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Background This is an updated version of the original Cochrane review first published in 2008. Scoliosis surgery is often associated with substantial blood loss and potentially detrimental effects in children. Antifibrinolytic agents are often used to reduce perioperative blood loss. Clinical trials have evaluated their efficacy in children undergoing surgical correction of scoliosis, but no systematic review has been published. This review was first published in 2008 and was updated in 2016. Objectives To assess the efficacy and safety of aprotinin, tranexamic acid and aminocaproic acid in reducing blood loss and transfusion requirements in children undergoing surgery for correction of idiopathic or secondary scoliosis. Search methods We ran the search for the previous review in June 2007. For this updated version, we searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 7), MEDLINE (1946 to August week 1 2015), Embase (1947 to 2015 week 38), Latin American Caribbean Health Sciences Literature (LILACS) (1982 to 14 August 2015), Database of Abstracts of Reviews of Effects (DARE; 2015, Issue 2) and reference lists of reviews and retrieved articles for randomized controlled trials in any language. We also checked the clinical trial registry at http://www.clinicaltrials.gov on 8 October 2015. Selection criteria We included blinded and unblinded randomized controlled trials (RCTs) that evaluated the effects of antifibrinolytics on perioperative blood loss in children 18 years of age or younger and undergoing scoliosis surgery. Data collection and analysis Two review authors independently extracted data. The primary outcome was total blood loss (intraoperative and postoperative combined). Secondary efficacy outcomes were the number of participants receiving blood transfusion (both autologous and allogeneic) or receiving allogeneic blood transfusion alone, and the total amount of blood transfused. Safety outcomes included the number of deaths, the number of participants reporting any adverse event or a serious adverse event, withdrawals due to adverse events and the number of participants experiencing a specific adverse event (i.e. renal insufficiency, hypersensitivity or thrombosis). We assessed methodological risk of bias for each included study and employed the GRADE approach to assess the overall quality of the evidence. Main results We included three new studies (201 participants) in this updated review, for a total of nine studies (455 participants). All but one study employed placebo as the control group intervention. For the primary outcome, antifibrinolytic drugs decreased the amount of perioperative blood loss by 427 mL (95% confidence interval (CI) 251 to 603 mL), for a reduction of over 20% versus placebo. We rated the quality of evidence for our primary outcome as low on the basis of unclear risk of bias for several domains in most studies and the small total number of participants. For secondary outcomes, fewer participants receiving antifibrinolytic drugs received transfusion (allogeneic or autologous) versus those receiving placebo (risk ratio (RR) 0.65, 95% CI 0.50 to 0.85, number needed to treat to prevent one additional harmful outcome (NNTp) 5; very low-quality evidence). Only two studies specifically evaluated the number of participants transfused with only allogeneic blood (risk difference (RD) -0.15, 95% CI -0.26 to -0.03, NNTp 7; very low-quality evidence). Antifibrinolytic drugs decreased the volume of blood transfused by 327 mL (95% CI -186 to -469 mL; low-quality evidence). No study reported deaths in active or control groups. Data were insufficient to allow performance of meta-analysis for any safety outcome. No studies adequately described their methods in assessing safety. The only adverse event of note occurred in one study, when three participants in the placebo group developed postoperative deep vein thrombosis. Authors' conclusions Since the last published version of this review (2008), we have found three new studies. Additional evidence shows that antifibrinolytics reduce the requirement for both autologous and allogeneic blood transfusion. Limited evidence of low to very low quality supports the use of antifibrinolytic drugs for reducing blood loss and decreasing the risk, and volume, of transfusion in children undergoing scoliosis surgery. Evidence is insufficient to support the use of a particular agent, although tranexamic acid may be preferred, given its widespread availability. The optimal dose regimen for any of these three agents has not been established. Although adverse events appear to occur infrequently, evidence is insufficient to confirm the safety of these agents, particularly for rare but potentially catastrophic events. No long-term safety data are available.

Background This is an updated version of the original Cochrane review published in Issue 10, 2011. Paracetamol (acetaminophen) is the most commonly prescribed analgesic for the treatment of acute pain. It may be administered orally, rectally, or intravenously. The efficacy and safety of intravenous (IV) formulations of paracetamol, IV paracetamol, and IV propacetamol (a prodrug that is metabolized to paracetamol), compared with placebo and other analgesics, is unclear. Objectives To assess the efficacy and safety of IV formulations of paracetamol for the treatment of postoperative pain in both adults and children. Search methods We ran the search for the previous review in May 2010. For this update, we searched the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 1), MEDLINE (May 2010 to 16 February 2016), EMBASE (May 2010 to 16 February 2016), LILACS (2010 to 2016), a clinical trials registry, and reference lists of reviews for randomized controlled trials (RCTs) in any language and we retrieved articles. Selection criteria Randomized, double-blind, placebo- or active-controlled single dose clinical trials of IV paracetamol or IV propacetamol for acute postoperative pain in adults or children. Data collection and analysis Two review authors independently extracted data, which included demographic variables, type of surgery, interventions, efficacy, and adverse events. We contacted study authors for additional information. We graded each included study for methodological quality by assessing risk of bias and employed the GRADE approach to assess the overall quality of the evidence. Main results We included 75 studies (36 from the original review and 39 from our updated review) enrolling a total of 7200 participants. Among primary outcomes, 36% of participants receiving IV paracetamol/propacetamol experienced at least 50% pain relief over four hours compared with 16% of those receiving placebo (number needed to treat to benefit (NNT) = 5; 95% confidence interval (CI) 3.7 to 5.6, high quality evidence). The proportion of participants in IV paracetamol/propacetamol groups experiencing at least 50% pain relief diminished over six hours, as reflected in a higher NNT of 6 (4.6 to 7.1, moderate quality evidence). Mean pain intensity at four hours was similar when comparing IV paracetamol and placebo, but was seven points lower on a 0 to 100 visual analog scale (0 = no pain, 100 = worst pain imaginable, 95% CI -9 to -6, low quality evidence) in those receiving paracetamol at six hours. For secondary outcomes, participants receiving IV paracetamol/propacetamol required 26% less opioid over four hours and 16% less over six hours (moderate quality evidence) than those receiving placebo. However, this did not translate to a clinically meaningful reduction in opioid-induced adverse events. Meta-analysis of efficacy comparisons between IV paracetamol/propacetamol and active comparators (e.g., opioids or nonsteroidal anti-inflammatory drugs) were either not statistically significant, not clinically significant, or both. Adverse events occurred at similar rates with IV paracetamol or IV propacetamol and placebo. However, pain on infusion occurred more frequently in those receiving IV propacetamol versus placebo (23% versus 1%). Meta-analysis did not demonstrate clinically meaningful differences between IV paracetamol/propacetamol and active comparators for any adverse event. Authors' conclusions Since the last version of this review, we have found 39 new studies providing additional information. Most included studies evaluated adults only. We reanalyzed the data but the results did not substantially alter any of our previously published conclusions. This review provides high quality evidence that a single dose of either IV paracetamol or IV propacetamol provides around four hours of effective analgesia for about 36% of patients with acute postoperative pain. Low to very low quality evidence demonstrates that both formulations are associated with few adverse events, although patients receiving IV propacetamol have a higher incidence of pain on infusion than both placebo and IV paracetamol.

Background Lidocaine administration produces pain due to its acidic pH. Objectives The objective of this review was to determine if adjusting the pH of lidocaine had any effect on pain resulting from non-intravascular injections in adults and children. We tested the hypothesis that adjusting the pH of lidocaine solution to a level closer to the physiologic pH reduces this pain. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, to June 2010); Ovid MEDLINE (1966 to June 2010); EMBASE (1988 to June 2010); LILACS (1982 to June 2010); CINAHL (1982 to June 2010); ISI Web of Science (1999 to June 2010); and abstracts of the meetings of the American Society of Anesthesiologists (ASA). We checked the full articles of selected titles. We did not apply any language restrictions. Selection criteria We included double-blinded, randomized controlled trials that compared pH-adjusted lidocaine with unadjusted lidocaine. We evaluated pain at the injection site, satisfaction and adverse events. We excluded studies in healthy volunteers. Data collection and analysis We separately analysed parallel-group and crossover trials; trials that evaluated lidocaine with or without epinephrine; and trials with pH-adjusted lidocaine solutions < 7.35 and ≥ 7.35. To explain heterogeneity, we separately analysed studies with a low and higher risk of bias due to the level of allocation concealment; studies that employed a low and a higher volume of injection; and studies that used lidocaine for different types of procedures. Main results We included 23 studies of which 10 had a parallel design and 13 were crossover studies. Eight of the 23 studies had moderate to high risk of bias due to the level of allocation concealment. Pain associated with the infiltration of buffered lidocaine was less than the pain associated with infiltration of unbuffered lidocaine in both parallel and crossover trials. In the crossover studies, the difference was -1.98 units (95% confidence interval (CI) -2.62 to -1.34) and in the parallel-group studies it was -0.98 units (95% CI -1.49 to -0.47) on a 0 to 10 scale. The magnitude of the pain decrease associated with buffered lidocaine was larger when the solution contained epinephrine. The risk of bias, volume of injection, and type of procedure failed to explain the heterogeneity of the results. Patients preferred buffered lidocaine (odds ratio 3.01, 95% CI 2.19 to 4.15). No adverse events or toxicity were reported. Authors' conclusions Increasing the pH of lidocaine decreased pain on injection and augmented patient comfort and satisfaction. Plain Language Summary Adjusting the pH of lidocaine solution for reducing pain on injection Lidocaine is frequently used to anaesthetize the skin prior to invasive procedures. Its administration produces pain that is thought to be due to the acidic pH of commercial preparations (pH levels between 3.5 and 7.0 compared with the physiologic pH which is between 7.35 and 7.45). The objective of this review was to determine the effect of increasing the pH of a commercial lidocaine preparation on pain associated with its injection in adults and children. We included 23 studies with 1067 participants in the meta-analysis. Increasing the pH of lidocaine reduced pain and improved patients' comfort and satisfaction. No adverse events were reported. Therefore, increasing the pH of commercial lidocaine solutions with bicarbonate immediately prior to their use should be considered.

Summary. Paracetamol is the most commonly prescribed analgesic for the treatment of acute pain. The efficacy and safety of i.v. formulations of paracetamol is unclear. We performed a systematic search (multiple databases, bibliographies, any language, to May 2010) for single-dose, randomized, controlled clinical trials of propacetamol or i.v. paracetamol for acute postoperative pain in adults or children. Thirty-six studies involving 3896 patients were included. For the primary outcome, 37% of patients (240/367) receiving propacetamol or i.v. paracetamol experienced at least 50% pain relief over 4 h compared with 16% (68/527) receiving placebo (number needed to treat¼4.0; 95% confidence interval, 3.5–4.8). The proportion of patients in propacetamol or i.v. paracetamol groups experiencing at least 50% pain relief diminished over 6 h. Patients receiving propacetamol or paracetamol required 30% less opioid over 4 h and 16% less opioid over 6 h than those receiving placebo. However, this did not translate to a reduction in opioid-induced adverse events (AEs). Similar comparisons between propacetamol or i.v. paracetamol and active comparators were either not statistically significant, not clinically significant, or both. AEs occurred at similar rates with propacetamol or i.v. paracetamol and placebo. However, pain on infusion occurred more frequently in those receiving propacetamol compared with placebo (23% vs 1%). A single dose of either propacetamol or i.v. paracetamol provides around 4 h of effective analgesia for about 37% of patients with acute postoperative pain. Both formulations are associated with few AEs, although patients receiving propacetamol have a higher incidence of pain on infusion.

Obesity is a central feature of the metabolic syndrome and is associated with increased risk for insulin resistance and typeII diabetes. Here, we investigated the contribution of human apoliproteinE3 and mouse apoliproteinE to the development of diet-induced obesity in response to western-type diet. Our data show that apolipoproteinE contributes to the development of obesity and other related metabolic disorders, and that human apolipoproteinE3 is more potent than mouse apolipoproteinE in promoting obesity in response to western-type diet. Specifically, we found that apolipoproteinE3 knock-in mice fed western-type diet for 24 weeks became obese and developed hyperglycemia, hyperinsulinemia, hyperleptinemia, glucose intolerance and insulin resistance that were more severe than in C57BL/6 mice. In contrast, apolipoproteinE-deficient mice fed western-type diet for the same period were resistant to diet-induced obesity, had normal plasma glucose, leptin and insulin levels, and exhibited normal responses to glucose tolerance and insulin resistance tests. Furthermore, low-density lipoprotein receptor-deficient mice were more sensitive to the development of diet-induced obesity and insulin resistance than apolipoprotein E-deficient mice, but were still more resistant than C57BL/6 mice, raising the possibility that low-density lipoprotein receptor mediates, at least in part, the effects of apolipoproteinE on obesity. Taken together, our findings suggest that, in addition to other previously identified mechanisms of obesity, apolipoproteinE and possibly the chylomicron pathway are also important contributors to the development of obesity and related metabolic dysfunctions in mice.

Background Lidocaine administration produces pain due to its acidic pH. Objectives The objective of this review was to determine if adjusting the pH of lidocaine had any effect on pain resulting from non-intravascular injections in adults and children. We tested the hypothesis that adjusting the pH of lidocaine solution to a level closer to the physiologic pH reduces this pain. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, to June 2010); Ovid MEDLINE (1966 to June 2010); EMBASE (1988 to June 2010); LILACS (1982 to June 2010); CINAHL (1982 to June 2010); ISI Web of Science (1999 to June 2010); and abstracts of the meetings of the American Society of Anesthesiologists (ASA). We checked the full articles of selected titles. We did not apply any language restrictions. Selection criteria We included double-blinded, randomized controlled trials that compared pH-adjusted lidocaine with unadjusted lidocaine. We evaluated pain at the injection site, satisfaction and adverse events. We excluded studies in healthy volunteers. Data collection and analysis We separately analysed parallel-group and crossover trials; trials that evaluated lidocaine with or without epinephrine; and trials with pH-adjusted lidocaine solutions < 7.35 and ≥ 7.35. To explain heterogeneity, we separately analysed studies with a low and higher risk of bias due to the level of allocation concealment; studies that employed a low and a higher volume of injection; and studies that used lidocaine for different types of procedures. Main results We included 23 studies of which 10 had a parallel design and 13 were crossover studies. Eight of the 23 studies had moderate to high risk of bias due to the level of allocation concealment. Pain associated with the infiltration of buffered lidocaine was less than the pain associated with infiltration of unbuffered lidocaine in both parallel and crossover trials. In the crossover studies, the difference was -1.98 units (95% confidence interval (CI) -2.62 to -1.34) and in the parallel-group studies it was -0.98 units (95% CI -1.49 to -0.47) on a 0 to 10 scale. The magnitude of the pain decrease associated with buffered lidocaine was larger when the solution contained epinephrine. The risk of bias, volume of injection, and type of procedure failed to explain the heterogeneity of the results. Patients preferred buffered lidocaine (odds ratio 3.01, 95% CI 2.19 to 4.15). No adverse events or toxicity were reported. Authors' conclusions Increasing the pH of lidocaine decreased pain on injection and augmented patient comfort and satisfaction.