Introduction Headache is a common chief complaint of children presenting to emergency departments (EDs). Approximately 0.5%–1% will have emergent intracranial abnormalities (EIAs) such as brain tumours or strokes. However, more than one-third undergo emergent neuroimaging in the ED, resulting in a large number of children unnecessarily exposed to radiation. The overuse of neuroimaging in children with headaches in the ED is driven by clinician concern for life-threatening EIAs and lack of clarity regarding which clinical characteristics accurately identify children with EIAs. The study objective is to derive and internally validate a stratification model that accurately identifies the risk of EIA in children with headaches based on clinically sensible and reliable variables. Methods and analysis Prospective cohort study of 28 000 children with headaches presenting to any of 18 EDs in the Pediatric Emergency Care Applied Research Network (PECARN). We include children aged 2–17 years with a chief complaint of headache. We exclude children with a clear non-intracranial alternative diagnosis, fever, neuroimaging within previous year, neurological or developmental condition such that patient history or physical examination may be unreliable, Glasgow Coma Scale score<14, intoxication, known pregnancy, history of intracranial surgery, known structural abnormality of the brain, pre-existing condition predisposing to an intracranial abnormality or intracranial hypertension, head injury within 14 days or not speaking English or Spanish. Clinicians complete a standardised history and physical examination of all eligible patients. Primary outcome is the presence of an EIA as determined by neuroimaging or clinical follow-up. We will use binary recursive partitioning and multiple regression analyses to create and internally validate the risk stratification model.

Patients with sickle cell disease (SCD) commonly experience vaso-occlusive pain episodes (VOE), which accounts for 78% of all emergency department (ED) visits among patients with SCD.1 SCD-VOE pain is often under-, and inconsistently, treated in the ED.2 In 2014, the National Heart, Lung, and Blood Institute (NHLBI) put forth guidelines to direct the care of patients presenting with VOE.3 Key guideline recommendations include: 1) triage as high priority with rapid evaluation of patients presenting with VOE, 2) use of parenteral opioids for moderate-to-severe pain with administration ≤30 minutes after ED triage or ≤60 minutes after registration, 3) pain reassessment and subsequent parenteral opioid dosing every 15–30 minutes until pain is controlled, 4) the administration of non-steroidal anti-inflammatory drugs (NSAIDS) as an analgesic adjuvant (if no contraindications exist), and 5) in euvolemic patients with SCD-VOE who are unable to drink fluids, intravenous hydration at no more than maintenance rate to avoid over-hydration. Our objective was to assess adherence to all NHLBI recommendations and the impact of timely opioid administration on hospital admission in a study of 20 academic pediatric EDs in the United States and Canada.

Patient reported outcomes (PROs) provide multidimensional perspectives on the impact of pain1, 2, 3, 4, 5 and have been assessed using the Patient Reported Outcomes Measurement Information System (PROMIS) in children with sickle cell disease (SCD) during outpatient visits,3,4 acute care utilization for pain,4,6 and in clinical trials to measure the effect of interventions.7, 8, 9 Here, we report the feasibility of collection of PROs of pain interference and fatigue at enrollment (baseline) from participants 3 to 21 years of age enrolled in a phase 2 randomized double-blind placebo-controlled trial of intravenous arginine therapy for acute SCD pain (NCT02536170),10 and examine the impact of an acute pain episode on these PROs.

Introduction/Objective:Acute pain episodes are a major cause of health care utilization (HCU) in sickle cell disease (SCD), and adolescence is associated with increased pain frequency. We sought to determine whether there were differences in acute pain trajectories by sex and frequency of pain episodes among adolescents with SCD who presented to the emergency department (ED).Methods:Retrospective review of electronic health records from a large, multicampus, pediatric SCD program.Results:Of the 113 adolescents included, the mean age was 16.6 (SD 0.9), 41.6% (n = 47) were female, 77.9% (n = 88) had HbSS or a similarly severe genotype, and 43.4% (n = 49) had ≥3 episodes of HCU for pain, which we defined as having history of high HCU for pain. Those with a history of high HCU for pain had higher mean pain intensity scores at presentation, were more likely to receive either intravenous or intranasal opioids, and were more likely to be hospitalized. In a model considering the 3-way interaction between sex, history of high HCU for pain, and follow-up time from the initial pain intensity score, adjusted for opioid per kilogram body weight, and prescription of hydroxyurea, adolescent female patients with high HCU for pain had the slowest decline in pain intensity during treatment for acute pain in the ED.Conclusion:Sex and history of high HCU for pain are associated with acute pain trajectories in adolescents with SCD presenting to the ED. These novel findings should be confirmed in future prospective studies.

Sickle cell disease (SCD) is the most common hemoglobinopathy in the US, affecting approximately 100,000 individuals in the US and millions worldwide. Pain is the hallmark of SCD, and a subset of patients experience pain virtually all of the time. Of interest, the arginine metabolome is associated with several pain mechanisms highlighted in this review. Since SCD is an arginine deficiency syndrome, the contribution of the arginine metabolome to acute and chronic pain in SCD is a topic in need of further attention. Normal arginine metabolism is impaired in SCD through various mechanisms that contribute to endothelial dysfunction, vaso-occlusion, pulmonary complications, risk of leg ulcers, and early mortality. Arginine is a semiessential amino acid that serves as a substrate for protein synthesis and is the precursor to nitric oxide (NO), polyamines, proline, glutamate, creatine, and agmatine. Since arginine is involved in multiple metabolic processes, a deficiency of this amino acid has the potential to disrupt many cellular and organ functions. NO is a potent vasodilator that is depleted in SCD and may contribute to vaso-occlusive pain. As the obligate substrate for NO production, arginine also plays a mechanistic role in SCD-related pain, although its contribution to pain pathways likely extends beyond NO. Low global arginine bioavailability is associated with pain severity in both adults and children with SCD as well as other non-SCD pain syndromes. Preliminary clinical studies of arginine therapy in SCD demonstrate efficacy in treating acute vaso-occlusive pain, as well as leg ulcers and pulmonary hypertension. Restoration of arginine bioavailability through exogenous supplementation of arginine is, therefore, a promising therapeutic target. Phase II clinical trials of arginine therapy for sickle-related pain are underway and a Phase III randomized controlled trial is anticipated in the near future.

Nitric oxide (NO) is a key regulator of vascular tone. Endothelial nitric oxide synthase (eNOS) is responsible for NO generation under normoxic conditions. Under hypoxia however, eNOS is inactive and red blood cells (RBC) provide an alternative NO generation pathway from nitrite to regulate hypoxic vasodilation. While nitrite reductase activity of hemoglobin is well acknowledged, little is known about generation of NO by intact RBC with physiological hemoglobin concentrations. We aimed to develop and apply a new approach to provide insights in the ability of RBC to convert nitrite into NO under hypoxic conditions. We established a novel experimental setup to evaluate nitrite uptake and the release of NO from RBC into the gas-phase under different conditions. NO measurements were similar to well-established clinical measurements of exhaled NO. Nitrite uptake was rapid, and after an initial lag phase NO release from RBC was constant in time under hypoxic conditions. The presence of oxygen greatly reduced NO release, whereas inhibition of eNOS and xanthine oxidoreductase (XOR) did not affect NO release. A decreased pH increased NO release under hypoxic conditions. Hypothermia lowered NO release, while hyperthermia increased NO release. Whereas fetal hemoglobin did not alter NO release compared to adult hemoglobin, sickle RBC showed an increased ability to release NO. Under all conditions nitrite uptake by RBC was similar. This study shows that nitrite uptake into RBC is rapid and release of NO into the gas-phase continues for prolonged periods of time under hypoxic conditions. Changes in the RBC environment such as pH, temperature or hemoglobin type, affect NO release.

Background: The role of pulmonary hypertension as a cause of mortality in sickle cell disease (SCD) is controversial. Methods and Results: We evaluated the relationship between an elevated estimated pulmonary artery systolic pressure and mortality in patients with SCD. We followed patients from the walk-PHaSST screening cohort for a median of 29 months. A tricuspid regurgitation velocity (TRV)≥3.0 m/s cuttof, which has a 67-75% positive predictive value for mean pulmonary artery pressure ≥25 mm Hg was used. Among 572 subjects, 11.2% had TRV≥3.0 m/sec. Among 582 with a measured NT-proBNP, 24.1% had values ≥160 pg/mL. Of 22 deaths during follow-up, 50% had a TRV≥3.0 m/sec. At 24 months the cumulative survival was 83% with TRV≥3.0 m/sec and 98% with TRV<3.0 m/sec (p<0.0001). The hazard ratios for death were 11.1 (95%CI 4.1-30.1; p<0.0001) for TRV≥3.0 m/sec, 4.6 (1.8-11.3; p = 0.001) for NT-proBNP≥160 pg/mL, and 14.9 (5.5-39.9; p<0.0001) for both TRV≥3.0 m/sec and NT-proBNP≥160 pg/mL. Age >47 years, male gender, chronic transfusions, WHO class III-IV, increased hemolytic markers, ferritin and creatinine were also associated with increased risk of death. Conclusions: A TRV≥ 3.0 m/sec occurs in approximately 10% of individuals and has the highest risk for death of any measured variable. The study is registered in ClinicalTrials.gov with identifier: NCT00492531.

In recent years, evidence has accumulated indicating that the enzyme arginase, which converts L-arginine into L-ornithine and urea, plays a key role in the pathogenesis of pulmonary disorders such as asthma through dysregulation of L-arginine metabolism and modulation of nitric oxide (NO) homeostasis. Allergic asthma is characterized by airway hyperresponsiveness, inflammation, and remodeling. Through substrate competition, arginase decreases bioavailability of L-arginine for nitric oxide synthase (NOS), thereby limiting NO production with subsequent effects on airway tone and inflammation. By decreasing L-arginine bioavailability, arginase may also contribute to the uncoupling of NOS and the formation of the proinflammatory oxidant peroxynitrite in the airways. Finally, arginase may play a role in the development of chronic airway remodeling through formation of L-ornithine with downstream production of polyamines and L-proline, which are involved in processes of cellular proliferation and collagen deposition. Further research on modulation of arginase activity and L-arginine bioavailability may reveal promising novel therapeutic strategies for asthma.

In recent years, evidence has increased that asthma predisposes to complications of sickle cell disease (SCD), such as pain crises, acute chest syndrome, pulmonary hypertension, and stroke, and is associated with increased mortality. An obstructive pattern of pulmonary function, along with a higher-than-expected prevalence of airway hyper-responsiveness (AHR) when compared to the general population, has led some researchers to suspect that underlying hemolysis may contribute to the development of a pulmonary disease similar to asthma in patients with SCD. While the pathophysiologic mechanism in atopic asthma involves up-regulation of Th2 cytokines, mast cell- and eosinophil-driven inflammation, plus increased activity of inducible nitric oxide synthase (iNOS) and arginase in airway epithelium resulting in obstructive changes and AHR, the exact mechanisms of AHR, obstructive and restrictive lung disease in SCD is unclear. It is known that SCD is associated with a proinflammatory state and an enhanced inflammatory response is seen during vaso-occlusive events (VOE). Hemolysis-driven acute-on-chronic inflammation and dysregulated arginine-nitric oxide metabolism are potential mechanisms by which pulmonary dysfunction could occur in patients with SCD. In patients with a genetic predisposition of atopic asthma, these changes are probably more severe and result in increased susceptibility to sickle cell complications. Early recognition and aggressive management of asthma based on established National Institutes of Health asthma guidelines is recommended in order to minimize morbidity and mortality.

Background: Nitrous oxide (N O) is an inhalational medication that has anxiolytic, amnestic, potent venodilatory and mild-to-moderate analgesic properties commonly used in the emergency department (ED) setting. N2O has a rapid onset of action (<5 minutes) and recovery (<5 minutes) and can be quickly titrated to effect without the need for IV access. It has few side effects, does not require renal or hepatic metabolism for excretion and has no reports of allergic reaction. Priapism is a serious complication of sickle cell disease (SCD) affecting approximately 35% of males, with an adverse impact on quality of life. Treatment options are limited and not evidence based, including hydration, alkalization, analgesia, oxygenation to prevent further sickling, and exchange transfusion. Patients who do not respond within 4 hours often require a painful invasive procedure that includes aspiration of blood from the corpus cavernosum and phenylephrine injections. Case reports have described a therapeutic benefit from oral pseudoephedrine, sildenafil, and intravenous (IV) arginine, however controlled clinical trials are lacking. Although a 50:50 nitrous oxide/oxygen mix is commonly used in France to enhance analgesia in patients with SCD and vasoocclusive pain events (VOE) not sufficiently responding to IV morphine, there are no reports of its use to treat priapism. We describe the effects of N2O for the treatment of acute priapism associated with SCD in a pediatric ED. Methods: This is a case series of two adolescent boys with Hb-SS who on 3 separate occasions presented to the ED with acute priapism that failed oral therapy (pseudoephedrine and opioids). N2O gas was utilized to help facilitate IV catheter placement. Results: In each presentation (at ages 8 and 10 years for patient 1; age 15 years for patient 2), the patient experienced complete resolution of the priapism within 4-15 min of receiving N2O (max 60%). The patients were discharged from the ED following each presentation and had no recurrence during the subsequent week. Conclusions: Priapism is a challenging complication of SCD associated with long-term morbidity and a paucity of treatment options. Opioids are commonly used. Given the risks and inconsistent results of current recommended therapy, N2O may represent a potential opioid-sparing treatment option for priapism presenting to the ED that warrants further investigation. Although anecdotal, N2O inhalation is an intervention to consider during a time when a treating ED physician may have few alternatives.