Context: Diabetic macular oedema (DMO) is a common complication of diabetic retinopathy. Antiangiogenic therapy with anti-vascular endothelial growth factor (anti-VEGF) can reduce oedema, improve vision, and prevent further visual loss. These drugs have replaced laser photocoagulation as the standard of care for people with DMO. In the previous update of this review, we found moderate-quality evidence that, at 12 months, aflibercept was slightly more effective than ranibizumab and bevacizumab for improving vision in people with DMO, although the difference may have been clinically insignificant (less than 0.1 logarithm of the minimum angle of resolution (logMAR), or five Early Treatment Diabetic Retinopathy Study (ETDRS) letters, or one ETDRS line).

The objective of this updated review was to compare the effectiveness and safety of the different anti-VEGF drugs in RCTs at longer followup (24 months).

We included randomised controlled trials (RCTs) that compared any anti-angiogenic drug with an anti-VEGF mechanism of action versus another anti-VEGF drug, another treatment, sham, or no treatment in people with DMO.

Intravitreal bevacizumab (avastin) injection alone or combined with triamcinolone versus macular photocoagulation as primary treatment of diabetic macular edema.

Abstract:
To report the efficacy of a single intravitreal bevacizumab injection alone or in combination with intravitreal triamcinolone acetonide versus macular laser photocoagulation (MPC) as primary treatment of diabetic macular edema (DME).

In this randomized, three-arm clinical trial, 103 eyes of 97 patients with clinically significant DME and no previous treatment were enrolled. The eyes were randomly assigned to one of three study arms: the intravitreal bevacizumab (IVB) group, patients who received 1.25 mg of intravitreal bevacizumab (37 eyes); the IVB/IVT group, patients who received 1.25 mg of intravitreal bevacizumab and 2 mg of intravitreal triamcinolone (33 eyes); and the MPC group, patients who underwent focal or modified grid laser (33 eyes). Primary outcome measure was change in visual acuity.

Visual acuity changes +/- SD at 12 weeks were -0.22 +/- 0.23, -0.13 +/- 0.31, and + 0.08 +/- 0.31 logarithm of the minimal angle of resolution in the IVB, IVB/IVT, and MPC groups, respectively. The marginal regression model based on generalized estimating equation analysis demonstrated that the visual acuity changes in the groups were statistically significant at both 6 weeks (P < 0.0001) and 12 weeks (P = 0.024). The significant treatment effect was demonstrated at both 6 weeks and 12 weeks in the IVB group and only at 6 weeks in the IVB/IVT group. Significant central macular thickness (CMT) reduction was observed in eyes in the IVB and IVB/IVT groups only up to 6 weeks; however, CMT changes were not significant in the groups.

Up to 12 weeks, intravitreal bevacizumab treatment of patients with DME yielded better visual outcome than laser photocoagulation, although it was not associated with a significant decrease in CMT. No further beneficial effect of intravitreal triamcinolone could be demonstrated. Further clinical trials with longer follow-up are required to evaluate the long-term visual outcomes and complication profiles after primary treatment with such medications.

Randomized trial of intravitreal bevacizumab alone or combined with triamcinolone versus macular photocoagulation in diabetic macular edema.

Abstract:
To compare the results of intravitreal bevacizumab (IVB) injection alone or in combination with intravitreal triamcinolone acetonide (IVT) versus macular laser photocoagulation (MPC) as a primary treatment of diabetic macular edema (DME).

Randomized 3-arm clinical trial.

A total of 150 eyes of 129 patients with clinically significant DME and no previous treatment.

The eyes were randomly assigned to 1 of the 3 study arms: the IVB group, patients who received 1.25 mg IVB (50 eyes); the IVB/IVT group, patients who received 1.25 mg of IVB and 2 mg of IVT (50 eyes); and the MPC group, patients who underwent focal or modified grid laser (50 eyes). Retreatment was performed at 12-week intervals whenever indicated.

Change in best-corrected visual acuity (VA) at week 24.

VA changes among the groups were statistically significant at 6 (P<0.001) and 24 (P = 0.012) weeks. The significant treatment effect was demonstrated in the IVB group at all follow-up visits and in the IVB/IVT group at 6 and 12 weeks. VA changes +/- standard deviation at 36 weeks were -0.28+/-0.25, -0.04+/-0.33, and +0.01+/-0.27 logarithm of minimum angle of resolution in the IVB, IVB/IVT, and MPC groups, respectively (P = 0.053). Significant central macular thickness (CMT) reduction was observed in all groups only up to 6 weeks; however, CMT changes were not significant among the groups in all visits. Overall, retreatment was required for 27 eyes up to 36 weeks (14 in the IVB group, 10 in the IVB/IVT group, and 3 in the MPC group). In the IVB group, in which a greater VA improvement was observed, only 1 injection was required in 72% of the cases. VA improvement >2 Snellen lines at 36 weeks was detected in 37%, 25%, and 14.8% of patients in the IVB, IVB/IVT, and MPC groups, respectively.

Intravitreal bevacizumab injection in patients with DME yielded a better visual outcome at 24 weeks compared with macular photocoagulation. A change in CMT beyond the 6-week time point that corresponded to the vision change was not detected. No adjunctive effect of IVT was demonstrated.

The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Primary End Point (Six Months) Results of the Ranibizumab for Edema of the mAcula in diabetes (READ-2) study.

Abstract:
To compare ranibizumab with focal/grid laser or a combination of both in diabetic macular edema (DME).

Prospective, randomized, interventional, multicenter clinical trial.

A total of 126 patients with DME.

Subjects were randomized 1:1:1 to receive 0.5 mg of ranibizumab at baseline and months 1, 3, and 5 (group 1, 42 patients), focal/grid laser photocoagulation at baseline and month 3 if needed (group 2, 42 patients), or a combination of 0.5 mg of ranibizumab and focal/grid laser at baseline and month 3 (group 3, 42 patients).

The primary end point was the change from baseline in best-corrected visual acuity (BCVA) at month 6.

At month 6, the mean gain in BCVA was significantly greater in group 1 (+7.24 letters, P = 0.01, analysis of variance) compared with group 2 (-0.43 letters), and group 3 (+3.80 letters) was not statistically different from groups 1 or 2. For patients with data available at 6 months, improvement of 3 lines or more occurred in 8 of 37 (22%) in group 1 compared with 0 of 38 (0%) in group 2 (P = 0.002, Fisher exact test) and 3 of 40 (8%) in group 3. Excess foveal thickness was reduced by 50%, 33%, and 45% in groups 1, 2, and 3, respectively.

During a span of 6 months, ranibizumab injections by the current protocol had a significantly better visual outcome than focal/grid laser treatment in patients with DME.

A phase II randomized double-masked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, for diabetic macular edema.

Abstract:
To evaluate the safety and efficacy of pegaptanib sodium injection (pegaptanib) in the treatment of diabetic macular edema (DME).

Randomized, double-masked, multicenter, dose-ranging, controlled trial.

Individuals with a best-corrected visual acuity (VA) between 20/50 and 20/320 in the study eye and DME involving the center of the macula for whom the investigator judged photocoagulation could be safely withheld for 16 weeks.

Intravitreous pegaptanib (0.3 mg, 1 mg, 3 mg) or sham injections at study entry, week 6, and week 12 with additional injections and/or focal photocoagulation as needed for another 18 weeks. Final assessments were conducted at week 36.

Best-corrected VA, central retinal thickness at the center point of the central subfield as assessed by optical coherence tomography measurement, and additional therapy with photocoagulation between weeks 12 and 36.

One hundred seventy-two patients appeared balanced for baseline demographic and ocular characteristics. Median VA was better at week 36 with 0.3 mg (20/50), as compared with sham (20/63) (P = 0.04). A larger proportion of those receiving 0.3 mg gained VAs of > or =10 letters (approximately 2 lines) (34% vs. 10%, P = 0.003) and > or =15 letters (18% vs. 7%, P = 0.12). Mean central retinal thickness decreased by 68 microm with 0.3 mg, versus an increase of 4 microm with sham (P = 0.02). Larger proportions of those receiving 0.3 mg had an absolute decrease of both > or =100 microm (42% vs. 16%, P = 0.02) and > or =75 microm (49% vs. 19%, P = 0.008). Photocoagulation was deemed necessary in fewer subjects in each pegaptanib arm (0.3 mg vs. sham, 25% vs. 48%; P = 0.04). All pegaptanib doses were well tolerated. Endophthalmitis occurred in 1 of 652 injections (0.15%/injection; i.e., 1/130 [0.8%] pegaptanib subjects) and was not associated with severe visual loss.

In this phase II trial, subjects assigned to pegaptanib had better VA outcomes, were more likely to show reduction in central retinal thickness, and were deemed less likely to need additional therapy with photocoagulation at follow-up.

A phase II randomized clinical trial of intravitreal bevacizumab for diabetic macular edema.

Abstract:
To provide data on the short-term effect of intravitreal bevacizumab for diabetic macular edema (DME).

Randomized phase II clinical trial.

One hundred twenty-one eyes of 121 subjects (109 eligible for analysis) with DME and Snellen acuity equivalent ranging from 20/32 to 20/320.

Random assignment to 1 of 5 groups: (A) focal photocoagulation at baseline (n = 19), (B) intravitreal injection of 1.25 mg of bevacizumab at baseline and 6 weeks (n = 22), (C) intravitreal injection of 2.5 mg of bevacizumab at baseline and 6 weeks (n = 24), (D) intravitreal injection of 1.25 mg of bevacizumab at baseline and sham injection at 6 weeks (n = 22), or (E) intravitreal injection of 1.25 mg of bevacizumab at baseline and 6 weeks with photocoagulation at 3 weeks (n = 22).

Central subfield thickness (CST) on optical coherence tomography and best-corrected visual acuity (VA) were measured at baseline and after 3, 6, 9, 12, 18, and 24 weeks.

At baseline, median CST was 411 mum and median Snellen VA equivalent was 20/50. Compared with group A, groups B and C had a greater reduction in CST at 3 weeks and about 1 line better median VA over 12 weeks. There were no meaningful differences between groups B and C in CST reduction or VA improvement. A CST reduction > 11% (reliability limit) was present at 3 weeks in 36 of 84 (43%) bevacizumab-treated eyes and 5 of 18 (28%) eyes treated with laser alone, and at 6 weeks in 31 of 84 (37%) and 9 of 18 (50%) eyes, respectively. Combining focal photocoagulation with bevacizumab resulted in no apparent short-term benefit or adverse outcomes. Endophthalmitis developed in 1 eye. The following events occurred during the first 24 weeks in subjects treated with bevacizumab without attributing cause to the drug: myocardial infarction (n = 2), congestive heart failure (n = 1), elevated blood pressure (n = 3), and worsened renal function (n = 3).

These results demonstrate that intravitreal bevacizumab can reduce DME in some eyes, but the study was not designed to determine whether treatment is beneficial. A phase III trial would be needed for that purpose.

Intravitreal bevacizumab with or without triamcinolone for refractory diabetic macular edema; a placebo-controlled, randomized clinical trial.

Abstract:
To evaluate the effect of three intravitreal injections of bevacizumab (IVB) alone or combined with triamcinolone (IVT) in the first injection for treatment of refractory diabetic macular edema (DME).

In this prospective, placebo-controlled, randomized clinical trial, 115 eyes of 101 patients with refractory DME were included. Subjects were randomly assigned to one of the three study arms: 1) three injections of IVB (1.25 mg/0.05 ml) at 6-week intervals, 2) combined IVB and IVT (1.25 mg/0.05 ml and 2 mg/0.05 ml respectively) followed by two injections of IVB at 6-week intervals, and 3) sham injection (control group). The primary outcome measure was change in central macular thickness (CMT). Secondary outcome measures were change in best-corrected logMAR visual acuity (BCVA ) and incidence of potential adverse events.

Central macular thickness was reduced significantly in both the IVB and IVB/IVT groups. At week 24, CMT change compared to the baseline was -95.7 microm (95% CI, -172.2 to -19.26) in the IVB group, -92.1 microm (95% CI, -154.4 to -29.7) in the IVB/IVT group, and 34.9 microm (95% CI, 7.9 to 61.9) in the control group. There was a significant difference between the IVB and control groups (P = 0.012) and between the IVB/IVT and control groups (P = 0.022). Improvement of BCVA was initiated at weeks 6 and 12 in the IVB/IVT and IVB groups respectively. In terms of BCVA change compared to the baseline at 24 weeks, the differences between the IVB and control groups (P = 0.01) and also between the IVB/IVT and control groups (P = 0.006) were significant. No significant differences were detected in the changes of CMT and BCVA between the IVB and IVB/IVT groups (P = 0.99). Anterior chamber reaction was noticed in eight (19.5%) and seven (18.9%) eyes respectively in the IVB and IVB/IVT groups the day after injection, and it resolved with no sequel. Elevation of IOP occurred in three eyes (8.1%) in the IVB/IVT group.

Three consecutive intravitreal injections of bevacizumab had a beneficial effect on refractory DME in terms of CMT reduction and BCVA improvement. Addition of triamcinolone in the first injection seemed to induce earlier visual improvement; however, it did not show any significant additive effect later during follow-up.

Intravitreal triamcinolone versus bevacizumab for treatment of refractory diabetic macular oedema (IBEME study).

Abstract:
The aim of this study was to compare the morphological and visual acuity outcomes associated with a single intravitreal injection of triamcinolone acetonide versus bevacizumab for the treatment of refractory diffuse diabetic macular oedema.

Twenty-eight patients were randomly assigned to receive a single intravitreal injection of either 4 mg/0.1 ml triamcinolone acetonide or 1.5 mg/0.06 ml bevacizumab. Comprehensive ophthalmic evaluation was performed at baseline and at weeks 1, 4, 8 (+/-1), 12 (+/-2) and 24 (+/-2) after treatment. Main outcome measures included central macular thickness measured with optical coherence tomography (OCT) and best corrected Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity.

Twenty-six patients (26 eyes) completed all study visits (two patients missed two consecutive study visits). Central macular thickness was significantly reduced in the intravitreal triamcinolone group compared with the bevacizumab group at weeks 4, 8, 12 and 24 (p<0.05). Logarithm of the minimum angle of resolution (LogMAR) best-corrected visual acuity was significantly higher at weeks 8 (0.69; approximately 20/100(+1)) and 12 (0.74; 20/100(-2)) in the intravitreal triamcinolone group compared with the bevacizumab group (weeks 8 (0.83; approximately 20/125(-1)) and 12 (0.86; 20/160(+2))) (p<0.05). Significant change from baseline in mean intraocular pressure (mmHg) was seen at week 4 (+2.25) only in the intravitreal triamcinolone group (p<0.0001). No patient had observed cataract progression during the study.

One single intravitreal injection of triamcinolone may offer certain advantages over bevacizumab in the short-term management of refractory diabetic macular oedema, specifically with regard to changes in central macular thickness. The actual clinical relevance of our preliminary findings, however, remains to be determined in future larger studies.

Intravitreal bevacizumab versus combined bevacizumab-triamcinolone versus macular laser photocoagulation in diabetic macular edema.

Abstract:
To evaluate the additive effect of triamcinolone to bevacizumab in comparison to standard macular laser photocoagulation versus bevacizumab in the management of diabetic macular edema (DME).

In a prospective, randomized clinical trial, 130 eyes of 110 patients with type 2 diabetes with DME were included. Eligible eyes were randomly assigned to 1.25 mg intravitreal bevacizumab (42 eyes) (IVB group) or combination of 1.25 mg bevacizumab and 2 mg triamcinolone acetonide (41 eyes) (IVB+IVT group) or macular laser photocoagulation (47 eyes) (MPC). Central macular thickness (CMT) and visual acuity changes at week 6 and 16 were assessed.

The mean age of the patients was 57 -/+7 years. Patients were followed 16 weeks. At week 6, all the three groups showed significant reduction in CMT but the reductions for IVB and IVB+IVT were significantly more than MPC (p<0.001). At week 16, the response was not stable for IVB (p<0.001), but IVB+IVT maintained its superior status to MPC (p<0.001). At week 16, visual acuities were essentially unchanged for the two groups of MPC and IVB and improvement for IVB+IVT was marginal and at most was 0.1 log MAR. No patient developed uveitis, endophthalmitis, or thromboembolic event.

Single intravitreal bevacizumab or triamcinolone plus bevacizumab injection brought about significantly greater macular thickness reduction in diabetic patients in comparison to standard laser treatment. However, the response for bevacizumab alone was short-lived. Reduction in macular thickness was only marginally associated with visual acuity improvement in the triamcinolone plus bevacizumab injection group.

Intravitreal bevacizumab and/or macular photocoagulation as a primary treatment for diffuse diabetic macular edema.

Abstract:
To evaluate the efficacy of intravitreal injection of bevacizumab (IVB) followed by modified grid laser photocoagulation (MGP) versus each alone as a primary treatment of diffuse diabetic macular edema.

A randomized 3-arm clinical trial in which 62 eyes of 48 patients with diffuse diabetic macular edema were enrolled. Eyes were randomly distributed to 1 of 3 study groups: 19 eyes underwent MGP (MGP group), 21 eyes received 1.25 mg of IVB (IVB group), and 22 eyes received IVB followed by MGP (combined group). All eyes underwent a complete ophthalmic examination including fluorescein angiography and optical coherence tomography at baseline and at 1, 3, and 6 months, after treatment. Fluorescein angiography was performed at the 3 and 6 months follow up visits. The outcome measures were the change compared with baseline in central macular thickness (CMT), changes in best-corrected visual acuity (BCVA), changes in fluorescein angiography leakage, and any reported complication. A P value less than 0.05 was considered statistically significant.

One month after treatment, the reduction in the mean CMT versus baseline was 49.88 μm (10.45%) in MGP group, 150.92 μm (31.30%) in IVB group, and 110.30 μm (23.77%) in the combined group, with a corresponding improvement in the mean BCVA. At 1 month, the improvement in CMT was better than baseline in all groups, yet only significant in the IVB group (P < 0.05) and the combined group (P < 0.05). The improvement in mean BCVA was significant in the IVB (P < 0.05) and the combined groups at 1 month (P < 0.05). At 3 months, the mean CMT was still better than baseline in all groups but this improvement was significant only in the combined group (P < 0.05). The improvement in the mean BCVA was significant only in the IVB and the combined groups (P < 0.05). Six months after treatment, the reduction in the mean CMT was significant in the combined group only (P < 0.05) and there was no significant improvement in the mean BCVA in all groups (P > 0.05). The BCVA did not deteriorate below baseline in all eyes included in the study, except three eyes in the MGP group. No complication related to the intravitreal injection was reported in the injected eyes.

Combined therapy with IVB and sequential MGP 3 weeks later appeared to be superior to MGP or IVB alone in reducing macular thickening and improving visual acuity. However, no significant improvement in BCVA occurs 6 months after treatment. A combination of IVB and sequential MGP could be used as an initial treatment of diffuse diabetic macular edema.

Randomized trial evaluating short-term effects of intravitreal ranibizumab or triamcinolone acetonide on macular edema after focal/grid laser for diabetic macular edema in eyes also receiving panretinal photocoagulation.

Abstract:
To evaluate 14-week effects of intravitreal ranibizumab or triamcinolone in eyes receiving focal/grid laser for diabetic macular edema and panretinal photocoagulation.

Three hundred and forty-five eyes with a visual acuity of 20/320 or better, center-involved diabetic macular edema receiving focal/grid laser, and diabetic retinopathy receiving prompt panretinal photocoagulation were randomly assigned to sham (n = 123), 0.5-mg ranibizumab (n = 113) at baseline and 4 weeks, and 4-mg triamcinolone at baseline and sham at 4 weeks (n = 109). Treatment was at investigator discretion from 14 weeks to 56 weeks.

Mean changes (±SD) in visual acuity letter score from baseline were significantly better in the ranibizumab (+1 ± 11; P < 0.001) and triamcinolone (+2 ± 11; P < 0.001) groups compared with those in the sham group (-4 ± 14) at the 14-week visit, mirroring retinal thickening results. These differences were not maintained when study participants were followed for 56 weeks for safety outcomes. One eye (0.9%; 95% confidence interval, 0.02%-4.7%) developed endophthalmitis after receiving ranibizumab. Cerebrovascular/cardiovascular events occurred in 4%, 7%, and 3% of the sham, ranibizumab, and triamcinolone groups, respectively.

The addition of 1 intravitreal triamcinolone injection or 2 intravitreal ranibizumab injections in eyes receiving focal/grid laser for diabetic macular edema and panretinal photocoagulation is associated with better visual acuity and decreased macular edema by 14 weeks. Whether continued long-term intravitreal treatment is beneficial cannot be determined from this study.


Context: Observational studies in preterm newborns suggest that delay in administering amino acids (AA) could result in a protein catabolic state and impact on growth and development.

The objective of this review was to compare the efficacy and safety of early versus late administration of intravenous AA in neonates born at < 37 weeks of gestation.

We included randomised controlled trials (RCTs) comparing early administration of AA with late administration in premature newborn infants. We defined early administration of AA solution as the administration of AA in isolation or with total parenteral nutrition within the first 24 hours of birth, and late administration as the administration of AA in isolation or with total parenteral nutrition after the first 24 hours of birth.

Metabolic responses to early and high protein supplementation in a randomized trial evaluating the prevention of hyperkalemia in extremely low birth weight infants.

Abstract:
To determine whether early and higher intravenous amino acid (EHAA) supplementation decreases hyperkalemia in extremely low birth weight (ELBW) infants (<1000 g).

Infants were enrolled at birth in a randomized, double-masked, prospective fashion and treated for 7 days. The standard group (SAA) infants received intravenous amino acid (AA) starting at 0.5 g x kg(-1) x d(-1) and increased by 0.5 g x kg(-1) every day to a maximum of 3 g x kg(-1) x d(-1). EHAA group infants received 2 g x kg(-1) x d(-1) of AA soon after birth and advanced by 1 g x kg(-1) every day to 4 g x kg(-1) x d(-1). Data analysis was by SPSS 11.5, with statistical significance at alpha = 0.05 and 90% power to determine a difference in mean K(+) level of 2.

Sixty-two patients, mean gestational age of 26.0 +/- 2.0 weeks and birth weight of 775 +/- 136 g, were enrolled. Hyperkalemia (K(+) > or =6.5 mEq/L) occurred in 13% of the studied population; no difference in incidence of hyperkalemia was found between the SAA and EHAA groups (16% vs 10%, respectively, P = .70). Serum blood urea nitrogen was higher in the EHAA group. AA infusion was stopped early in 6 patients for high blood urea nitrogen or elevated ammonia level.

During the study period, hyperkalemia decreased significantly and was not affected by EHAA supplementation in the first week of life.

The effects of early parenteral amino acids on sick premature infants.

Abstract:
To study the effects of early parenteral amino acid administration on body weight, fluid compartments and metabolic parameters during the first week of life in sick premature infants.

Appropriate for gestational age, sick premature infants were randomized into two groups. Group A infants (n=8, birth weight 1258±339 g) were supplemented with amino acids starting within 24 h of birth and advanced to 2.5 g/kg per day by day 3. Group G infants (n=9, birth weight 1182±214 g) received amino acids starting on day 4 of life. Energy intake was comparable in the 2 groups. Amino acid concentrations and nitrogen balance studies were performed on day 3 of life. Total body water and extracellular water were measured on day 1 and 8 and change in intracellular volume was calculated.

There was no significant difference between the 2 groups in terms of weight, intracellular volume change from day 1 to day 8 of life, despite a significant (P<0.01) difference in protein intake. Plasma ammonia levels were comparable in the 2 groups, but plasma urea levels were significantly higher in group A vs. group G infants (7.2±3.4 mmol/L vs. 3.2±1.2 mmol/L respectively, P<0.01). Nitrogen balance was positive in all group A infants and negative in group G infants. Nitrogen loss was inversely correlated with energy intake in group G infants (P<0.05). The mean plasma amino acid concentrations in group A infants (compared to those of group G) were within previously reported ranges in older premature infants.

There was no significant effect on body weight and redistribution of body fluid compartments in infants receiving amino acids early during the first week of life. Serum urea concentrations were significantly higher in infants receiving early amino acids. Nitrogen losses in infants who did not receive amino acids were inversely correlated with energy intake during the first 3 days of life.

Low birthweight infants and total parenteral nutrition immediately after birth. II. Randomised study of biochemical tolerance of intravenous glucose, amino acids, and lipid.

Abstract: This randomised study aimed to compare the biochemical tolerance of three parenteral regimens administered during the first 48 hours of life. Twenty nine infants were randomised to either: (a) glucose 10%; (b) glucose 10%/amino acids; (c) glucose 10%/amino acids/lipid. Blood samples for plasma amino acid profiles, cholesterol, and triglyceride concentrations were taken on arrival in the neonatal unit and again between 36 and 48 hours of life. Arterial or capillary blood gas analysis and blood glucose estimates were performed routinely during the first 48 hours of life. There was a sharp decline in plasma amino acid concentrations in the group following (a) compared with the two groups following (b) and (c) regimens. In all groups plasma triglyceride and cholesterol were not significantly different before and after 48 hours of lipid infusion. Peak mean (SE) bilirubin concentrations (203 (12) v 181 (19) v 220 (20) mumol/l) and the need for phototherapy (nine v eight v five infants) were similar for each of the groups. Hypoglycaemia occurred most frequently during the (b) regimen and least commonly in the (c) group. There are potential health gains from giving parenteral nutrition to low birthweight infants immediately after birth, and this study indicates that restriction of nutritional intake immediately after birth in preterm infants may cause significant metabolic disturbance. This can be prevented by starting a regimen of intravenous amino acids and lipid immediately after birth.

Effect of intravenous amino acids on protein metabolism of preterm infants during the first three days of life.

Abstract: Twenty-three preterm infants with respiratory distress syndrome (mean birth weight 1.07 kg, SD 0.24 kg) were randomly assigned to receive glucose alone or glucose with amino acids (1.5 g.kg-1.d-1) i.v. beginning on the 1st d of life. Blood ammonia and serum urea, CO2 content, sodium, potassium, chloride, and ionized calcium concentrations were normal and did not differ between treatment groups. Nitrogen balance was significantly greater in the group that received amino acids [88 (SD 54) versus -135 (SD 45) mg.kg-1.d-1]. In 12 infants (seven, glucose-only; five, glucose and amino acids), leucine kinetic studies were also performed on the 3rd d of life. These 12 infants received a 4-h primed constant infusion of L-[1-13C]leucine. Blood and breath were collected and analyzed for [1-13C]ketoisocaproate and 13CO2, respectively. Leucine turnover and oxidation were calculated. Both leucine turnover and oxidation were significantly higher in the group receiving amino acids than in the glucose-only group [241 (SD 38) versus 164 (SD 25) mumol.kg-1.h-1 and 71 (SD 22) versus 40 (SD 17) mumol.kg-1.h-1, respectively]. In addition, the calculated rate of protein synthesis was higher in the group receiving amino acids [6.9 (SD 1.1) versus 5.0 (SD 1.2) g.kg-1.d-1]. These data indicate that the i.v. administration of amino acids (1.5 g.kg-1.d-1) to ill preterm infants beginning on the 1st d of life improves whole-body protein balance as a result of increased protein synthesis.

Early parenteral feeding of amino acids.

Abstract: Serial 24 hour balance studies of nitrogen and energy were carried out over 10 days in two groups of ventilator dependent preterm infants, of comparable weight and gestational age. In one group (n = 10) a parenteral amino acid source (Vamin 9) was started within 24 hours of birth, and in the other group (n = 11) it was not started until 72 hours. The feeding protocol was otherwise identical. The nitrogen intake (286 compared with 21 mg/kg/day), energy intake (188 compared with 151 kJ), and nitrogen retention (120 compared with -133 mg/kg/day), were all significantly higher during the first three days of life in the group in which the amino acid solution was started early. There were no differences by 7-10 days. The early introduction of amino acids improves the early nutritional state of sick preterm infants.

[Intensive early amino acid supplementation is efficacious and safe in the management of preterm infants].

Abstract:
To evaluate the efficacy and safety of the parenteral administration of various quantities of amino acid in preterm infants.

Preterm infants (birth weight 1000-2000 g) recruited into the study were randomized into three groups. High amino acid group (HP): 2.4 g/(kg.d) of amino acid IV within 24 hours after birth increasing by increments of 1.2 g/(kg.d) to a maximum of 3.6 g/(kg. d); medium amino acid group (MP): 1.0 g/(kg.d) of amino acid IV 24 hours after birth, increasing by increments of 0.5 g/(kg.d) until a maximum of 3.0 g/(kg.d); and low amino acid group (LP): 0.5 g/(kg.d) of amino acid on D3, increasing by increments of 0.5 g/(kg.d) until a maximum of 3.0 g/(kg.d) as the final dose.

Totally 96 preterm infants were recruited: HP 34, MP 32 and LP 30. There were no significant differences in demographic or clinical characteristics among the 3 groups. HP group showed lower postnatal weight loss (43.4 g, 95% CI 74.3, 12.6) and weight loss% (2.84%, 95% CI 4.79%, 0.71%) than LP group. HP group showed shorter length of stay in NICU (5.25 d), days to reach 2000 g (7.03 d) and days to tolerate 100 kcal/(kg.d) enteral nutrition (4.52 d) than LP group. Cost of hospitalization was significantly lower in HP group than in LP group (-6275 RMB, 1 US$=8 RMB) and MP group (-5715 RMB). Mean serum RBP (D4), threonine and tyrosine levels were significantly higher in HP group than in LP group. Serum insulin levels were similar; mean serum glucose level was lower in HP group than in LP group. HP infants had lower incidence of sepsis than LP infants (21.9% vs 40.0%). There were no significant differences in the levels of blood ammonia, acid-base balance (as determined by pH and NaHCO3-), BUN, Cr, AST, and ALT.

Intensive and early administration of intravenous amino acid [2.4 g/(kg.d)] improves preterm infants' growth and the tolerance of enteral feeding. It also reduces the cost of hospitalization, and the incidence of sepsis.

Amino acid administration to premature infants directly after birth.

Abstract:
To test the hypothesis that the administration of 2.4 g amino acids (AA)/(kg.d) to very low birth weight infants is safe and results in a positive nitrogen balance.

We conducted a randomized, clinical trial. Preterm infants with birth weights <1500 g received either glucose and 2.4 g AA/(kg.d) from birth onward (n=66) or solely glucose during the first day with a stepwise increase in AA intake to 2.4 g AA/(kg.d) on day 3 (n=69). Blood gas analysis was performed daily during the first 6 postnatal days; blood urea nitrogen levels were determined on days 2, 4, and 6; AA plasma concentrations and nitrogen balances were determined on days 2 and 4. Student t tests, Mann-Whitney tests, and chi2 tests were performed to compare groups.

Infants supplemented with AA had no major adverse side effects. Their blood urea nitrogen levels were higher, nitrogen balance turned positive upon AA administration, and more AA concentrations were within reference ranges.

High-dose AA administration to very low birth weight infants can be introduced safely from birth onward and results in an anabolic state.

Effects of early amino acid administration on leucine and glucose kinetics in premature infants.

Abstract: We previously showed that, in prematurely born infants, an anabolic state without metabolic acidosis can be achieved upon intravenous amino acid (AA) administration in the immediate postnatal phase, despite a low energy intake. We hypothesized that the anabolic state resulted from an increased protein synthesis and not a decreased proteolysis. Furthermore, we hypothesized that the energy needed for the higher protein synthesis rate would be derived from an increased glucose oxidation. To test our hypotheses, 32 ventilated premature infants (<1500 g) received intravenously either solely glucose or glucose and 2.4 g AA/kg/d immediately postnatally. On postnatal d 2, each group received primed continuous infusions of either [1-13C]leucine or [U-13C6]glucose. 13CO2 enrichments in expiratory air and plasma [1-13C]alpha-KICA (as an intracellular leucine precursor) and [U-13C6]glucose enrichments were measured by mass spectrometry techniques. The AA administration resulted in an increased incorporation of leucine into body protein and a higher leucine oxidation rate, whereas leucine release from proteolysis was not affected. Glucose oxidation rate did not increase upon AA administration. In conclusion, the anabolic state resulting from AA administration in the immediate postnatal period resulted from increased protein synthesis and not decreased proteolysis. The energy needed for the additional protein synthesis was not derived from an increased glucose oxidation.

Observational outcome results following a randomized controlled trial of early amino acid administration in preterm infants.

Abstract:
Several reports have investigated amino acid administration in premature infants during the early postnatal phase. Most of these previous studies, however, have only evaluated short-term in-hospital outcomes. Our aim was to describe long-term outcomes in premature infants previously subjected to different nutritional regimens in a randomized controlled trial. The primary outcome was survival without major disabilities, and the secondary outcomes included anthropometry and mental development.

Infants born <32 weeks' gestation and <1500 g were randomized to receive glucose (n = 69) or glucose with 2.4 g · kg(-1) · day(-1 amino acids) (n = 63) from birth. From postnatal day 3 onward, the nutritional intake was similar. At 2 years of corrected age, the surviving infants were assessed for neurodevelopmental outcome and anthropometry.

Ninety-seven percent of the surviving infants were examined at follow-up, with no overall effect on survival without major disabilities. Boys, however, had a normal outcome significantly more often if amino acids were administered from birth onward (crude odds ratio 3.8, 95% confidence interval 1.3-11.4) and following adjustment for confounders (odds ratio 6.2, 95% confidence interval 1.0-38.0). The secondary outcomes exhibited no differences in anthropometric data. The mental developmental index was lower in the small number of girls who survived without major disabilities following the early administration of amino acids.

In this hypothesis-generating outcome study, premature boys, but not girls, benefited from amino acid administration directly following birth. The observed lower mental developmental index in a subgroup of girls, however, warrants further studies.


Context: Laryngeal mask airway surfactant administration (S-LMA) has the potential benefit of surfactant administration whilst avoiding endotracheal intubation and ventilation, ventilator-induced lung injury and bronchopulmonary dysplasia (BPD).

To evaluate the benefits and harms of S-LMA either as prophylaxis or treatment (rescue) compared to placebo, no treatment, or intratracheal surfactant administration via an endotracheal tube (ETT) with the intent to rapidly extubate (InSurE) or extubate at standard criteria (S-ETT) or via other less-invasive surfactant administration (LISA) methods on morbidity and mortality in preterm infants with or at risk of respiratory distress syndrome (RDS).

Randomised controlled trials (RCTs), cluster- or quasi-RCTs of S-LMA compared to placebo, no treatment, or other routes of administration (nebulised, pharyngeal instillation of surfactant before the first breath, thin endotracheal catheter surfactant administration or intratracheal surfactant instillation) on morbidity and mortality in preterm infants at risk of RDS. We considered published, unpublished and ongoing trials.

Implementation of Surfactant Administration through Laryngeal or Supraglottic Airways (SALSA): A Jordanian NICU's Journey to Improve Surfactant Administration.

Abstract: Administration of liquid surfactant through an endotracheal tube for the treatment of respiratory distress syndrome has been the standard of care for decades. Surfactant administration through laryngeal or supraglottic airways (SALSA) is a simplified procedure for delivery of surfactant that is less invasive and better tolerated. The Al Bashir Maternity and Children’s Hospital NICU in Amman, Jordan, implemented SALSA as a potentially better practice in 2019 with the objective to effectively and efficiently deliver surfactant in a minimally invasive way and to decrease the adverse events associated with intubation−surfactant−extubation (InSurE) and laryngoscopy. The quality improvement initiative was conducted from March 2019 to December 2019. All infants who weighed 750 g or more who required surfactant were eligible. As physicians were trained in the technique and use expanded, we were able to use plan−do−study−act cycles to observe differences between SALSA and InSurE. The primary aim was the optimization of non-invasive ventilation by the effective and efficient delivery of surfactant. Balancing measures included episodes of bradycardia while receiving surfactant or the need for a second dose of surfactant. We evaluated 220 infants who received surfactant by SALSA or InSurE with a mean gestational age of 32 weeks and a mean birth weight of 1.8 kg. The Respiratory Severity Score (RSS) prior to surfactant administration was 2.7 in the SALSA group compared to 2.9 in the InSurE group (p = 0.024). Those in the InSurE group had a lower mean heart rate during the procedure (p =< 0.0001) and were more likely to need a second dose of surfactant (p = 0.026) or require intubation for mechanical ventilation (p = 0.022). Both groups were effectively delivered surfactant as evidenced by improvement in their RSS over an 8 h period. SALSA was a more time efficient surfactant delivery method (93 vs. 111 secs, p =< 0.0001). Implementation of SALSA into the Al Bashir NICU was successful. We found that it was equally effective to InSurE, but was a more efficient method of delivery. Infants who received surfactant by this method tolerated it well.

ProSealTM laryngeal mask airway for surfactant administration in the treatment of respiratory distress syndrome in a premature infant.

Abstract: The administration of surfactant via tracheal cannula with mechanical ventilation is the conventional treatment for infant respiratory distress syndrome. Hemodynamic and respiratory changes due to tracheal intubation and the need for premedication justify the search for less invasive alternatives of surfactant administration. The objective of this study was to describe the use of the ProSealTM laryngeal mask airway as an option for the treatment of respiratory distress syndrome in a premature infant born at 31 weeks of gestation, at 1335 g, with respiratory difficulty after the first hour of life and exhibiting the clinical and radiologic features of respiratory distress syndrome. The surfactant was administered with the use of the ProSealTM laryngeal mask airway at 3.5 hours of life. It was well tolerated, with no need for tracheal intubation. Normal gasometry and radiologic improvement were observed after three and six hours of administration. Oxygen administration was suspended after eight days, with no comorbidities at discharge. The laryngeal mask airway seems to be a painless and less invasive alternative to treat respiratory distress syndrome and may reduce the need for tracheal intubation and mechanical ventilation. The efficacy and advantages of this route of treatment should be confirmed in a study of an adequate sample.

The laryngeal mask airway for administration of surfactant in two neonates with respiratory distress syndrome.

Abstract: We report the successful use of the Classic laryngeal mask airway to provide brief access to the intratracheal space for the administration of surfactant in two neonates with respiratory distress syndrome.

Surfactant Administration Through Laryngeal or Supraglottic Airways.

Abstract: Noninvasive ventilation is frequently used in the treatment of infants with respiratory distress syndrome. This practice is often effective in higher gestational age neonates, but can be difficult in those with lower gestational ages as surfactant deficiency can be severe. While noninvasive ventilation avoids the negative effects of intubation and ventilator-induced lung injury, failure of this mode of support does occur with relative frequency and is primarily caused by the poorly compliant, surfactant-deficient lung. Because of the potential problems associated with laryngoscopy and intubation, neonatologists have developed various methods to deliver surfactant in minimally invasive ways with the aim of improving the success of noninvasive ventilation. Methods of minimally invasive surfactant administration include various thin catheter techniques, aerosolization/nebulization, and the use of a laryngeal mask airway/supraglottic airway device. The clinician should recognize that currently the only US Food and Drug Administration-approved device to deliver surfactant is an endotracheal tube and all methods reviewed here are considered off-label use. This review will focus primarily on surfactant administration through laryngeal or supraglottic airways, providing a review of the history of this technique, animal and human trials, and comparison with other minimally invasive techniques. In addition, this review provides a step-by-step instruction guide on how to perform this procedure, including a multimedia tutorial to facilitate learning.

ProSeal LMA for surfactant administration.

Laryngeal mask airway for surfactant administration in a newborn animal model.

Abstract: Premature infants are subjected to adverse effects of intubation to benefit from surfactant. We hypothesized that administration of surfactant through a laryngeal mask airway (LMA) is as effective as administration through an endotracheal tube (ETT) and that time and physiologic changes during instrumentation will be less in the LMA group. This study is a randomized, controlled trial using newborn pigs. Lung injury was induced via surfactant washout. Animals were randomized into groups: 1) LMA placed, no surfactant administered (control; n = 8); 2) surfactant via an LMA (LMA group; n = 8); and 3) surfactant via an ETT (ETT group; n = 8). We demonstrated that partial pressure of oxygen in arterial blood (Pao2) levels of the LMA and ETT groups were not statistically different. Time for successful placement of LMA was 19 ± 1 s versus ETT 123 ± 35 s (mean ± SEM); number of attempts for successful LMA placement was 1.1 (1-2) versus ETT 1.9 (1-7) [mean (range)]. Administration of surfactant via an LMA compared with an ETT resulted in similar improvements in oxygenation. Placement of the device required less time and fewer attempts. These data suggest that further study in human neonates is justified. If proven effective, some infants with respiratory distress may be able to receive surfactant while avoiding intubation.

Laryngeal mask airway used as a delivery conduit for the administration of surfactant to preterm infants with respiratory distress syndrome.

Abstract:
The laryngeal mask airway (LMA(TM), Laryngeal Mask Co. Ltd, Jersey, UK) is a supraglottic device used to administer positive pressure ventilation (PPV) in adults, pediatric and neonatal patients.

To avoid endotracheal intubation, we evaluated the feasibility and practicality of administering surfactant via the LMA(TM) in preterm infants with respiratory distress syndrome (RDS).

Infants less than 72 h old with a gestational age of < or =35 weeks and a birth weight of >800 g, treated with nasal continuous positive airway pressure (CPAP, 5 cm H2O) for RDS were eligible for inclusion in the study if the arterial-to-alveolar oxygen tension ratio (a/APO2) was <0.20 over a period of >60 min.

Eight preterm infants, median gestational age 31 (range 28-35) weeks; birth weight 1,700 (880-2,520) g, treated with nasal CPAP for RDS were enrolled. Three hours after surfactant instillation, the mean a/APO2 was significantly increased (0.13 +/- 0.04 to 0.34 +/- 0.11; p < 0.01) without complications.

The LMA may be a useful and noninvasive conduit for the administration of surfactant therapy. A large randomized comparative clinical trial will be required to confirm the efficacy of this technique.

Catheter and Laryngeal Mask Endotracheal Surfactant Therapy: the CALMEST approach as a novel MIST technique.

Abstract:
Neonatal respiratory distress syndrome (RDS) is a major cause of mortality and morbidity among preterm infants. Although the INSURE (INtubation, SURfactant administration, Estubation) technique for surfactant replacement therapy is so far the gold standard method, over the last years new approaches have been studied, i.e. less invasive surfactant administration (LISA) or minimally invasive surfactant therapy (MIST). Here we propose an originally modified MIST, called CALMEST (Catheter And Laryngeal Mask Endotracheal Surfactant Therapy), using a particular laryngeal mask as a guide for a thin catheter to deliver surfactant directly in the trachea.

We performed a preliminary study on a mannequin and a subsequent in vivo pilot trial.

This novel procedure is quick, effective and well tolerated and might represent an improvement in reducing neonatal stress. Ultimately, CALMEST offers an alternative approach that could be extremely useful for medical staff with low expertise in laryngoscopy and intubation.

Surfactant Administration Through Laryngeal or Supraglottic Airways (SALSA): A Viable Method for Low-Income and Middle-Income Countries.

Abstract: Administration of liquid surfactant through an endotracheal tube for the treatment of respiratory distress syndrome has been the standard of care for decades. A skilled health care provider is needed to perform this procedure. In lower-income and middle-income countries (LMICs), healthcare resources are often limited, leading to increased mortality of premature infants, many of whom would benefit from surfactant administration. Therefore, having a simplified procedure for delivery of surfactant without the need for advanced skills could be life-saving, potentially diminish gaps in care, and help ensure more equitable global neonatal survival rates. Modifications to the standard approach of surfactant administration have been put into practice and these include: INtubation-SURfactant-Extubation (INSURE), thin catheter surfactant administration (TCA), aerosolized surfactant, and surfactant administration through laryngeal or supraglottic airways (SALSA). Although there is a need for larger studies to evaluate the comparative effectiveness of these newer methods, these methods are being embraced by the global community and being implemented in various settings throughout the world. Because the SALSA technique does not require laryngoscopy, a provider skilled in laryngoscopy is not required for the procedure. Therefore, because of the ease of use and safety profile, the SALSA technique should be strongly considered as a viable method of delivering surfactant in LMICs.


Context: This is an updated version of a Cochrane Review first published in 2014. Phimosis is a condition in which the prepuce (foreskin) cannot be fully retracted past the head of the penis (glans). Phimosis is often treated surgically by circumcision or prepuce plasty; however, reports of non-invasive treatment using topical corticosteroids applied for four to eight weeks have suggested favorable outcomes.

To assess the effects of topical corticosteroids applied to the stenotic portion of the prepuce for the treatment of phimosis in boys compared with placebo or no treatment.

We included all randomized controlled trials (RCTs) that compared the use of any topical corticosteroid with placebo or no treatment for boys with any type or degree of phimosis.

Effect of topical steroid on non-retractile prepubertal foreskin by a prospective, randomized, double-blind study.

Abstract:
The present study, conducted in Hong Kong, aimed to evaluate the effect of topical steroid in non-retractile prepubertal foreskin by a prospective, randomized, double-blind design.

137 boys with non-retractile foreskin were randomized to betamethasone (n = 66) or placebo (n = 71 ) for 4 weeks with application of the cream twice daily. Non-responders to treatment were offered steroid treatment for a further 4 weeks.

The mean pretreatment grade of the foreskin in the steroid and control groups was 5.08 +/- 0.66 and 4.97 +/- 0.70, respectively. At the 4-week follow-up, 49 of the former (74%) had a retractile foreskin (grade less than or equal to 3, mean 2.38 +/- 1.41). In contrast, only 31 of the control group (44%) had a retractile foreskin (less than or equal to 3, mean 3.55 +/- 1.55) (p < 0.001). Only 14 boys were circumcised because 43 of the remaining 57 boys had a retractile foreskin after 4 weeks of treatment.

when treatment is necessary, application of topical steroid as a first line of treatment may avoid surgery in almost 90% of cases.

The response of balanitis xerotica obliterans to local steroid application compared with placebo in children.

Abstract:
We evaluated the clinical effectiveness of topical steroid application for balanitis xerotica obliterans in children and analyzed the association of any clinical response with histological findings.

Our double-blind, placebo controlled, randomized study included 40 boys in whom balanitis xerotica obliterans was diagnosed clinically by cicatricial phimosis. The severity of phimosis was graded into 4 groups. Patients were randomized to receive the topical application of 0.05% mometasone furoate or placebo. After 5 weeks phimosis severity was reevaluated and all patients underwent circumcision. Surgical specimens were histologically typed as an early, intermediate or late form of balanitis xerotica obliterans.

Seven patients were withdrawn from the study. In the steroid group 7 boys had clinical improvement and 10 had no change. Histological study showed an early, intermediate and late form of balanitis xerotica obliterans in 5, 5 and 7 cases, respectively. Of cases with clinical improvement 5 were the early and 2 the intermediate type. In the placebo group 5 cases worsened clinically and 11 did not change. Histological evaluation revealed an early, intermediate and late form of balanitis xerotica obliterans in 3, 7 and 6 boys, respectively. Of the 5 cases with histological worsening, disease was the early, intermediate and late type in 2, 2 and 1, respectively.

Applying a potent topical steroid affects improvement in balanitis xerotica obliterans in the histologically early and intermediate stages of disease, and may inhibit further worsening in the late stage.

Psychological trauma of circumcision in the phallic period could be avoided by using topical steroids.

Abstract:
The objective of our study was to assess the efficacy of topical steroids in the treatment of phimosis and evaluate patients using the Diagnostic and Statistical Manual-III-Revised (DSM-III-R) test with the aim of eliminating castration anxiety of circumcision in the phallic period.

One hundred and forty-nine children with phimosis who required circumcision were included the study. The average age of the children was 4.47 years. All children underwent the DSM-III-R test and their parents were questioned. Patients were separated randomly into three groups. Group I comprised 51 children who would undergo circumcision; group II comprised 50 children who would be treated with a topical corticosteroid (0.05% bethamethasone cream) twice daily for 1 month; and group III comprised 48 children who would be treated with a topical placebo cream. On the 5th day of treatment, parents were told to retract the prepuce and were given hygiene routine instructions. Patients were seen immediately after treatment and again 2 months later.

In group II, 16 of the 50 children had non-retractable prepuce. Forty-two cases of phimosis were corrected after treatment. Eight patients received further monthly treatment and five benefited from the second course of treatment. In group III, 17 of the 48 patients had non-retractable prepuce and four had satisfactory results. Forty-four patients received placebo treatment for another month and eventually, 40 children underwent circumcision in this group. DSM-III-R test results showed a significant shift to anxiety in the circumcision group. The were no significant differences in the other groups.

Topical steroids for the treatment of phimosis is a highly effective treatment alternative to surgery. It avoids or delays circumcision and can be practised during the phallic period to decrease castration anxiety. The treatment is suitable for patients from any religious or cultural background.

An 18-month follow-up study after randomized treatment of phimosis in boys with topical steroid versus placebo.

Abstract:
To evaluate the treatment of phimosis using topical steroid.

This was a follow-up study after a prospective, randomized, double-blind study. A total of 137 boys with phimosis were randomly assigned to either betamethasone treatment or placebo for 4 weeks, with application of the cream twice daily. Non-responders to treatment were offered steroid treatment for a further 4 weeks. All patients were invited to a follow-up examination after 18 months.

The mean pre-treatment phimosis grades in the steroid and control groups were 5.08+/-0.66 and 4.97+/-0.70, respectively. At the 4-week follow-up, 49 boys (74%) in the steroid group were cured, compared to only 31 (44%) in the control group. Fourteen boys were circumcised after another 4 weeks of treatment; 43 of the remaining 57 boys (17 in the steroid group; 40 in the control group) had been cured. After a total of 92 boys took part in the 18-month follow-up study: 79 had been cured and 13 had suffered a relapse. Twenty-six patients did not took part in the follow-up investigation. No side-effects were noted.

When treatment is necessary for phimosis, we recommend application of topical steroid as first-line treatment because surgery can then be avoided in 85% of cases. This first randomized, double-blind, follow-up study shows that the treatment effect persists for at least 18 months.

Topical hydrocortisone and physiotherapy for nonretractile physiologic phimosis in infants.

Abstract: The effect of hydrocortisone (HC), the steroid of lowest potency, and physiotherapy (PT) on non-retractile physiologic phimosis (PP) and the reduction of subsequent recurrent UTI was evaluated in male infants with UTI. Seventy-eight male infants with febrile UTI and nonretractile PP were prospectively randomized into HC (Plancol, n=39) and control (Vaseline, n=39) groups. Topical application of HC as a thin film around the preputial margin twice a day for four weeks with PT was instructed. The response rate in the HC group was 89.7% (35/39), which was significantly higher than the rate (20.5%; 8/39) in the control group (P<0.05). In the HC group, the response rate was much higher (96.1%) in the subgroup with PT than in the group without PT. Most of the response (88.5%) was observed within two weeks. During the following year, the recurrent rate of UTI was 7.1% (2/28) in the infants with retractile prepuces, which was significantly less than than the rate (29.6%; 8/27) in infants with nonretractile prepuces (P<0.05). In conclusion, topical HC and PT for 2-4 weeks proved to be a simple, safe and effective treatment for nonretractile PP in infants with UTI, and this procedure was beneficial in reducing recurrent UTI.

Topical steroid treatment of phimosis in boys.

Abstract:
We evaluate whether steroid application alone or retraction and hygiene are responsible for successful results in boys treated with topical steroids for phimosis.

A prospective study was performed, which included a control group of 42 patients with phimosis seen at our outpatient department from January to June 1997. During that time we trained the parent to retract and clean the foreskin only. From July 1997 to June 1998 topical steroid cream was prescribed in addition to retraction and hygiene in 276 boys with phimosis. All cases were divided into 3 subgroups of asymptomatic, symptomatic and buried penis.

The response rate was greater than 95% in patients who received topical steroid treatment in addition to improved hygiene. Only 13 boys (less than 5%) had no response to steroid treatment. Of the control patients 23 (55%) had no response to gentle retraction and personal hygiene. There was a significant difference (p<0.001) in response rate between the study and control groups. However, the subgroup with a buried penis responded poorly to steroid, retraction and hygiene treatment. There was significant difference (p<0.001) in response rate between the buried penis and other steroid groups but no significant difference (p>0.05) in the control group.

Phimosis is a physiological condition in neonates due to natural adhesion between the foreskin and the glans. Chronic infection due to poor hygiene is responsible for most cases of childhood phimosis. Circumcision is the traditional treatment of choice for phimosis or unretractable foreskin, although it is not always desired by parents or surgeons. Topical steroid cream is an easy, safe and nonsurgical alternative for phimosis. However, boys with a buried penis are not good candidates for steroid treatment.

Highly potent and moderately potent topical steroids are effective in treating phimosis: a prospective randomized study.

Abstract:
We report a prospective randomized study comparing the effects of highly potent and moderately potent topical steroids in treating pediatric phimosis.

A total of 70 boys 1 to 12 years old with phimosis were randomly assigned to receive topical application of either betamethasone valerate 0.06% (a highly potent steroid) or clobetasone butyrate 0.05% (a moderately potent steroid). Parents of the boys were instructed to retract the foreskin gently without causing pain, and to apply the topical steroids over the stenotic opening of the prepuce twice daily for 4 weeks, then for another 4 weeks if no improvement was achieved. Retractibility of the prepuce was graded from 0 to 5. Response to treatment was arbitrarily defined as improvement in the retractibility score of more than 2 points.

Mean treatment and followup periods were 4.3 and 19.1 weeks, respectively. The response rates in boys treated with betamethasone valerate and clobetasone butyrate were 81.3% and 77.4%, respectively (p = 0.63). Mean retractibility score decreased from 3.9 +/- 1.0 to 1.7 +/- 1.1, and 4.2 +/- 1.0 to 1.9 +/- 1.0 in the betamethasone and clobetasone groups, respectively. Both steroids were effective in all age groups. Pretreatment retractibility score did not affect treatment outcomes. No adverse effect was encountered.

Highly potent and moderately potent topical steroids are of comparable effectiveness in treating phimosis. A less potent steroid may be considered first to decrease the risk of the potential adverse effects.

Phimosis: stretching methods with or without application of topical steroids?

Abstract: Phimosis has been defined as unretractable foreskin without adherences or a circular band of tight prepuce preventing full retraction. We suggested a new treatment protocol combining betamethasone with stretching exercises to reduce the number of patients requiring surgery for phimosis. Between January 2003 and September 2004, 247 boys aged 4 to 14 years (mean 7.6) were included in this consecutive, prospective, open study. Patients were treated with 0.05% betamethasone cream applied to the distal aspect of the prepuce twice daily for the first 15 days, then once daily for 15 more days. Preputial gymnastics started 1 week after topical application of betamethasone. Ninety-six percent of patients receiving 1 or more cycles of betamethasone showed complete resolution of phimosis. There was a significant difference (P < .001) in response rate between the study and control groups. Only 10 boys in the study group had no response to steroid and stretching. Treatment with topical steroids, combined with stretching exercises, is a suitable alternative to surgical correction (preputial plasty/circumcision).

[Comparative effectiveness of 0.1% metilprednisolone aceponate and 0.05% betamethasone dipropionate among children with nonretractable prepuce].

Abstract:
To compare clinical improvement between treatment with metilprednisolone aceponate vs. betamethasone dipropionate among children with nonretractable prepuce.

Between August 2001 and November 2002, we carried out a double blind and controlled clinical trial in 34 children with a diagnosis of nonretracable prepuce. Children were randomly assigned to one of the following groups and topical treatment was administered: Group A; metilprednisolone aceponate 0. I 1% and Group B; betamethasone dipropionate 0.05%.

Improvement was noted in 88.2% of our sample studied; (n= 15) children from group A and 76.4% (n= 13) childrenfrom group B; however, we did not observe a significant difference when comparing percentages between the two groups (chi2 = 0.2; p = 0.6).

The percentage of clinical improvement was similar between the two groups of topical steroid treatment administered.

Phimosis and topical steroids: new clinical findings.

Abstract: Phimosis has been defined as unretractable foreskin without adherences and/or a circular band of tight prepuce preventing full retraction. The aim of this study is to evaluate the efficacy (response rate) of topical steroids for the treatment of tight phimosis at different age stages. After using the same medication with different dosage schemes, a retrospective analysis was carried out to assess the efficacy of topical steroids in the treatment of tight phimosis. Patients were divided into three groups: group A (betamethasone scheme A), group B (betamethasone scheme B) and group C (control group). Remission of phimosis, with a complete exposure and without a narrowing behind the glans, was considered a complete response to treatment. The outcomes were then related to dosage scheme and patient's age. The dosage for group A was more effective than the dosage for groups B and C (control group). Phimosis resolved in 90% (group A), 72% (group B) and 56% (group C) of cases. A successful treatment was closely related to the age of patients at the beginning of steroid application. The results showed that treatment with topical steroids, which in general gives good results, proved to be much more successful in patients aged between 4 and 8 years, suggesting the efficacy of an early beginning of the treatment.


Context: Balancing the risk of bleeding and thrombosis after acute myocardial infarction (AMI) is challenging, and the optimal antithrombotic therapy remains uncertain. The potential of non-vitamin K antagonist oral anticoagulants (NOACs) to prevent ischaemic cardiovascular events is promising, but the evidence remains limited.

To evaluate the efficacy and safety of non-vitamin-K-antagonist oral anticoagulants (NOACs) in addition to background antiplatelet therapy, compared with placebo, antiplatelet therapy, or both, after acute myocardial infarction (AMI) in people without an indication for anticoagulation (i.e. atrial fibrillation or venous thromboembolism).

We searched for randomised controlled trials (RCTs) that evaluated NOACs plus antiplatelet therapy versus placebo, antiplatelet therapy, or both, in people without an indication for anticoagulation after an AMI.

Apixaban, an oral, direct, selective factor Xa inhibitor, in combination with antiplatelet therapy after acute coronary syndrome: results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) trial.

Abstract:
After an acute coronary syndrome, patients remain at risk of recurrent events. Apixaban, an oral direct factor Xa inhibitor, is a novel anticoagulant that may reduce these events but also poses a risk of bleeding.

Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) was a phase 2, double-blind, placebo-controlled, dose-ranging study. Patients (n=1715) with recent ST-elevation or non-ST-elevation acute coronary syndrome were randomized to 6 months of placebo (n=611) or 1 of 4 doses of apixaban: 2.5 mg twice daily (n=317), 10 mg once daily (n=318), 10 mg twice daily (n=248), or 20 mg once daily (n=221). Nearly all patients received aspirin; 76% received clopidogrel. The primary outcome was International Society of Thrombosis and Hemostasis major or clinically relevant nonmajor bleeding. A secondary outcome was cardiovascular death, myocardial infarction, severe recurrent ischemia, or ischemic stroke. At the recommendation of the Data Monitoring Committee, the 2 higher-dose apixaban arms were discontinued because of excess total bleeding. Compared with placebo, apixaban 2.5 mg twice daily (hazard ratio, 1.78; 95% confidence interval, 0.91 to 3.48; P=0.09) and 10 mg once daily (hazard ratio, 2.45; 95% confidence interval, 1.31 to 4.61; P=0.005) resulted in a dose-dependent increase in major or clinically relevant nonmajor bleeding. Apixaban 2.5 mg twice daily (hazard ratio, 0.73; 95% confidence interval, 0.44 to 1.19; P=0.21) and 10 mg once daily (hazard ratio, 0.61; 95% confidence interval, 0.35 to 1.04; P=0.07) resulted in lower rates of ischemic events compared with placebo. The increase in bleeding was more pronounced and the reduction in ischemic events was less evident in patients taking aspirin plus clopidogrel than in those taking aspirin alone.

We observed a dose-related increase in bleeding and a trend toward a reduction in ischemic events with the addition of apixaban to antiplatelet therapy in patients with recent acute coronary syndrome. The safety and efficacy of apixaban may vary depending on background antiplatelet therapy. Further testing of apixaban in patients at risk of recurrent ischemic events is warranted.

Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial.

Abstract:
Rivaroxaban is an oral direct factor Xa inhibitor that has been effective in prevention of venous thromboembolism in patients undergoing elective orthopaedic surgery. However, its use after acute coronary syndromes has not been investigated. In this setting, we assessed the safety and efficacy of rivaroxaban and aimed to select the most favourable dose and dosing regimen.

In this double-blind, dose-escalation, phase II study, undertaken at 297 sites in 27 countries, 3491 patients stabilised after an acute coronary syndrome were stratified on the basis of investigator decision to use aspirin only (stratum 1, n=761) or aspirin plus a thienopyridine (stratum 2, n=2730). Participants were randomised within each strata and dose tier with a block randomisation method at 1:1:1 to receive either placebo or rivaroxaban (at doses 5-20 mg) given once daily or the same total daily dose given twice daily. The primary safety endpoint was clinically significant bleeding (TIMI major, TIMI minor, or requiring medical attention); the primary efficacy endpoint was death, myocardial infarction, stroke, or severe recurrent ischaemia requiring revascularisation during 6 months. Safety analyses included all participants who received at least one dose of study drug; efficacy analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00402597.

Three patients in stratum 1 and 26 in stratum 2 never received the study drug. The risk of clinically significant bleeding with rivaroxaban versus placebo increased in a dose-dependent manner (hazard ratios [HRs] 2.21 [95% CI 1.25-3.91] for 5 mg, 3.35 [2.31-4.87] for 10 mg, 3.60 [2.32-5.58] for 15 mg, and 5.06 [3.45-7.42] for 20 mg doses; p<0.0001). Rates of the primary efficacy endpoint were 5.6% (126/2331) for rivaroxaban versus 7.0% (79/1160) for placebo (HR 0.79 [0.60-1.05], p=0.10). Rivaroxaban reduced the main secondary efficacy endpoint of death, myocardial infarction, or stroke compared with placebo (87/2331 [3.9%] vs 62/1160 [5.5%]; HR 0.69, [95% CI 0.50-0.96], p=0.0270). The most common adverse event in both groups was chest pain (248/2309 [10.7%] vs 118/1153 [10.2%]).

The use of an oral factor Xa inhibitor in patients stabilised after an acute coronary syndrome increases bleeding in a dose-dependent manner and might reduce major ischaemic outcomes. On the basis of these observations, a phase III study of low-dose rivaroxaban as adjunctive therapy in these patients is underway.

Johnson & Johnson Pharmaceutical Research & Development and Bayer Healthcare AG.

Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial.

Abstract:
After an acute coronary syndrome, patients remain at risk of recurrent ischaemic events, despite contemporary treatment, including aspirin and clopidogrel. We evaluated the safety and indicators of efficacy of the novel oral direct thrombin inhibitor dabigatran.

In this double-blind, placebo-controlled, dose-escalation trial, 1861 patients (99.2% on dual antiplatelet treatment) in 161 centres were enrolled at mean 7.5 days (SD 3.8) after an ST-elevation (60%) or non-ST-elevation (40%) myocardial infarction and randomized to twice daily treatment with dabigatran 50 mg (n = 369), 75 mg (n = 368), 110 mg (n = 406), 150 mg (n = 347), or placebo (n = 371). Primary outcome was the composite of major or clinically relevant minor bleeding during the 6-month treatment period. There were 96 primary outcome events and, compared with placebo, a dose-dependent increase with dabigatran, hazard ratio (HR) 1.77 (95% confidence intervals 0.70, 4.50) for 50 mg; HR 2.17 (0.88, 5.31) for 75 mg; HR 3.92 (1.72, 8.95) for 110 mg; and HR 4.27 (1.86, 9.81) for 150 mg. Compared with placebo, D-dimer concentrations were reduced in all dabigatran dose groups by an average of 37 and 45% at weeks 1 and 4, respectively (P< 0.001). Fourteen (3.8%) patients died, had a myocardial infarction or stroke in the placebo group compared with 17 (4.6%) in 50 mg, 18 (4.9%) in 75 mg, 12 (3.0%) in 110 mg, and 12 (3.5%) in the 150 mg dabigatran groups.

Dabigatran, in addition to dual antiplatelet therapy, was associated with a dose-dependent increase in bleeding events and significantly reduced coagulation activity in patients with a recent myocardial infarction.

Rationale and design of the Anti-Xa therapy to lower cardiovascular events in addition to standard therapy in subjects with acute coronary syndrome-thrombolysis in myocardial infarction 51 (ATLAS-ACS 2 TIMI 51) trial: a randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of rivaroxaban in subjects with acute coronary syndrome.

Abstract:
Although therapy with aspirin or aspirin plus a thienopyridine reduces the incidence of long-term adverse cardiovascular events among patients with acute coronary syndrome (ACS), there remains a significant residual risk of cardiovascular death, recurrent myocardial infarction (MI), and stroke. In a phase 2 trial (ClinicalTrials.gov NCT00402597) in which the addition of the factor Xa inhibitor rivaroxaban was compared with placebo, among ACS patients receiving either aspirin alone or dual-antiplatelet therapy with aspirin and a thienopyridine, the end point of death, MI, or stroke compared with placebo was reduced (87/2331 [3.9%] vs 62/1160 [5.5%]; hazard ratio 0.69, [95% CI 0.50-0.96], P = .027). Two candidate doses of rivaroxaban were selected for further evaluation in a pivotal phase 3.

The second ATLAS-ACS 2 TIMI 51 Trial is an international, randomized, double-blind, event-driven (n = 983) phase 3 trial involving more than 15,570 patients hospitalized with ACS (ClinicalTrials.gov NCT00809965). All patients are treated with a background of standard therapy including low-dose aspirin, and patients are stratified by the administration of a thienopyridine (clopidogrel or ticlopidine; stratum 2) or not (stratum 1). Within each stratum, patients are randomly assigned in a 1:1:1 ratio to receive rivaroxaban 2.5 mg twice daily, or rivaroxaban 5 mg twice daily, or placebo twice daily. The primary efficacy end point is the composite of cardiovascular death, MI, or stroke. The primary safety end point is thrombolysis in MI major bleeding not associated with coronary artery bypass graft surgery.

The ATLAS-ACS 2 TIMI 51 is testing the hypothesis that anticoagulation with the oral factor Xa inhibitor rivaroxaban reduces cardiovascular death, MI, and stroke among patients with ACS treated with guideline-based therapies for ACS.

Apixaban with antiplatelet therapy after acute coronary syndrome.

Abstract:
Apixaban, an oral, direct factor Xa inhibitor, may reduce the risk of recurrent ischemic events when added to antiplatelet therapy after an acute coronary syndrome.

We conducted a randomized, double-blind, placebo-controlled clinical trial comparing apixaban, at a dose of 5 mg twice daily, with placebo, in addition to standard antiplatelet therapy, in patients with a recent acute coronary syndrome and at least two additional risk factors for recurrent ischemic events.

The trial was terminated prematurely after recruitment of 7392 patients because of an increase in major bleeding events with apixaban in the absence of a counterbalancing reduction in recurrent ischemic events. With a median follow-up of 241 days, the primary outcome of cardiovascular death, myocardial infarction, or ischemic stroke occurred in 279 of the 3705 patients (7.5%) assigned to apixaban (13.2 events per 100 patient-years) and in 293 of the 3687 patients (7.9%) assigned to placebo (14.0 events per 100 patient-years) (hazard ratio with apixaban, 0.95; 95% confidence interval [CI], 0.80 to 1.11; P=0.51). The primary safety outcome of major bleeding according to the Thrombolysis in Myocardial Infarction (TIMI) definition occurred in 46 of the 3673 patients (1.3%) who received at least one dose of apixaban (2.4 events per 100 patient-years) and in 18 of the 3642 patients (0.5%) who received at least one dose of placebo (0.9 events per 100 patient-years) (hazard ratio with apixaban, 2.59; 95% CI, 1.50 to 4.46; P=0.001). A greater number of intracranial and fatal bleeding events occurred with apixaban than with placebo.

The addition of apixaban, at a dose of 5 mg twice daily, to antiplatelet therapy in high-risk patients after an acute coronary syndrome increased the number of major bleeding events without a significant reduction in recurrent ischemic events. (Funded by Bristol-Myers Squibb and Pfizer; APPRAISE-2 ClinicalTrials.gov number, NCT00831441.).

Rivaroxaban in patients with a recent acute coronary syndrome.

Abstract:
Acute coronary syndromes arise from coronary atherosclerosis with superimposed thrombosis. Since factor Xa plays a central role in thrombosis, the inhibition of factor Xa with low-dose rivaroxaban might improve cardiovascular outcomes in patients with a recent acute coronary syndrome.

In this double-blind, placebo-controlled trial, we randomly assigned 15,526 patients with a recent acute coronary syndrome to receive twice-daily doses of either 2.5 mg or 5 mg of rivaroxaban or placebo for a mean of 13 months and up to 31 months. The primary efficacy end point was a composite of death from cardiovascular causes, myocardial infarction, or stroke.

Rivaroxaban significantly reduced the primary efficacy end point, as compared with placebo, with respective rates of 8.9% and 10.7% (hazard ratio in the rivaroxaban group, 0.84; 95% confidence interval [CI], 0.74 to 0.96; P=0.008), with significant improvement for both the twice-daily 2.5-mg dose (9.1% vs. 10.7%, P=0.02) and the twice-daily 5-mg dose (8.8% vs. 10.7%, P=0.03). The twice-daily 2.5-mg dose of rivaroxaban reduced the rates of death from cardiovascular causes (2.7% vs. 4.1%, P=0.002) and from any cause (2.9% vs. 4.5%, P=0.002), a survival benefit that was not seen with the twice-daily 5-mg dose. As compared with placebo, rivaroxaban increased the rates of major bleeding not related to coronary-artery bypass grafting (2.1% vs. 0.6%, P<0.001) and intracranial hemorrhage (0.6% vs. 0.2%, P=0.009), without a significant increase in fatal bleeding (0.3% vs. 0.2%, P=0.66) or other adverse events. The twice-daily 2.5-mg dose resulted in fewer fatal bleeding events than the twice-daily 5-mg dose (0.1% vs. 0.4%, P=0.04).

In patients with a recent acute coronary syndrome, rivaroxaban reduced the risk of the composite end point of death from cardiovascular causes, myocardial infarction, or stroke. Rivaroxaban increased the risk of major bleeding and intracranial hemorrhage but not the risk of fatal bleeding. (Funded by Johnson & Johnson and Bayer Healthcare; ATLAS ACS 2-TIMI 51 ClinicalTrials.gov number, NCT00809965.).

Rationale and design of a randomized, double-blind, event-driven, multicentre study comparing the efficacy and safety of oral rivaroxaban with placebo for reducing the risk of death, myocardial infarction or stroke in subjects with heart failure and significant coronary artery disease following an exacerbation of heart failure: the COMMANDER HF trial.

Abstract:
Thrombin is a critical element of crosstalk between pathways contributing to worsening of established heart failure (HF). The aim of this study is to explore the efficacy and safety of rivaroxaban 2.5 mg bid compared with placebo (with standard care) after an exacerbation of HF in patients with reduced ejection fraction (HF-rEF) and documented coronary artery disease.

This is an international prospective, multicentre, randomized, double-blind, placebo-controlled, event-driven study of approximately 5000 patients for a targeted 984 events. Patients must have a recent symptomatic exacerbation of HF, increased plasma concentrations of natriuretic peptides (B-type natriuretic peptide ≥200 pg/mL or N-terminal pro-B-type natriuretic peptide ≥800 pg/mL), with left ventricular ejection fraction ≤40% and coronary artery disease. Patients requiring anticoagulation for atrial fibrillation or other conditions will be excluded. After an index event (overnight hospitalization, emergency department or observation unit admission, or unscheduled outpatient parenteral treatment for worsening HF), patients will be randomized 1:1 to rivaroxaban or placebo (with standard of care). The primary efficacy outcome event is a composite of all-cause mortality, myocardial infarction or stroke. The principal safety outcome events are the composite of fatal bleeding or bleeding into a critical space with potential permanent disability, bleeding events requiring hospitalization and major bleeding events according to International Society on Thrombosis and Haemostasis bleeding criteria.

COMMANDER HF is the first prospective study of a target-specific oral antithrombotic agent in HF. It will provide important information regarding rivaroxaban use following an HF event in an HF-rEF patient population with coronary artery disease.

Design of a Randomized Placebo-Controlled Trial to Assess Dabigatran and Omeprazole in Patients with Myocardial Injury after Noncardiac Surgery (MANAGE).

Abstract:
Worldwide approximately 200 million adults undergo major surgery annually, of whom 8 million are estimated to suffer a myocardial injury after noncardiac surgery (MINS). There is currently no trial data informing the management of MINS. Antithrombotic agents such as direct oral anticoagulants might prevent major vascular complications in patients with MINS.

The Management of Myocardial Injury After Noncardiac Surgery (MANAGE) trial is a large international blinded randomized controlled trial of dabigatran vs placebo in patients who suffered MINS. We used a partial factorial design to also determine the effect of omeprazole vs placebo in reducing upper gastrointestinal bleeding and complications. Both study drugs were initiated in eligible patients within 35 days of suffering MINS and continued for a maximum of 2 years. The primary outcome is a composite of major vascular complications for the dabigatran trial and a composite of upper gastrointestinal complications for the omeprazole trial. We present the rationale and design of the trial and baseline characteristics of enrolled patients.

The trial randomized 1754 patients between January 2013 and July 2017. Patients' mean age was 69.9 years, 51.1% were male, 14.3% had a history of peripheral artery disease, 6.6% had a history of stroke or transient ischemic attack, 12.9% had a previous myocardial infarction, and 26.0% had diabetes. The diagnosis of MINS was on the basis of an isolated ischemic troponin elevation in 80.4% of participants.

MANAGE is the first randomized controlled trial to evaluate a potential treatment of patients who suffered MINS.