Rationale: The preterm lung is susceptible to injury during transition to air breathing at birth. It remains unclear whether rapid or gradual lung aeration at birth causes less lung injury. Objectives: To examine the effect of gradual and rapid aeration at birth on: 1) the spatiotemporal volume conditions of the lung; and 2) resultant regional lung injury. Methods: Preterm lambs (125 6 1 d gestation) were randomized at birth to receive: 1) tidal ventilation without an intentional recruitment (no-recruitment maneuver [No-RM]; n = 19); 2) sustained inflation (SI) until full aeration (n = 26); or 3) tidal ventilation with an initial escalating/de-escalating (dynamic) positive end-expiratory pressure (DynPEEP; n = 26). Ventilation thereafter continued for 90 minutes at standardized settings, including PEEP of 8 cm H 2 O. Lung mechanics and regional aeration and ventilation (electrical impedance tomography) were measured throughout and correlated with histological and gene markers of early lung injury. Measurements and Main Results: DynPEEP significantly improved dynamic compliance (P , 0.0001). An SI, but not DynPEEP or NoRM , resulted in preferential nondependent lung aeration that became less uniform with time (P = 0.0006). The nondependent lung was preferential ventilated by 5 minutes in all groups, with ventilation only becoming uniform with time in the NoRM and DynPEEP groups. All strategies generated similar nondependent lung injury patterns. Only an SI caused greater upregulation of dependent lung gene markers compared with unventilated fetal controls (P , 0.05). Conclusions: Rapidly aerating the preterm lung at birth creates heterogeneous volume states, producing distinct regional injury patterns that affect subsequent tidal ventilation. Gradual aeration with tidal ventilation and PEEP produced the least lung injury.

Ineffective aeration during the first inflations at birth creates regional aeration and ventilation defects, initiating injurious pathways. This study aimed to compare a sustained first inflation at birth or dynamic end-expiratory supported recruitment during tidal inflations against ventilation without intentional recruitment on gas exchange, lung mechanics, spatiotemporal regional aeration and tidal ventilation, and regional lung injury in preterm lambs. Lambs (127 ± 2 d gestation), instrumented at birth, were ventilated for 60 minutes from birth with either lung-protective positive pressure ventilation (control) or as per control after either an initial 30 seconds of 40 cm H2O sustained inflation (SI) or an initial stepwise end-expiratory pressure recruitment maneuver during tidal inflations (duration 180 s; open lung ventilation [OLV]). At study completion, molecular markers of lung injury were analyzed. The initial use of an OLV maneuver, but not SI, at birth resulted in improved lung compliance, oxygenation, end-expiratory lung volume, and reduced ventilatory needs compared with control, persisting throughout the study. These changes were due to more uniform inter- and intrasubject gravity-dependent spatiotemporal patterns of aeration (measured using electrical impedance tomography). Spatial distribution of tidal ventilation was more stable after either recruitment maneuver. All strategies caused regional lung injury patterns that mirrored associated regional volume states. Irrespective of strategy, spatiotemporal volume loss was consistently associated with up-regulation of early growth response-1 expression. Our results show that mechanical and molecular consequences of lung aeration at birth are not simply related to rapidity of fluid clearance; they are also related to spatiotemporal pressure-volume interactions within the lung during inflation and deflation.

A sustained first inflation (SI) at birth may aid lung liquid clearance and aeration, but the impact of SI duration relative to the volume-response of the lung is poorly understood. We compared three SI strategies: 1) variable duration defined by attaining volume equilibrium using real-time electrical impedance tomography (EIT; SI plat); 2) 30 s beyond equilibrium (SI long); 3) short 30-s SI (SI30); and 4) positive pressure ventilation without SI (no-SI) on spatiotemporal aeration and ventilation (EIT), gas exchange, lung mechanics, and regional early markers of injury in preterm lambs. Fifty-nine fetal-instrumented lambs were ventilated for 60 min after applying the allocated first inflation strategy. At study completion molecular and histological markers of lung injury were analyzed. The time to SI volume equilibrium, and resultant volume, were highly variable; mean (SD) 55 (34) s, coefficient of variability 59%. SI plat and SIlong resulted in better lung mechanics, gas exchange and lower ventilator settings than both no-SI and SI30. At 60 min, alveolar-arterial difference in oxygen was a mean (95% confidence interval) 130 (13, 249) higher in SI30 vs. SIlong group (two-way ANOVA). These differences were due to better spatiotemporal aeration and tidal ventilation, although all groups showed redistribution of aeration towards the nondependent lung by 60 min. Histological lung injury scores mirrored spatiotemporal change in aeration and were greatest in SI 30 group (P Ͻ 0.01, Kruskal-Wallis test). An individualized volume-response approach to SI was effective in optimizing aeration, homogeneous tidal ventilation, and respiratory outcomes, while an inadequate SI duration had no benefit over positive pressure ventilation alone. sustained inflation; neonatal resuscitation; lung mechanics; lung volume; variability; electrical impedance tomography; lung injury THE MAJORITY OF EXTREMELY preterm infants require respiratory assistance in the delivery room (41). In part this is because many of these infants do not have the ability to generate the initial prolonged high transpulmonary pressures required to drive lung fluid from the main airways, allow alveolar aeration, establish functional residual capacity (FRC), and then maintain it during tidal ventilation, essential processes for efficient gas exchange and lung protection (19,31). Recently, applying an initial sustained inflation (SI) at birth, consisting of an elevated pressure applied for longer than needed for usual tidal inflation, followed by sufficient positive end-expiratory pressure (PEEP), has been proposed as a method of generating the initial transpulmonary pressure needed at birth (10,18,20). SI has been extensively investigated in preterm animals (15,26,29,32,33,(35)(36)(37)(38) and humans (10, 18, 34) with conflicting results. Some studies suggested SI improved aeration, FRC, and cerebral oxygen delivery (29,32,33), while others failed to demonstrate any benefit over standard respiratory support with sufficient PEEP (26,(35)(36)(37). SI was associated wi...

Background: In translational animal studies both a sustained inflation (SI) and PEEP have been associated with better lung aeration at birth, but the role of each on lung injury is inconclusive. We aimed to determine the effect of different PEEP and SI strategies at birth on early development of lung injury pathways. Method: 70 antenatal-steroid exposed lambs (125d AE 1d) were instrumented during caesarean section. Lambs were randomly assigned to either 1) Positive Pressure Ventilation (PPV; n = 20) using volume targeted ventilation at PEEP 8 cmH 2 O (maximum PIP 35 cmH 2 O, V T 7 ml/kg), 2) Volumetric Sustained Inflation 1 at 35 cmH 2 O until full aeration was visualised using electrical impedance tomography (SI; n = 23), or 3) 3-min Dynamic PEEP strategy 1 guided by breath-to-breath compliance (n = 27). All lambs were treated at 10 min with surfactant 200 mg/kg, and then received PPV for 90 min, with measurement of mechanics and gas exchange throughout. Standardised samples from the gravity-dependent and non-dependent lung were analysed for early injury mRNA markers (EGR1, CYR61, CTGF, IL-6,-8,-1B) and histology. Results: All groups expressed injury in the non-dependent lung compared to unventilated fetal controls across all injury parameters (p < 0.0001 ANOVA). In the dependent lung, only SI resulted in higher EGR1, CYR61, CTGF, IL-6,-1B expression compared to PPV and dynamic PEEP (p < 0.0001 ANOVA), and both were not different from fetal controls. Dynamic PEEP had better oxygenation throughout (p < 0.0001, two-way ANOVA) Conclusions: This large preterm lamb study is the first to show significant injury differences between SI and PEEP starte-gies. Early lung injury was heterogeneous and greater in the dependent lung following a SI. This suggests that achieving aeration slowly using tidal inflations maybe more beneficial than a SI. Reference: 1. Tingay DG et al. Background: Volume targeted ventilation (VTV) is widely used and may reduce lung injury, but this assumes the clinically set V T (V Tset) is accurately delivered. The aims of this prospective observational study were to determine the relationship between V Tset , expiratory V T (V Te) and endotracheal tube leak in a modern neonatal VTV ventilator, and the resultant PaCO 2 relationship with and without VTV. Method: Continuous inflations were recorded for 24 hours in 100 infants receiving synchronised mechanical ventilation (SLE5000, SLE Ltd, UK) with VTV (n = 77 infants) or without, and either the manufacturer's V4 (n = 50) or newer V5 (n = 50) VTV algorithm. For every inflation the set V Tset , V Te and leak were determined (maximum 90000 inflations/infant). If PaCO 2 was sampled (maximum 2/infant), this was compared with the average V T data from the preceeding 15 minutes. Results: A total of 7,917,020 inflations were analysed. Using VTV the V Tset-V Te bias (95% CI) was 0.3 (−0.12, 0.19) mL/kg. Leak influenced V Tset-V Te bias with V4 algorithm (r 2 = −0.64, p < 0.0001; linear regression) but not V5 (r 2 = 0.04, p = 0.21). Overall 80% of V Te were AE...

Objective. To determine the risk factors for recurrent lupus nephritis, allograft loss, and survival among patients with systemic lupus erythematosus (SLE) undergoing kidney transplantation.Methods. The archival records of all kidney transplant recipients with a prior diagnosis of SLE (according to the American College of Rheumatology criteria) from June 1977 to June 2007 were reviewed. Patients who had died or lost the allograft within 90 days of engraftment were excluded. Time-to-event data were examined by univariable and multivariable Cox proportional hazards regression analyses.Results. Two hundred twenty of nearly 7,000 renal transplantations were performed in 202 SLE patients during the 30-year interval. Of the 177 patients who met the criteria for study entry, the majority were women (80%) and African American (65%), the mean age was 35.6 years, and the mean disease duration was 11.2 years. Recurrent lupus nephritis was noted in 20 patients (11%), allograft loss in 69 patients (39%), and death in 36 patients (20%). African American ethnicity was found to be associated with a shorter time-to-event for recurrent lupus nephritis (hazard ratio [HR] 4.63, 95% confidence interval [95% CI] 1.29-16.65) and death (HR 2.47, 95% CI 0.91-6.71), although, with the latter, the association was not statistically significant. Recurrent lupus nephritis and chronic rejection of the kidney transplant were found to be risk factors for allograft loss (HR 2.48, 95% CI 1.09-5.60 and HR 2.72, 95% CI 1.55-4.78, respectively). In patients with recurrent lupus nephritis, the lesion in the engrafted kidney was predominantly mesangial, compared with a predominance of proliferative or membranous lesions in the native kidneys.Conclusion. African American ethnicity was independently associated with recurrent lupus nephritis. Allograft loss was associated with chronic transplant rejection and recurrence of lupus nephritis. Recurrent lupus nephritis is infrequent and relatively benign, without influence on a patient's survival.

The parameter estimates are similar to those described for propacetamol. There was no evidence of hepatotoxicity. Unconjugated hyperbilirubinaemia impacts upon CL, dictating dose reduction.

Methotrexate (MTX) remains the cornerstone therapy for patients with rheumatoid arthritis (RA), with well-established safety and efficacy profiles and support in international guidelines. Clinical and radiologic results indicate benefits of MTX monotherapy and combination with other agents, yet patients may not receive optimal dosing, duration, or route of administration to maximize their response to this drug. This review highlights best practices for MTX use in RA patients. First, to improve the response to oral MTX, a high initial dose should be administered followed by rapid titration. Importantly, this approach does not appear to compromise safety or tolerability for patients. Treatment with oral MTX, with appropriate dose titration, then should be continued for at least 6 months (as long as the patient experiences some response to treatment within 3 months) to achieve an accurate assessment of treatment efficacy. If oral MTX treatment fails due to intolerability or inadequate response, the patient may be “rescued” by switching to subcutaneous delivery of MTX. Consideration should also be given to starting with subcutaneous MTX given its favorable bioavailability and pharmacodynamic profile over oral delivery. Either initiation of subcutaneous MTX therapy or switching from oral to subcutaneous administration improves persistence with treatment. Upon transition from oral to subcutaneous delivery, MTX dosage should be maintained, rather than increased, and titration should be performed as needed. Similarly, if another RA treatment is necessary to control the disease, the MTX dosage and route of administration should be maintained, with titration as needed.

BackgroundCurrent sustained lung inflation (SI) approaches use uniform pressures and durations. We hypothesized that gestational-age-related mechanical and developmental differences would affect the time required to achieve optimal lung aeration, and resultant lung volumes, during SI delivery at birth in lambs.Methods49 lambs, in five cohorts between 118 and 139 days of gestation (term 142 d), received a standardized 40 cmHO SI, which was delivered until 10 s after lung volume stability (optimal aeration) was visualized on real-time electrical impedance tomography (EIT), or to a maximum duration of 180 s. Time to stable lung aeration (T) within the whole lung, gravity-dependent, and non-gravity-dependent regions, was determined from EIT recordings.ResultsT was inversely related to gestation (P<0.0001, Kruskal-Wallis test), with the median (range) being 229 (85,306) s and 72 (50,162) s in the 118-d and 139-d cohorts, respectively. Lung volume at T increased with gestation from a mean (SD) of 20 (17) ml/kg at 118 d to 56 (13) ml/kg at 139 d (P=0.002, one-way ANOVA). There were no gravity-dependent regional differences in T or aeration.ConclusionsThe trajectory of aeration during an SI at birth is influenced by gestational age in lambs. An understanding of this may assist in developing SI protocols that optimize lung aeration for all infants.