Elaine M. Pascoe

Avoidance of nitrous oxide for patients undergoing major surgery: a randomized controlled trial.

Background: Nitrous oxide is widely used in anesthesia, often administered at an inspired concentration around 70%. Although nitrous oxide interferes with vitamin B12, folate metabolism, and deoxyribonucleic acid synthesis and prevents the use of high inspired oxygen concentrations, the consequences of these effects are unclear. Methods: Patients having major surgery expected to last at least 2 h were randomly assigned to nitrous oxide–free (80% oxygen, 20% nitrogen) or nitrous oxide–based (70% N2O, 30% oxygen) anesthesia. Patients and observers were blind to group identity. The primary endpoint was duration of hospital stay. Secondary endpoints included duration of intensive care stay and postoperative complications; the latter included severe nausea and vomiting, and the following major complications: pneumonia, pneumothorax, pulmonary embolism, wound infection, myocardial infarction, venous thromboembolism, stroke, awareness, and death within 30 days of surgery. Results: Of 3,187 eligible patients, 2,050 consenting patients were recruited. Patients in the nitrous oxide–free group had significantly lower rates of major complications (odds ratio, 0.71; 95% confidence interval, 0.56–0.89; P = 0.003) and severe nausea and vomiting (odds ratio, 0.40; 95% confidence interval, 0.31–0.51; P < 0.001), but median duration of hospital stay did not differ substantially between groups (7.0 vs. 7.1 days; P = 0.06). Among patients admitted to the intensive care unit postoperatively, those in the nitrous oxide–free group were more likely to be discharged from the unit on any given day than those in the nitrous oxide group (hazard ratio, 1.35; 95% confidence interval, 1.05–1.73; P = 0.02). Conclusions: Avoidance of nitrous oxide and the concomitant increase in inspired oxygen concentration decreases the incidence of complications after major surgery, but does not significantly affect the duration of hospital stay. The routine use of nitrous oxide in patients undergoing major surgery should be questioned.

Acute lung injury in pediatric intensive care in Australia and New Zealand: a prospective, multicenter, observational study

Objective: Acute lung injury (ALI) is poorly defined in children. The objective of this prospective study was to clarify the incidence, demographics, management strategies, outcome, and mortality predictors of ALI in children in Australia and New Zealand. Design: Multicenter prospective study during a 12-month period. Setting: Intensive care unit. Patients: All children admitted to intensive care and requiring mechanical ventilation were screened daily for development of ALI based on American-European Consensus Conference guidelines. Identified patients were followed for 28 days or until death or discharge. Interventions: None. Measurements and Main Results: There were 117 cases of ALI during the study period, giving a population incidence of 2.95/100,000 <16 yrs. ALI accounted for 2.2% of pediatric intensive care unit admissions. Mortality was 35% for ALI, and this accounted for 30% of all pediatric intensive care unit deaths during the study period. Significant preadmission risk factors for mortality were chronic disease, older age, and immunosuppression. Predictors of mortality during admission were ventilatory requirements (peak inspiratory pressures, mean airway pressure, positive end-expiratory pressure) and indexes of respiratory severity on day 1 (Pao2/Fio2 ratio and oxygenation index). Higher maximum and median tidal volumes were associated with reduced mortality, even when corrected for severity of lung disease. Development of single and multiple organ failure was significantly associated with mortality. Conclusions: ALI in children is uncommon but has a high mortality rate. Risk factors for mortality are easily identified. Ventilatory variables and indexes of lung severity were significantly associated with mortality.

Effects of uric acid-lowering therapy on renal outcomes: a systematic review and meta-analysis.

BACKGROUND Non-randomized studies suggest an association between serum uric acid levels and progression of chronic kidney disease (CKD). The aim of this systematic review is to summarize evidence from randomized controlled trials (RCTs) concerning the benefits and risks of uric acid-lowering therapy on renal outcomes. METHODS Medline, Excerpta Medical Database and Cochrane Central Register of Controlled Trials were searched with English language restriction for RCTs comparing the effect of uric acid-lowering therapy with placebo/no treatment on renal outcomes. Treatment effects were summarized using random-effects meta-analysis. RESULTS Eight trials (476 participants) evaluating allopurinol treatment were eligible for inclusion. There was substantial heterogeneity in baseline kidney function, cause of CKD and duration of follow-up across these studies. In five trials, there was no significant difference in change in glomerular filtration rate from baseline between the allopurinol and control arms [mean difference (MD) 3.1 mL/min/1.73 m2, 95% confidence intervals (CI) -0.9, 7.1; heterogeneity χ2=1.9, I2=0%, P=0.75]. In three trials, allopurinol treatment abrogated increases in serum creatinine from baseline (MD -0.4 mg/dL, 95% CI -0.8, -0.0 mg/dL; heterogeneity χ2=3, I2=34%, P=0.22). Allopurinol had no effect on proteinuria and blood pressure. Data for effects of allopurinol therapy on progression to end-stage kidney disease and death were scant. Allopurinol had uncertain effects on the risks of adverse events. CONCLUSIONS Uric acid-lowering therapy with allopurinol may retard the progression of CKD. However, adequately powered randomized trials are required to evaluate the benefits and risks of uric acid-lowering therapy in CKD.

Synbiotics Easing Renal Failure by Improving Gut Microbiology (SYNERGY): A Randomized Trial

BACKGROUND AND OBJECTIVES The generation of key uremic nephrovascular toxins, indoxyl sulfate (IS), and p-cresyl sulfate (PCS), is attributed to the dysbiotic gut microbiota in CKD. The aim of our study was to evaluate whether synbiotic (pre- and probiotic) therapy alters the gut microbiota and reduces serum concentrations of microbiome-generated uremic toxins, IS and PCS, in patients with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Predialysis adult participants with CKD (eGFR=10-30 ml/min per 1.73 m(2)) were recruited between January 5, 2013 and November 12, 2013 to a randomized, double-blind, placebo-controlled, crossover trial of synbiotic therapy over 6 weeks (4-week washout). The primary outcome was serum IS. Secondary outcomes included serum PCS, stool microbiota profile, eGFR, proteinuria-albuminuria, urinary kidney injury molecule-1, serum inflammatory biomarkers (IL-1β, IL-6, IL-10, and TNF-α), serum oxidative stress biomarkers (F2-isoprostanes and glutathione peroxidase), serum LPS, patient-reported health, Gastrointestinal Symptom Score, and dietary intake. A prespecified subgroup analysis explored the effect of antibiotic use on treatment effect. RESULTS Of 37 individuals randomized (age =69±10 years old; 57% men; eGFR=24±8 ml/min per 1.73 m(2)), 31 completed the study. Synbiotic therapy did not significantly reduce serum IS (-2 μmol/L; 95% confidence interval [95% CI], -5 to 1 μmol/L) but did significantly reduce serum PCS (-14 μmol/L; 95% CI, -27 to -2 μmol/L). Decreases in both PCS and IS concentrations were more pronounced in patients who did not receive antibiotics during the study (n=21; serum PCS, -25 μmol/L; 95% CI, -38 to -12 μmol/L; serum IS, -5 μmol/L; 95% CI, -8 to -1 μmol/L). Synbiotics also altered the stool microbiome, particularly with enrichment of Bifidobacterium and depletion of Ruminococcaceae. Except for an increase in albuminuria of 38 mg/24 h (P=0.03) in the synbiotic arm, no changes were observed in the other secondary outcomes. CONCLUSION In patients with CKD, synbiotics did not significantly reduce serum IS but did decrease serum PCS and favorably modified the stool microbiome. Large-scale clinical trials are justified.

Meningiomas in children and adolescents: a meta-analysis of individual patient data

BACKGROUND The epidemiological, prognostic, and therapeutic features of child and adolescent meningioma are poorly defined. Clinical knowledge has been drawn from small case series and extrapolation from adult studies. This study was done to pool and analyse the clinical evidence on child and adolescent meningioma. METHODS Searches of PubMed, Medline, and Embase identified 35 case series of child and adolescent meningioma completed over the past 21 years. Individual patient data were obtained from 30 studies via direct communication with investigators. Primary outcomes were relapse-free survival (RFS) and overall survival. Prognostic variables were extent of initial surgery, use of upfront radiotherapy, age, sex, presence of neurofibromatosis, tumour location, and tumour grade. RFS and overall survival were analysed using Kaplan-Meier survival curves and multivariable Cox regression models. FINDINGS From a total of 677 children and adolescents with meningioma, 518 were eligible for RFS analysis and 547 for overall survival analysis. Multivariable analysis showed that patients who underwent initial gross-total resection had better RFS (hazard ratio 0·16, 95% CI 0·10-0·25; p<0·0001) and overall survival (0·21, 0·11-0·39; p<0·0001) than those who had subtotal resection. No significant benefit was seen for upfront radiotherapy in terms of RFS (0·59, 0·30-1·16; p=0·128) or overall survival (1·10, 0·53-2·28; p=0·791). Patients with neurofibromatosis type 2 (NF2) had worse RFS than those without neurofibromatosis (2·36, 1·23-4·51; p=0·010). There was a significant change in overall survival with time between patients with NF2 compared with those without neurofibromatosis (1·45, 1·09-1·92; p=0·011); although overall survival was initially better for patients with NF2 than for those without neurofibromatosis, overall survival at 10 years was worse for patients with NF2. Patients with WHO grade III tumours had worse RFS than those with WHO grade I (3·90, 2·10-7·26; p<0·0001) and grade II tumours (2·49, 1·11-5·56; p=0·027). INTERPRETATION Extent of initial surgical resection is the strongest independent prognostic factor for child and adolescent meningioma. No benefit for upfront radiotherapy was noted. Hence, aggressive surgical management, to achieve gross-total resection, is the initial treatment of choice. In the event of a subtotal resection, repeat resection is recommended to achieve maximum extirpation. Close observation is warranted for patients who have a subtotal resection or who have WHO grade III tumours. Patients without neurofibromatosis should have a minimum 10-year follow-up, whereas patients with NF2 should be considered a special risk category, necessitating life-long follow-up. FUNDING None.

Is atropine needed with ketamine sedation? A prospective, randomised, double blind study

Objective: To compare atropine with placebo as an adjunct to ketamine sedation in children undergoing minor painful procedures. Outcome measures included hypersalivation, side effect profile, parental/patient satisfaction, and procedural success rate. Methods: Children aged between 1 and 16 years of age requiring ketamine procedural sedation in a tertiary emergency department were randomised to receive 0.01 mg/kg of atropine or placebo. All received 4 mg/kg of intramuscular ketamine. Tolerance and sedation scores were recorded throughout the procedure. Side effects were recorded from the start of sedation until discharge. Parental and patient satisfaction scores were obtained at discharge and three to five days after the procedure, with the opportunity to report side effects encountered at home. Results: A total of 83 patients aged 13 months to 14.5 years (median age 3.4 years) were enrolled over a 16 month period. Hypersalivation occurred in 11.4% of patients given atropine compared with 30.8% given placebo (odds ratio (OR) 0.29, 95% confidence interval (CI) 0.09 to 0.91). A transient rash was observed in 22.7% of the atropine group compared with 5.1% of the placebo group (OR 5.44, 95% CI 1.11 to 26.6). Vomiting during recovery occurred in 9.1% of atropine patients compared with 25.6% of placebo patients (OR 0.29, 95% CI 0.09 to 1.02). There was a trend towards better tolerance in the placebo group. No patient experienced serious side effects. Conclusion: Ketamine sedation was successful and well tolerated in all cases. The use of atropine as an adjunct for intramuscular ketamine sedation in children significantly reduces hypersalivation and may lower the incidence of post-procedural vomiting. Atropine is associated with a higher incidence of a transient rash. No serious adverse events were noted.

Monitoring electrical skin conductance: a tool for the assessment of postoperative pain in children?

Background:Monitoring changes in electrical skin conductance has been described as a potentially useful tool for the detection of acute pain in adults. The aim of this study was to test the method in pediatric patients. Methods:A total of 180 postoperative pediatric patients aged 1–16 yr were included in this prospective, blinded observational study. After arrival in the recovery unit, pain was assessed by standard clinical pain assessment tools (1–3 yr: Face Legs Activity Cry Consolability Scale, 4–7 yr: Revised Faces Scale, 8–16 yr: Visual Analogue Scale) at various time points during their stay in the recovery room. The number of fluctuations in skin conductance per second (NFSC) was recorded simultaneously. Results:Data from 165 children were used for statistical analysis, and 15 patients were excluded. The area under the Receiver Operating Characteristic curve for predicting moderate to severe pain from NFSC was 0.82 (95% confidence interval 0.79–0.85). Over all age groups, an NFSC cutoff value of 0.13 was found to distinguish between no or mild versus moderate or severe pain with a sensitivity of 90% and a specificity of 64% (positive predictive value 35%, negative predictive value 97%). Conclusions:NFSC accurately predicted the absence of moderate to severe pain in postoperative pediatric patients. The measurement of NFSC may therefore provide an additional tool for pain assessment in this group of patients. However, more research is needed to prospectively investigate the observations made in this study and to determine the clinical applicability of the method.

Tramadol vs morphine during adenotonsillectomy for obstructive sleep apnea in children.

Background:  Optimal analgesia for children undergoing adenotonsillectomy for obstructive sleep apnea (OSA) is controversial. Tramadol may represent a superior choice over morphine in this group, with a potential to cause less postoperative sedation and respiratory depression. Optimal perioperative analgesia may allow expensive and time‐consuming preoperative work‐up and postoperative monitoring to be rationalized.

Dietary protein-fiber ratio associates with circulating levels of indoxyl sulfate and p-cresyl sulfate in chronic kidney disease patients

BACKGROUND AND AIMS Indoxyl sulfate (IS) and p-cresyl sulfate (PCS) are uremic toxins derived solely from colonic bacterial fermentation of protein. Dietary fiber may counteract this by limiting proteolytic bacterial fermentation. However, the influence of dietary intake on the generation of IS and PCS has not been adequately explored in chronic kidney disease (CKD). METHODS AND RESULTS This cross-sectional study included 40 CKD participants (60% male; age 69 ± 10 years; 45% diabetic) with a mean estimated glomerular filtration rate (eGFR) of 24 ± 8 mL/min/1.73 m(2), who enrolled in a randomized controlled trial of synbiotic therapy. Total and free serum IS and PCS were measured at baseline by ultra-performance liquid chromatography. Dietary intake was measured using in-depth diet histories collected by a dietitian. Associations between each toxin, dietary fiber (total, soluble and insoluble), dietary protein (total, and amino acids: tryptophan, tyrosine and phenylalanine), and the protein-fiber index (ratio of protein to fiber) were assessed using linear regression. Dietary fiber was associated with free and total serum PCS (r = -0.42 and r = -0.44, both p < 0.01), but not IS. No significant association was observed between dietary protein and either toxin. The protein-fiber index was associated with total serum IS (r = 0.40, p = 0.012) and PCS (r = 0.43, p = 0.005), independent of eGFR, sex and diabetes. CONCLUSION Dietary protein-fiber index is associated with serum IS and PCS levels. Such association, beyond fiber and protein alone, highlights the importance of the interplay between these nutrients. We speculate that dietary modification towards a lower protein-fiber index may contribute to lowering IS and PCS.

Factors associated with the performance of a blood-based interferon-γ release assay in diagnosing tuberculosis

Background Indeterminate results are a recognised limitation of interferon-γ release assays (IGRA) in the diagnosis of latent tuberculosis (TB) infection (LTBI) and TB disease, especially in children. We investigated whether age and common co-morbidities were associated with IGRA performance in an unselected cohort of resettled refugees. Methods A retrospective cross-sectional study of refugees presenting for their post-resettlement health assessment during 2006 and 2007. Refugees were investigated for prevalent infectious diseases, including TB, and for common nutritional deficiencies and haematological abnormalities as part of standard clinical screening protocols. Tuberculosis screening was performed by IGRA; QuantiFERON-TB Gold in 2006 and QuantiFERON-TBGold In-Tube in 2007. Results Complete data were available on 1130 refugees, of whom 573 (51%) were children less than 17 years and 1041 (92%) were from sub-Saharan Africa. All individuals were HIV negative. A definitive IGRA result was obtained in 1004 (89%) refugees, 264 (26%) of which were positive; 256 (97%) had LTBI and 8 (3%) had TB disease. An indeterminate IGRA result was obtained in 126 (11%) refugees (all failed positive mitogen control). In multivariate analysis, younger age (linear OR  = 0.93 [95% CI 0.91–0.95], P<0.001), iron deficiency anaemia (2.69 [1.51–4.80], P = 0.001), malaria infection (3.04 [1.51–6.09], P = 0.002), and helminth infection (2.26 [1.48–3.46], P<0.001), but not vitamin D deficiency or insufficiency, were associated with an indeterminate IGRA result. Conclusions Younger age and a number of common co-morbidities are significantly and independently associated with indeterminate IGRA results in resettled predominantly African refugees.