040570. RESULTS: A total of 159 children met the inclusion criteria, of whom 119 (75%) were randomised between April and July 2017, representing a rate of 10 patients per month per site. The mean time to randomisation from first contact with an intensive care team was 1.9 (SD 2.2) h. Consent to continue in the study was obtained in 107 cases (90%); the children's parents/legal representatives were supportive of the consent process. The median (interquartile range, IQR) of time-weighted individual mean SpO2 was 94.9% (92.6-97.1) in the conservative oxygenation group and 97.5% (96.2-98.4) in the liberal group [difference 2.7%, 95% confidence interval (95% CI) 1.3-4.0%, p < 0.001]. Median (IQR) time-weighted individual mean FiO2 was 0.28 (0.24-0.37) in the conservative group and 0.37 (0.30-0.42) in the liberal group (difference 0.08, 95% CI 0.03-0.13, p < 0.001). There were no significant between-group differences in length of stay, duration of organ support or mortality. Two prespecified serious adverse events (cardiac arrests) occurred, both in the liberal oxygenation group. CONCLUSION: A definitive clinical trial of peripheral oxygen saturation targets is feasible in critically ill children.

Protocol for a randomised pilot multiple centre trial of conservative versus liberal oxygenation targets in critically ill children (Oxy-PICU).

INTRODUCTION: Optimal targets for systemic oxygenation in paediatric critical illness are unknown. Observational data indicate that high levels of arterial oxygenation are associated with poor outcomes in resuscitation of the newborn and in adult critical illness. Within paediatric intensive care units (PICUs), staff prevent severe hypoxia wherever possible, but beyond this there is no consensus. Practice varies widely with age, diagnosis, treating doctor and local or national guidelines followed, though peripheral blood oxygen saturations (SpO2) of >95% are often targeted. The overall aim of this pilot study is to determine the feasibility of performing a randomised trial in critically ill children comparing current practice of liberal SpO2 targets with a more conservative target. METHODS AND ANALYSIS: Oxy-PICU is a pragmatic, open, pilot randomised controlled trial in infants and children requiring mechanical ventilation and receiving supplemental oxygen for abnormal gas exchange accepted for emergency admission to one of three participating UK PICUs. The study groups will be either a conservative SpO2 target of 88%-92% (inclusive) or a liberal SpO2 target of >94%. Infants and children who fulfil all inclusion criteria and none of the exclusion criteria will be randomised 1:1 by a secure web-based system to one of the two groups. Baseline demographics and clinical status will be recorded as well as daily measures of oxygenation and organ support. Discharge outcomes will also be recorded. In addition to observational data, blood and urine samples will be taken to identify biochemical markers of oxidative stress. Outcomes are targeted at assessing study feasibility with a primary outcome of adequate study recruitment (target: 120 participants). ETHICS AND DISSEMINATION: The trial received Health Research Authority approval on 1 June 2017 (16/SC/0617). Study findings will be disseminated in national and international conferences and peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03040570.

Where's the capital? A geographical essay.

This paper is inspired by Thomas Piketty's book Capital in the Twenty-First Century. Piketty does a wonderful job of tracing income and wealth over time, and relating changes to trends of economic and population growth, and drawing out the implications for inequality, inheritance and even democracy. But, he says relatively little about where capital is located, how capital accumulation in one place relies on activities elsewhere, how capital is urbanized with advanced capitalism and what life is like in spaces without capital. This paper asks 'where is the geography in Capital' or 'where is the geography of capital in Capital'? Following Piketty's lead, the paper develops its analysis through a number of important novels. It examines, first, the debate that Jane Austen ignored colonialism and slavery in her treatment of nineteenth century Britain, second, how Balzac and then Zola provide insight to the urban political economy of capital later in the century, and third, how Katherine Boo attends to inequality as the everyday suffering of the poor.

The potent M1 receptor allosteric agonist GSK1034702 improves episodic memory in humans in the nicotine abstinence model of cognitive dysfunction.

Episodic memory deficits are a core feature of neurodegenerative disorders. Muscarinic M(1) receptors play a critical role in modulating learning and memory and are highly expressed in the hippocampus. We examined the effect of GSK1034702, a potent M(1) receptor allosteric agonist, on cognitive function, and in particular episodic memory, in healthy smokers using the nicotine abstinence model of cognitive dysfunction. The study utilized a randomized, double-blind, placebo-controlled, cross-over design in which 20 male nicotine abstained smokers were tested following single doses of placebo, 4 and 8 mg GSK1034702. Compared to the baseline (nicotine on-state), nicotine abstinence showed statistical significance in reducing immediate (p=0.019) and delayed (p=0.02) recall. GSK1034702 (8 mg) significantly attenuated (i.e. improved) immediate recall (p=0.014) but not delayed recall. None of the other cognitive domains was modulated by either nicotine abstinence or GSK1034702. These findings suggest that stimulating M(1) receptor mediated neurotransmission in humans with GSK1034702 improves memory encoding potentially by modulating hippocampal function. Hence, selective M(1) receptor allosteric agonists may have therapeutic benefits in disorders of impaired learning including Alzheimer's disease.

Distinct muscarinic acetylcholine receptor subtypes mediate pre- and postsynaptic effects in rat neocortex.

BACKGROUND: Cholinergic transmission has been implicated in learning, memory and cognition. However, the cellular effects induced by muscarinic acetylcholine receptors (mAChRs) activation are poorly understood in the neocortex. We investigated the effects of the cholinergic agonist carbachol (CCh) and various agonists and antagonists on neuronal activity in rat neocortical slices using intracellular (sharp microelectrode) and field potential recordings. RESULTS: CCh increased neuronal firing but reduced synaptic transmission. The increase of neuronal firing was antagonized by pirenzepine (M1/M4 mAChRs antagonist) but not by AF-DX 116 (M2/M4 mAChRs antagonist). Pirenzepine reversed the depressant effect of CCh on excitatory postsynaptic potential (EPSP) but had marginal effects when applied before CCh. AF-DX 116 antagonized the depression of EPSP when applied before or during CCh. CCh also decreased the paired-pulse inhibition of field potentials and the inhibitory conductances mediated by GABA(A) and GABA(B) receptors. The depression of paired-pulse inhibition was antagonized or prevented by AF-DX 116 or atropine but only marginally by pirenzepine. The inhibitory conductances were unaltered by xanomeline (M1/M4 mAChRs agonist), yet the CCh-induced depression was antagonized by AF-DX 116. Linopirdine, a selective M-current blocker, mimicked the effect of CCh on neuronal firing. However, linopirdine had no effect on the amplitude of EPSP or on the paired-pulse inhibition, indicating that M-current is involved in the increase of neuronal excitability but neither in the depression of EPSP nor paired-pulse inhibition. CONCLUSIONS: These data indicate that the three effects are mediated by different mAChRs, the increase in firing being mediated by M1 mAChR, decrease of inhibition by M2 mAChR and depression of excitatory transmission by M4 mAChR. The depression of EPSP and increase of neuronal firing might enhance the signal-to-noise ratio, whereas the concomitant depression of inhibition would facilitate long-term potentiation. Thus, this triade of effects may represent a "neuronal correlate" of attention and learning.

N-desmethylclozapine (NDMC) is an antagonist at the human native muscarinic M(1) receptor.

N-desmethylclozapine (NDMC) has been reported to display partial agonism at the human recombinant and rat native M(1) mAChR, a property suggested to contribute to the clinical efficacy of clozapine. However, the profile of action of NDMC at the human native M(1) mAChR has not been reported. The effect of NDMC on M(1) mAChR function was investigated in human native tissues by assessing its effect on (1) M(1) mAChR-mediated stimulation of [(35)S]-GTPgammaS-G(q/11)alpha binding to human post mortem cortical membranes and (2) the M(1) mAChR-mediated increase in neuronal firing in human neocortical slices. NDMC displayed intrinsic activities of 46+/-9%, compared to oxo-M, at the human recombinant M(1) receptor, in FLIPR studies and 35+/-4% at rat native M(1) receptors in [(35)S]-GTPgammaS-G(q/11)alpha binding studies. In [(35)S]-GTPgammaS-G(q/11)alpha binding studies in human cortex, oxo-M stimulated binding by 240+/-26% above basal with a pEC(50) of 6.56+/-0.05. In contrast, NDMC did not stimulate [(35)S]-GTPgammaS-G(q/11)alpha binding to human cortical membranes but antagonised the response to oxo-M (2microM) showing a pK(B) of 6.8, comparable to its human recombinant M(1) mAChR affinity (pK(i)=6.9) derived from [(3)H]-NMS binding studies. In human, contrary to the rat neocortical slices, NDMC did not elicit a significant increase in M(1) mAChR-mediated neuronal firing, and attenuated a carbachol-induced increase in neuronal firing when pre-applied. These data indicate that, whereas NDMC displays moderate to low levels of partial agonism at the human recombinant and rat native M(1) mAChR, respectively, it acts as an antagonist at the M(1) mAChR in human cortex.

In vitro and in vivo comparison of two non-peptide tachykinin NK3 receptor antagonists: Improvements in efficacy achieved through enhanced brain penetration or altered pharmacological characteristics.

Clinical evaluation of tachykinin NK(3) receptor antagonists has provided support for the therapeutic utility of this target in schizophrenia. However, these studies have not been entirely conclusive, possibly because of the pharmacokinetic limitations of these molecules. In the search for tachykinin NK(3) receptor antagonists with improved properties, we have discovered GSK172981 and GSK256471. Both compounds demonstrated high affinity for recombinant human (pK(i) values 7.7 and 8.9, respectively) and native guinea pig (pK(i) values 7.8 and 8.4, respectively) tachykinin NK(3) receptors. In vitro functional evaluations revealed GSK172981 to be a competitive antagonist (pA(2)=7.2) at cloned human tachykinin NK(3) receptor whereas GSK256471 diminished the neurokinin B-induced E(max) response, indicative of non-surmountable antagonist pharmacology (pA(2)=9.2). GSK172981 also exhibited a competitive profile in antagonizing neurokinin B-stimulated neuronal activity recorded from the guinea pig medial habenula slices (apparent pK(B)=8.1), whilst GSK256471 abolished the agonist-induced response. Central nervous system penetration by GSK172981 and GSK256471 was indicated by dose-dependent ex vivo tachykinin NK(3) receptor occupancy in medial prefrontal cortex (ED(50) values of 0.8 and 0.9 mg/kg, i.p., respectively) and the dose-dependent attenuation of agonist-induced "wet dog shake" behaviours in guinea pigs. Finally, in vivo microdialysis studies demonstrated that acute GSK172981 (30 mg/kg, i.p.) and GSK256471 (1mg/kg, i.p.) attenuated haloperidol-induced increases in extracellular dopamine in the guinea pig nucleus accumbens. Taken together, these in vitro and in vivo characterisations of the tachykinin NK(3) receptor antagonists GSK172981 and GSK256471 support their potential utility in the treatment of schizophrenia.

In vitro and in vivo characterization of the non-peptide NK3 receptor antagonist SB-223412 (talnetant): potential therapeutic utility in the treatment of schizophrenia.

Neurokinin-3 (NK3) receptors are concentrated in forebrain and basal ganglia structures within the mammalian CNS. This distribution, together with the modulatory influence of NK3 receptors on monoaminergic neurotransmission, has led to the hypothesis that NK3 receptor antagonists may have therapeutic efficacy in the treatment of psychiatric disorders. Here we describe the in vitro and in vivo characterization of the highly selective NK3 receptor antagonist talnetant (SB-223412). Talnetant has high affinity for recombinant human NK3 receptors (pKi 8.7) and demonstrates selectivity over other neurokinin receptors (pKi NK2 = 6.6 and NK1<4). In native tissue-binding studies, talnetant displayed high affinity for the guinea pig NK3 receptor (pKi 8.5). Functionally, talnetant competitively antagonized neurokinin B (NKB)-induced responses at the human recombinant receptor in both calcium and phosphoinositol second messenger assay systems (pA2 of 8.1 and 7.7, respectively). In guinea pig brain slices, talnetant antagonized NKB-induced increases in neuronal firing in the medial habenula (pKB = 7.9) and senktide-induced increases in neuronal firing in the substantia nigra pars compacta (pKB = 7.7) with no diminution of maximal agonist efficacy, suggesting competitive antagonism at native NK3 receptors. Talnetant (3-30 mg/kg i.p.) significantly attenuated senktide-induced 'wet dog shake' behaviors in the guinea pig in a dose-dependent manner. Microdialysis studies demonstrated that acute administration of talnetant (30 mg/kg i.p.) produced significant increases in extracellular dopamine and norepinephrine in the medial prefrontal cortex and attenuated haloperidol-induced increases in nucleus accumbens dopamine levels in the freely moving guinea pigs. Taken together, these data demonstrate that talnetant is a selective, competitive, brain-penetrant NK3 receptor antagonist with the ability to modulate mesolimbic and mesocortical dopaminergic neurotransmission and hence support its potential therapeutic utility in the treatment of schizophrenia.

Evaluation of the mGlu8 receptor as a putative therapeutic target in schizophrenia.

Aberrant glutamatergic neurotransmission may underlie the pathogenesis of schizophrenia and metabotropic glutamate receptors (mGluRs) have been implicated in the disease. We have established the localization of the group III mGluR subtype, mGluR8, in the human body and investigated the biological effects of the selective mGluR8 agonist (S)-3,4-dicarboxyphenylglycine ((S)-3,4-DCPG) in schizophrenia-related animal models. The mGlu8 receptor has a widespread CNS distribution with expression observed in key brain regions associated with schizophrenia pathogenesis including the hippocampus. (S)-3,4-DCPG inhibited synaptic transmission and increased paired-pulse facilitation in rat hippocampal slices supporting the role of mGluR8 as a presynaptic autoreceptor. Using the rat Maximal Electroshock Seizure Threshold (MEST) test, (S)-3,4-DCPG (30 mg/kg, i.p.) reduced seizure activity confirming the compound to be centrally active following systemic administration. (S)-3,4-DCPG did not reverse (locomotor) hyperactivity induced by acute administration of phenylcyclidine (PCP, 1-32 mg/kg, i.p.) or amphetamine (3-30 mg/kg, i.p.) in Sprague-Dawley rats. However, 10 nmol (i.c.v.) (S)-3.4-DCPG did reverse amphetamine-induced hyperactivity in mice although it also inhibited spontaneous locomotor activity at this dose. In addition, mGluR8 null mutant mouse behavioral phenotyping revealed an anxiety-related phenotype but no deficit in sensorimotor gating. These data provide a potential role for mGluR8 in anxiety and suggest that mGluR8 may not be a therapeutic target for schizophrenia.