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Oxygen (O2) delivery, which is fundamental to supporting patients with critical illness, is a function of blood O2 content and flow. This article reviews red blood cell (RBC) physiology and dysfunction relevant to disordered O2 delivery in the critically ill. Flow is the focus of O2 delivery regulation: O2 content is relatively fixed, whereas flow fluctuates greatly. Thus, blood flow volume and distribution vary to maintain coupling between O2 delivery and demand. This article reviews conventional RBC physiology influencing O2 delivery and introduces a paradigm for O2 delivery homeostasis based on coordinated gas transport and vascular signaling by RBCs.

Aim In-hospital cardiac arrest occurs in >5000 children each year in the US and almost half will not survive to discharge. Animal data demonstrate that an immediate post-resuscitation burst of hypertension is associated with improved survival. We aimed to determine if systolic and diastolic invasive arterial blood pressures immediately (0–20 min) after return of spontaneous circulation (ROSC) are associated with survival and neurologic outcomes at hospital discharge. Methods This is a secondary analysis of the Pediatric Intensive Care Quality of CPR (PICqCPR) study of invasively measured blood pressures during intensive care unit CPR. Patients were eligible if they achieved ROSC and had at least one invasively measured blood pressure within the first 20 min following ROSC. Post-ROSC blood pressures were normalized for age, sex and height. “Immediate hypertension” was defined as at least one systolic or diastolic blood pressure >90th percentile. The primary outcome was survival to hospital discharge. Results Of 102 children, 70 (68.6%) had at least one episode of immediate post-CPR diastolic hypertension. After controlling for pre-existing hypotension, duration of CPR, calcium administration, and first documented rhythm, patients with immediate post-CPR diastolic hypertension were more likely to survive to hospital discharge (79.3% vs. 54.5%; adjusted OR = 2.93; 95%CI, 1.16–7.69). Conclusions In this post hoc secondary analysis of the PICqCPR study, 68.6% of subjects had diastolic hypertension within 20 min of ROSC. Immediate post-ROSC hypertension was associated with increased odds of survival to discharge, even after adjusting for covariates of interest.

AIM: The primary aim of this study was to evaluate the association between chest compression rates and 1) arterial blood pressure and 2) survival outcomes during pediatric in-hospital cardiopulmonary resuscitation (CPR). METHODS: Prospective observational study of children ≥37 weeks gestation and 120–140, >140) and outcomes. RESULTS: Compression rate data were available for 164 patients. More than half (98/164; 60%) were < 1 year old. Return of circulation was achieved in 148/164 (90%); survival to hospital discharge in 77/164 (47%). Percentage of events with average rate within Guidelines was 32.9%. Compared to Guidelines, higher rate categories were associated with lower systolic blood pressures (>120–140, p=0.010; >140, p=0.077), but not survival. A rate between 80

Gramicidin A, a topical antibiotic made from alternating L and D amino acids, is characterized by its wide central pore; upon insertion into membranes, it forms channels that disrupts ion gradients. We present helical peptidomimetics with this characteristic wide central pore that have been designed to mimic gramicidin A channels. Mimetics were designed using molecular modeling focused on oligomers of heterochiral dipeptides of proline analogs, in particular azaproline (AzPro). Molecular Dynamics simulations in water confirmed the stability of the designed helices. A sixteen-residue Formyl-(AzPro-Pro)(8)-NHCH(2)CH(2)OH helix was synthesized as well as a full thirty-two residue Cbz-(AzPro-Pro)(16)-O(t)Bu channels. No liposomal lysis activity was observed suggesting lack of channel formation, possibly due to inappropriate hydrogen-bonding interactions in the membrane. These peptidomimetics also did not hemolyze red blood cells, unlike gramicidin A.

There are three key issues relating anemia and transfusion: 1) anemia may be well tolerated by patients with physiologic reserve, 2) donor red blood cell physiology is impaired compared to that for native red blood cells, and 3) patients transfused for indications other than anemia attributable oxygen delivery failure have worse outcomes than those who are not transfused. Current approaches to transfusion decision-making (TDM) lack the ability to: 1) differentiate between patients who require transfusions and those that do not and 2) guide transfusion timing and amount based upon oxygen delivery-based targets. This review explores approaches to TDM and how continued advances are leading to a revolution in the field of transfusion medicine itself.

S-nitrosation of cysteine thiols (SNOs), commonly referred to as S-nitrosylation, is a cysteine oxoform that plays an important role in cellular signaling and impacts protein function and stability. Direct labeling of SNOs in cells with the flexibility to perform a wide range of cellular and biochemical assays remains a bottleneck as all SNO-targeted probes to date employ a single analytical modality such as biotin or a specific fluorophore. We therefore developed a clickable, alkyne-containing SNO probe ‘PBZyn’ based on the o-phosphino-benzoyl group warhead that enables multi-modal analysis via click conjugation. We demonstrate the utility of PBZyn to assay SNOs using in situ cellular imaging, protein blotting and affinity purification, as well as mass spectrometry. The flexible PBZyn probe will greatly facilitate investigation into the regulation of SNOs.

BACKGROUND: Decreased tumor necrosis factor (TNF)-α production in whole blood following ex vivo lipopolysaccharide (LPS) stimulation indicates suppression of the toll-like receptor (TLR)4 pathway. This is associated with increased mortality in pediatric influenza critical illness. Whether anti-viral immune signaling pathways are also suppressed in these patients is unclear. OBJECTIVES: We sought to evaluate suppression of the TLR4 and the anti-viral retinoic acid-inducible gene-I (RIG-I) pathways with clinical outcomes in children with severe influenza infection. METHODS: In this 24-center, prospective, observational cohort study of children with confirmed influenza infection, blood was collected within 72 hours of intensive care unit admission. Ex vivo whole blood stimulations were performed with matched controls using the viral ligand, polyinosinic-polycytidylic acid (poly(I:C))-low molecular weight/LyoVec™ and LPS to evaluate interferon (IFN)-α and TNF-α production capacities (RIG-I and TLR4 pathways, respectively). RESULTS: Suppression of either IFNα or TNFα production capacity was associated with longer duration of mechanical ventilation and hospitalization, and increased organ dysfunction. Children with suppression of both RIG-I and TLR4 pathways (n=33/103, 32%) were more likely to have prolonged (≥7 days) multiple organ dysfunction syndrome (30.3% vs 8.6%, p=0.004) or prolonged hypoxemic respiratory failure (39.4% vs 11.4% p=0.001) compared to those with single- or no pathway suppression. CONCLUSIONS: Suppression of both RIG-I and TLR4 signaling pathways, essential for respective anti-viral and anti-bacterial pathogens responses, is common in previously immunocompetent children with influenza-related critical illness and is associated with bacterial co-infection and adverse outcomes. Prospective testing of both pathways may aid in risk-stratification and in immune monitoring.

This chapter summarizes the principles of RSNO measurement in the gas phase, utilizing ozone-based chemiluminescence and the copper cysteine (2C) ± carbon monoxide (3C) reagent. Although an indirect method for quantifying RSNOs, this assay represents one of the most robust methodologies available. It exploits the NO• detection sensitivity of ozone based chemiluminscence, which is within the range required to detect physiological concentrations of RSNO metabolites. Additionally, the specificity of the copper cysteine (2C and 3C) reagent for RSNOs negates the need for sample pretreatment, thereby minimizing the likelihood of sample contamination (false positive results), NO species inter-conversion, or the loss of certain highly labile RSNO species. Herein, we outline the principles of this methodology, summarizing key issues, potential pitfalls and corresponding solutions.

Summary Background Outcomes after traumatic brain injury are worsened by secondary insults; modern intensive-care units address such challenges through use of best-practice pathways. Organisation of intensive-care units has an important role in pathway effectiveness. We aimed to assess the effect of a paediatric neurocritical care programme (PNCP) on outcomes for children with severe traumatic brain injury. Methods We undertook a retrospective cohort study of 123 paediatric patients with severe traumatic brain injury (Glasgow coma scale scores ≤8, without gunshot or abusive head trauma, cardiac arrest, or Glasgow coma scale scores of 3 with fixed and dilated pupils) admitted to the paediatric intensive-care unit of the St Louis Children's Hospital (St Louis, MO, USA) between July 15, 1999, and Jan 15, 2012. The primary outcome was rate of categorised hospital discharge disposition before and after implementation of a PNCP on Sept 17, 2005. We developed an ordered probit statistical model to assess adjusted outcome as a function of initial injury severity. We assessed care-team behaviour by comparing timing of invasive neuromonitoring and scored intensity of therapies targeting intracranial hypertension. Findings Characteristics of treated patients (aged 3–219 months) were much the same between treatment periods. Before PNCP implementation, 33 (52%) of 63 patients had unfavourable disposition at hospital discharge (death or admission to an inpatient facility) and 30 (48%) had a favourable disposition (home with or without treatment); after PNCP implementation, 20 (33%) of 60 patients had unfavourable disposition and 40 (67%) had favourable disposition (p=0·01). Seven (11%) patients died before PNCP implementation compared with two (3%) deaths after implementation. The probit model indicated that outcome improved across the spectrum of Glasgow coma scale scores after resuscitation (p=0·02); this improvement progressed with increasing injury severity. Kaplan-Meier analysis suggested that neuromonitoring was started earlier and maintained longer after implementation of the PNCP (p=0·03). Therapeutic intensity scores were increased for the first 3 days of treatment after PNCP implementation (p=0·0298 for day 1, p=0·0292 for day 2, and p=0·0471 for day 3). The probit model suggested that increasing age (p=0·03), paediatric risk of mortality III scores (p=0·0003), and injury severity scores (p=0·02) were reliably associated with increased probability of unfavourable outcomes whereas white race (p=0·01), use of intracranial pressure monitoring (p=0·001), and increasing Glasgow coma scale scores after resuscitation (p=0·04) were associated with increased probability of favourable outcomes. Interpretation Outcomes for children with traumatic brain injury can be improved by altering the care system in a way that stably implements a cooperative programme of accepted best practice. Funding St Louis Children's Hospital and the Sean Glanvill Foundations.

Red Blood Cell (RBC) transfusion is indicated to improve oxygen delivery to tissue, and for no other purpose. We have come to appreciate that donor RBCs are fundamentally altered during processing and storage, in a fashion that both impairs oxygen transport efficacy and introduces additional risk by perturbing both immune and coagulation systems. The protean biophysical and physiologic changes in RBC function arising from storage are termed the ‘storage lesion’; many have been understood for some time; for example, we know that the oxygen affinity of stored blood rises during the storage period1 and that intracellular allosteric regulators, notably 2,3-bisphosphoglyceric acid (DPG) and ATP, are depleted during storage. Our appreciation of other storage lesion features has emerged with improved understanding of coagulation, immune and vascular signaling systems. Herein we review key features of the ‘storage lesion’. Additionally, we call particular attention to the newly appreciated role of RBCs in regulating linkage between regional blood flow and regional O2 consumption by regulating the bioavailability of key vasoactive mediators in plasma, as well as discuss how processing and storage disturbs this key signaling function and impairs transfusion efficacy.

To characterize the clinical course, therapies, and outcomes of children with fatal and near-fatal asthma admitted to pediatric intensive care units (PICUs).This was a retrospective chart abstraction across the 8 tertiary care PICUs of the Collaborative Pediatric Critical Care Research Network (CPCCRN). Inclusion criteria were children (aged 1-18 years) admitted between 2005 and 2009 (inclusive) for asthma who received ventilation (near-fatal) or died (fatal). Data collected included medications, ventilator strategies, concomitant therapies, demographic information, and risk variables.Of the 261 eligible children, 33 (13%) had no previous history of asthma, 218 (84%) survived with no known complications, and 32 (12%) had complications. Eleven (4%) died, 10 of whom had experienced cardiac arrest before admission. Patients intubated outside the PICU had a shorter duration of ventilation (median, 25 hours vs 84 hours; P.001). African-Americans were disproportionately represented among the intubated children and had a shorter duration of intubation. Barotrauma occurred in 15 children (6%) before admission. Pharmacologic therapy was highly variable, with similar outcomes.Of the children ventilated in the CPCCRN PICUs, 96% survived to hospital discharge. Most of the children who died experienced cardiac arrest before admission. Intubation outside the PICU was correlated with shorter duration of ventilation. Complications of barotrauma and neuromyopathy were uncommon. Practice patterns varied widely among the CPCCRN sites.