Prone equals prone? Impact of positioning techniques on respiratory function in anesthetized and paralyzed healthy children

Objectives

Although the prone position is effectively used to improve oxygenation, its impact on functional residual capacity is controversial. Different techniques of body positioning might be an important confounding factor. The aim of this study was to determine the impact of two different prone positioning techniques on functional residual capacity and ventilation distribution in anesthetized, preschool-aged children.

Design

Functional residual capacity and lung clearance index, a measure of ventilation homogeneity, were calculated using a sulfur-hexafluoride multibreath washout technique. After intubation, measurements were taken in the supine position and, in random order, in the flat prone position and the augmented prone position (gel pads supporting the pelvis and the upper thorax).

Setting

Pediatric anesthesia unit of university hospital.

Patients and participants

Thirty preschool children without cardiopulmonary disease undergoing elective surgery.

Measurements and results

Mean (range) age was 48.5 (24–80) months, weight 17.2 (10.5–26.9)?kg, functional residual capacity (mean ±?SD) 22.9?±?6.2?ml.kg ^?1 in the supine position and 23.3?±?5.6?ml.kg ^?1 in the flat prone position, while lung clearance indices were 8.1?±?2.3 vs. 7.9?±?2.3, respectively. In contrast, functional residual capacity increased to 27.6 ± 6.5 ml.kg ^?1 (pp

Conclusions

Functional residual capacity and ventilation distribution were similar in the supine and flat prone positions, while these parameters improved significantly in the augmented prone position, suggesting that the technique of prone positioning has major implications for pulmonary function.

     

Pooled Aquablation Results for American Men with Lower Urinary Tract Symptoms due to Benign Prostatic Hyperplasia in Large Prostates (60–150 cc)

Introduction

To present short-term safety and efficacy data of men with lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH) treated with Aquablation.

Methods

Men with LUTs secondary to BPH (60–150 cc) underwent Aquablation treatment from February 2016 to December 2017 across 17 investigational sites in the USA from two contemporary investigational device exemption (IDE) studies called WATER (NCT02505919) and WATER II (NCT03123250).

Results

One hundred seven males with mean age of 67.3?±?6.5 years were treated with Aquablation; mean prostate volume was 99.4?±?24.1 cc. The pooled results show that large prostates have an average procedure time of less than 36 min and discharge on average 1.6?±?1 days. The IPSS decreased by 16.7?±?8.1 points at 3 months and Q_max increased by 11.2?±?12.4 ml/s. The Clavien-Dindo (CD) grade 2 or higher event rate at 3 months was 29%. A non-hierarchical breakdown for CD events yielded 18% grade 2 and 19% grade 3 or higher.

Conclusion

Men with LUTS secondary to BPH (60–150 cc) in a pooled analysis were treated safely and effectively with Aquablation up to 3 months postoperatively.

Trial Registration

ClinicalTrials.gov identifiers, NCT02505919 and NCT03123250.

Funding

PROCEPT BioRobotics.

     

Apnoeic oxygenation via high-flow nasal cannula oxygen combined with non-invasive ventilation preoxygenation for intubation in hypoxaemic patients in the intensive care unit: the single-centre,blinded, randomised controlled OPTINIV trial

Purpose

High-flow nasal cannula oxygen (HFNC) has the potential to provide apnoeic oxygenation. We decided to assess in a proof-of-concept study whether the addition of HFNC to non-invasive ventilation (NIV) could reduce oxygen desaturation during intubation, compared with NIV alone for preoxygenation, in severely hypoxaemic intensive care unit (ICU) patients with respiratory failure.

Methods

We conducted a randomised, controlled, single-centre trial with assessor-blinded outcome assessment in patients admitted to the ICU. Hypoxaemic patients requiring orotracheal intubation for respiratory failure were randomised to receive preoxygenation using HFNC [flow = 60 L/min, fraction of inspired oxygen (FiO₂) = 100 %] combined with NIV (pressure support = 10 cmH₂O, positive end-expiratory pressure = 5 cmH₂O, FiO₂ = 100 %) in the intervention group or NIV alone in the reference group prior to intubation. The primary outcome was the lowest oxygen saturation (SpO₂) during the intubation procedure. Secondary outcomes were intubation-related complications and ICU mortality.

Results

Between July 2015 and February 2016, we randomly assigned 25 and 24 patients to the intervention and reference groups, respectively. In both groups the main reasons for respiratory failure were pneumonia and ARDS. During the intubation procedure, the lowest SpO₂ values were significantly higher in the intervention group than in the reference group [100 (95–100) % vs. 96 (92–99) %, p = 0.029]. After exclusion of two patients from analysis for protocol violation, no (0 %) patients in the intervention group and five (21 %) patients in the reference group had SpO₂ below 80 % (p = 0.050). We recorded no significant difference between the groups in intubation-related complications or ICU mortality.

Conclusions

A novel strategy for preoxygenation in hypoxaemic patients, adding HFNC for apnoeic oxygenation to NIV prior to orotracheal intubation, may be more effective in reducing the severity of oxygen desaturation than the reference method using NIV alone.

     

Oxygenation Status in Chronic Leg Ulcer After Topical Hemoglobin Application May Act as a Surrogate Marker to Find the Best Treatment Strategy and to Avoid Ineffective Conservative Long-term Therapy

Purpose

Chronic leg ulcers can be a challenge to treat and long-term therapy a significant cost factor in western public health budgets. Objective wound assessment assays enabling selection of appropriate wound therapy regimes would be desirable. Oxygenation status in ulcer tissue has obtained increased attention as a relevant factor in wound healing. To increase oxygenation in wounds, a topical hemoglobin spray was developed. Although favorable results have been noted, the link between clinical efficacy and the mode of action has not been demonstrated. The aims were to determine if changes in tissue oxygenation can be measured after topical application of hemoglobin on chronic wounds and to evaluate the findings in terms of therapy strategies.

Procedures

Photoacoustic imaging was used to measure the local oxygen saturation (StO₂) in leg ulcers before and after hemoglobin spray treatment. Sclerosis of the leg ulcers was histopathologically graded and the change in wound size was documented in a follow-up examination.

Results

Measuring 49 patients, an increase in StO₂ after topical hemoglobin application from on average 66.1 to 71 % (p = 0.017) after 20 min was observed. Depending on the increase in StO₂ (>10 % or <10 %) patients were stratified into a Responder and a Non-Responder group. Wound size significantly decreased in the Responder Group (p = 0.001), while no significant difference in the Non-Responder group (p = 0.950) was noted.

Conclusion

Our findings suggest that the likelihood of wound healing under conservative therapy can be predicted by measuring changes in StO₂ after topical hemoglobin application. This assay may reduce treatment time and costs by avoiding ineffective conservative long-term therapy.

Trial Registration

German Clinical Trials Register: DRKS00005993

     

Respiratory variations in aortic blood flow predict fluid responsiveness in ventilated children

Objective

To investigate whether respiratory variations in aortic blood flow velocity (ΔVpeak ao), systolic arterial pressure (ΔPS) and pulse pressure (ΔPP) could accurately predict fluid responsiveness in ventilated children.

Design and setting

Prospective study in a 18-bed pediatric intensive care unit.

Patients

Twenty-six children [median age 28.5 (16–44) months] with preserved left ventricular (LV) function.

Intervention

Standardized volume expansion (VE).

Measurements and main results

Analysis of aortic blood flow by transthoracic pulsed-Doppler allowed LV stroke volume measurement and on-line ΔVpeak ao calculation. The VE-induced increase in LV stroke volume was >?15% in 18 patients (responders) and p?=?0.001], whereas ΔPP and ΔPS did not significantly differ between groups. The prediction of fluid responsiveness was higher with ΔVpeak ao [ROC curve area 0.85 (95% IC 0.99–1.8), p?=?0.001] than with ΔPS (0.64) or ΔPP (0.59). The best cut-off for ΔVpeak ao was 12%, with sensitivity, specificity, and positive and negative predictive values of 81.2%, 85.7%, 93% and 66.6%, respectively. A positive linear correlation was found between baseline ΔVpeak ao and VE-induced gain in stroke volume (rho?=?0.68, p?=?0.001).

Conclusions

While respiratory variations in aortic blood flow velocity measured by pulsed Doppler before VE accurately predict the effects of VE, ΔPS and ΔPP are of little value in ventilated children.

     

Pharmacokinetics of a Single Dose of Azilsartan in Pediatric Patients: A Phase 3, Open-Label,Multicenter Study

Introduction

Azilsartan is an angiotensin II receptor blocker indicated for the treatment of patients with hypertension. The efficacy and safety of azilsartan are established in adults, but have not been evaluated in pediatric patients, nor has its pharmacokinetic profile been determined in pediatric patients.

Methods

In this phase 3, open-label, multicenter study, we investigated the pharmacokinetics and safety of single doses of azilsartan in six Japanese patients with hypertension, aged 9–14 years. The dose of azilsartan was 5 mg for three patients weighing less than 50 kg, with mean body weight at baseline of 27.5 kg, and 10 mg for three patients weighing at least 50 kg, with mean body weight at baseline of 65.9 kg.

Results

Mean maximum plasma concentration (C_max) of azilsartan was 888.3 and 831.3 ng/mL and median time to maximum concentration (T_max) of unchanged azilsartan was 3.0 and 4.0 h, in the 5-mg and 10-mg groups, respectively. Mean areas under the plasma concentration–time curve (AUC) from 0–24 h post-dose (AUC_0–24) and 0 h to infinity (AUC_0–inf) were 6350.3 and 6635.7 ng h/mL, respectively, in the 5-mg group, and 6871.7 and 7433.3 ng h/mL, respectively, in the 10-mg group. Both doses were well tolerated; no treatment-emergent adverse events considered to be related to azilsartan occurred during the study.

Conclusion

Our data suggest that pediatric patients weighing less than 50 kg may have? approximately 2-fold greater exposure to azilsartan than those weighing at least 50 kg at the same dose. Exposure to azilsartan in children weighing at least 50 kg is comparable to that in healthy adults at the same dose.

Trial Registration

ClinicalTrials.gov identifier, NCT02451150.

Funding

Takeda Pharmaceutical Co. Ltd.

     

Targeting two different levels of both arterial carbon dioxide and arterial oxygen after cardiac arrest and resuscitation: a randomised pilot trial

Purpose

We assessed the effects of targeting low-normal or high-normal arterial carbon dioxide tension (PaCO₂) and normoxia or moderate hyperoxia after out-of-hospital cardiac arrest (OHCA) on markers of cerebral and cardiac injury.

Methods

Using a 2³ factorial design, we randomly assigned 123 patients resuscitated from OHCA to low-normal (4.5–4.7 kPa) or high-normal (5.8–6.0 kPa) PaCO₂ and to normoxia (arterial oxygen tension [PaO₂] 10–15 kPa) or moderate hyperoxia (PaO₂ 20–25 kPa) and to low-normal or high-normal mean arterial pressure during the first 36 h in the intensive care unit. Here we report the results of the low-normal vs. high-normal PaCO₂ and normoxia vs. moderate hyperoxia comparisons. The primary endpoint was the serum concentration of neuron-specific enolase (NSE) 48 h after cardiac arrest. Secondary endpoints included S100B protein and cardiac troponin concentrations, continuous electroencephalography (EEG) and near-infrared spectroscopy (NIRS) results and neurologic outcome at 6 months.

Results

In total 120 patients were included in the analyses. There was a clear separation in PaCO₂ (p?<?0.001) and PaO₂ (p?<?0.001) between the groups. The median (interquartile range) NSE concentration at 48 h was 18.8 µg/l (13.9–28.3 µg/l) in the low-normal PaCO₂ group and 22.5 µg/l (14.2–34.9 µg/l) in the high-normal PaCO₂ group, p?=?0.400; and 22.3 µg/l (14.8–27.8 µg/l) in the normoxia group and 20.6 µg/l (14.2–34.9 µg/l) in the moderate hyperoxia group, p?=?0.594). High-normal PaCO₂ and moderate hyperoxia increased NIRS values. There were no differences in other secondary outcomes.

Conclusions

Both high-normal PaCO₂ and moderate hyperoxia increased NIRS values, but the NSE concentration was unaffected.

Registration

ClinicalTrials.gov, NCT02698917. Registered on January 26, 2016.

     

Lung ultrasonography for assessment of oxygenation response to prone position ventilation in ARDS

Purpose

Prone position (PP) improves oxygenation and outcome of acute respiratory distress syndrome (ARDS) patients with a PaO₂/FiO₂ ratio <150 mmHg. Regional changes in lung aeration can be assessed by lung ultrasound (LUS). Our aim was to predict the magnitude of oxygenation response after PP using bedside LUS.

Methods

We conducted a prospective multicenter study that included adult patients with severe and moderate ARDS. LUS data were collected at four time points: 1 h before (baseline) and 1 h after turning the patient to PP, 1 h before and 1 h after turning the patient back to the supine position. Regional lung aeration changes and ultrasound reaeration scores were assessed at each time. Overdistension was not assessed.

Results

Fifty-one patients were included. Oxygenation response after PP was not correlated with a specific LUS pattern. The patients with focal and non-focal ARDS showed no difference in global reaeration score. With regard to the entire PP session, the patients with non-focal ARDS had an improved aeration gain in the anterior areas. Oxygenation response was not associated with aeration changes. No difference in PaCO₂ change was found according to oxygenation response or lung morphology.

Conclusions

In ARDS patients with a PaO₂/FiO₂ ratio ≤150 mmHg, bedside LUS cannot predict oxygenation response after the first PP session. At the bedside, LUS enables monitoring of aeration changes during PP.

     

Bacterial ventilator-associated pneumonia: bronchoalveolar lavage results are not influenced by dilution

Objective

This study was designed to determine if bronchoalveolar lavage (BAL) quantitative culture results can be used confidently for the diagnosis of bacterial ventilator-associated pneumonia (VAP) without taking dilution into account.

Design

Prospective observational cohort study.

Setting

A 12-bed medical ICU in a teaching hospital.

Patients

A total of 241 BAL (three 50-mL aliquots) were performed in 127 patients presenting a suspicion of VAP.

Interventions

All consecutive adults who were ventilated more than 48 h were included if VAP was clinically suspected. A dilution factor, k, was developed according to the formula: dilution factor k = concentration of urea in plasma/concentration of urea in lavage fluid recovered. Using this dilution factor, the quantitative bacterial counts were interpreted accordingly with a corrected positive threshold at 10⁵ colony forming unit (CFU) mL^?1.

Measurements and results

Eighty-nine BAL with at least one micro-organism ≥10⁴ CFU mL^?1 were identified (37%). In 176 BAL (73%), k ranged from 10 to 100. Median k was 24.4 (9.7–40.2) in VAP group and 24.6 (13.1–57.8) in patients without pneumonia (NS). Among the 25 BAL with micro-organism counts of 10⁴ CFU mL^?1, 3 had a dilution factor lower than 10, resulting in corrected counts below the threshold of 10⁵ CFU mL^?1. Two out of 15 patients with micro-organism counts of 10³ CFU mL^?1 had corrected micro-organism counts of 10⁵ CFU mL^?1. Finally, only five BAL (2.1%) were misclassified when the dilution correction factor was applied.

Conclusions

Using urea as dilution factor, we showed that BAL dilution variations did not alter the interpretation of BAL quantitative bacterial culture when administrating three aliquots of 50 mL of saline.

     

Schmerztherapie bei Kindern und Jugendlichen mit Hämophilie

Background

Children and adolescents with severe hemophilia commonly suffer from acute and chronic pain as a consequence of hemophilia-related bleeding. Intervention-related pain also plays a major role. Despite its high prevalence in this patient group, hemophilia-related pain is not always adequately addressed and sufficiently treated.

Objectives

This paper discusses how to improve pain management for children and adolescents (0–18 years) with hemophilia and which specific features in this population should influence decisions in pain management.

Materials and methods

An expert panel discussed challenges in pain treatment in children and adolescents with hemophilia. Recommendations are based on evidence and clinical experience.

Result

Pain management in children with hemophilia needs improvement. Children with hemophilia are at risk of developing chronic pain and of suffering traumatization due to insufficient pain management. Pain therapy can be challenging in these children as both their age and the underlying disease limit the options in particular in pain medication. The expert panel developed recommendations to improve pain management in children with hemophilia.

     

Effects of Tiotropium Combined with Theophylline on Stable COPD Patients of Group B,D and its Impact on Small Airway Function: A Randomized Controlled Trial

Introduction

Tiotropium bromide has been widely used in clinical practice, while theophylline is another treatment option for chronic obstructive pulmonary disease (COPD). However, only a few relevant studies have investigated the long-term outcomes and efficacy of both in patients with COPD. We evaluated the effects of tiotropium and low-dose theophylline on stable COPD patients of groups B and D.

Methods

Eligible participants (n?=?170) were randomized and received either tiotropium 18 µg once daily with theophylline 100 mg twice daily (Group I) or tiotropium 18 µg once daily (Group II) for 6 months. COPD assessment test (CAT), modified Medical Research Council (mMRC) dyspnea scores and pulmonary function tests were measured before randomization and during the treatment.

Results

After 6 months of treatment, the CAT scores in both groups decreased significantly (11.41?±?3.56 and 11.08?±?3.05, p?<?0.0001). The changes of CAT (p?=?0.028) and mMRC scores (p?=?0.049) between the two groups differed after 1 month of treatment. In Group I, forced expiratory flow after 25% of the FVC% predicted (MEF₂₅% pred) was significantly improved after 3 months (4.84?±?8.73%, p?<?0.0001) and 6 months (6.21?±?8.65%, p?<?0.0001). There was a significant difference in small airway function tests (MEF₅₀% pred, MEF₂₅% pred, and MMEF% pred) between the two groups after 6 month of treatment (p?=?0.003, p?<?0.0001, and p?=?0.021, respectively).

Conclusions

Tiotropium combined with low-dose theophylline significantly improved the symptoms and general health of patients with stable COPD of groups B and D after 6 months of follow-up. Additionally, this therapy also improved the indicators of small airway function.

Trial Registration

Chinese Clinical Trial Registry (Registry ID: ChiCTR1800019027).

     

Targeting low-normal or high-normal mean arterial pressure after cardiac arrest and resuscitation: a randomised pilot trial

Purpose

We aimed to determine the feasibility of targeting low-normal or high-normal mean arterial pressure (MAP) after out-of-hospital cardiac arrest (OHCA) and its effect on markers of neurological injury.

Methods

In the Carbon dioxide, Oxygen and Mean arterial pressure After Cardiac Arrest and REsuscitation (COMACARE) trial, we used a 2³ factorial design to randomly assign patients after OHCA and resuscitation to low-normal or high-normal levels of arterial carbon dioxide tension, to normoxia or moderate hyperoxia, and to low-normal or high-normal MAP. In this paper we report the results of the low-normal (65–75 mmHg) vs. high-normal (80–100 mmHg) MAP comparison. The primary outcome was the serum concentration of neuron-specific enolase (NSE) at 48 h after cardiac arrest. The feasibility outcome was the difference in MAP between the groups. Secondary outcomes included S100B protein and cardiac troponin (TnT) concentrations, electroencephalography (EEG) findings, cerebral oxygenation and neurological outcome at 6 months after cardiac arrest.

Results

We recruited 123 patients and included 120 in the final analysis. We found a clear separation in MAP between the groups (p?<?0.001). The median (interquartile range) NSE concentration at 48 h was 20.6 µg/L (15.2–34.9 µg/L) in the low-normal MAP group and 22.0 µg/L (13.6–30.9 µg/L) in the high-normal MAP group, p?=?0.522. We found no differences in the secondary outcomes.

Conclusions

Targeting a specific range of MAP was feasible during post-resuscitation intensive care. However, the blood pressure level did not affect the NSE concentration at 48 h after cardiac arrest, nor any secondary outcomes.

     

Lack of agreement between thermodilution and electrical velocimetry cardiac output measurements

Objective

The modified algorithm for the non-invasive determination of cardiac output (CO) by electrical bioimpedance—electrical velocimetry (EV^®)—has been reported to give reliable results in comparison with echocardiography and pulmonary arterial thermodilution (PA-TD) in patients either before or after cardiac surgery. The present study was designed to determine whether EV^®-CO measurements reflect intraindividual changes in CO during cardiac surgery.

Design

Prospective, observational study.

Setting

Operating room (OR) and intensive care unit (ICU) of a university hospital.

Patients

Twenty-nine patients undergoing elective cardiac surgery.

Interventions

None.

Measurements

CO was determined simultaneously by PA-TD and EV^® after induction of anesthesia (t1) and 4.9?±?3.5?h after ICU admission (t2).

Results

TD-CO was 3.9?±?1.4 and 5.4?±?1.1 l/min at t1 and t2 (?p?®-CO was 4.3?±?1.1 and 4.9?±?1.5 l/min at t1 and t2 (?p?=?0.013). Bland–Altman analysis showed a bias of ?0.4 l/min and 0.4 l/min and a precision of 3.2 and 3.6 l/min (34.3% and 67.4%) at t1 and t2, respectively. Analysis of the individual pre- to postoperative changes in CO with both methods revealed bidirectional changes in n?=?12 patients and unidirectional changes with a difference greater than 50% and less than 50% in n?=?9 and n?=?8 patients, respectively.

Conclusions

The disagreement between PA-TD and EV^®-CO measurements after anesthesia induction and after ICU admission, as well as the fact that thoracic bioimpedance did not adequately reflect pre- to postoperative changes in CO, questions the reliability of EV^®-CO measurements in cardiac surgery patients and contrasts sharply with previous studies.

     

Effects of mannitol alone and mannitol plus furosemide on renal oxygen consumption,blood flow and glomerular filtration after cardiac surgery

Objective

Imbalance of the renal medullary oxygen supply/demand relationship can cause hypoxic medullary damage and ischaemic acute renal failure (ARF). The use of mannitol for prophylaxis/treatment of clinical ischaemic ARF is controversial and the effect of mannitol on renal oxygenation in man has not yet been investigated. We evaluated the effects of mannitol on renal oxygen consumption (RVO₂)_, renal blood flow (RBF) and glomerular filtration rate (GFR) in postoperative patients.

Design

Prospective interventional study.

Setting

University hospital cardiothoracic ICU.

Patients

Ten uncomplicated mechanically ventilated and sedated postcardiac surgery patients with preoperatively normal renal function.

Interventions

Mannitol infusion (225 mg/kg + 75 mg/kg/h) and combined mannitol and furosemide infusion (0.25 mg/kg + 0.25 mg/kg/h).

Measurements and results

Systemic haemodynamics were evaluated by a pulmonary artery catheter. RBF and GFR were measured by the renal vein thermodilution technique and by renal extraction of ⁵¹Cr–EDTA, respectively. Mannitol increased urine flow (60%), GFR (20%) and filtration fraction (FF) (20%) with no change in RBF. This was accompanied by an increase in renal sodium reabsorption (18%), RVO₂ (19%) and renal oxygen extraction (21%). When combined with mannitol, furosemide normalised sodium reabsorption, RVO₂, renal oxygen extraction with no change in RBF, while GFR and FF were still elevated compared to control.

Conclusions

In patients with normal renal function, mannitol increases GFR, which increases tubular sodium load, sodium reabsorption and RVO₂ after cardiac surgery. The lack of effect on RBF, indicates that mannitol impairs the renal oxygen supply/demand relationship. Furosemide normalised renal oxygenation when combined with mannitol.

     

Two-Year Data from a Long-Term Phase IV Study of Recombinant Human Growth Hormone in Short Children Born Small for Gestational Age

Introduction

This ongoing, prospective, open-label, non-comparative, multicenter phase IV study is evaluating the safety and efficacy of recombinant human growth hormone (rhGH; Omnitrope^®, Sandoz GmbH) in short children born small for gestational age (SGA). Here we report data from patients who have completed 2 years’ treatment.

Methods

Eligibility criteria included prepubertal children born SGA with growth disturbances defined as current height standard deviation score (HSDS) <?2.5 and parental adjusted SDS <?1; birth weight and/or length <?2 SDS; and failure of catch-up growth [height velocity (HV) SDS <0 during the last year] by 4 years of age or later. The primary study objective is to assess the long-term effect of Omnitrope treatment on the development of diabetes in short children born SGA. Secondary objectives include evaluation of efficacy, incidence and severity of adverse events (AEs), occurrence of malignancies during treatment, and detection of anti-rhGH antibodies during treatment.

Results

In total, 278 children have been enrolled and received study medication; 249 have completed 2 years of treatment. No child has developed diabetes mellitus during the first 2 years; no fasting glucose or 2-h oral glucose tolerance test value exceeded the pre-defined limits of >126 or >200 mg/dL, respectively. No adverse alterations in body mass were noted. Treatment-emergent AEs were experienced by 211 (76.2%) children; most of these were of mild-to-moderate intensity (99.3%) and considered unrelated to study medication (97.6%). Treatment with Omnitrope was effective; mean HSDS was ?3.39 at baseline, ?2.57 at 1 year and ?2.15 at 2 years of treatment. Mean HVSDS (peak-centered) also improved, from ?2.13 at baseline to +4.16 at 1 year and +2.23 at 2 years.

Conclusion

In this second interim analysis, short children born SGA were safely and effectively treated with rhGH (Omnitrope), and 2 years’ treatment had no major adverse impact on carbohydrate metabolism or body mass.

Funding

Sandoz.

     

Impact of the driving pressure on mortality in obese and non-obese ARDS patients: a retrospective study of 362 cases

Purpose

The relation between driving pressure (plateau pressure-positive end-expiratory pressure) and mortality has never been studied in obese ARDS patients. The main objective of this study was to evaluate the relationship between 90-day mortality and driving pressure in an ARDS population ventilated in the intensive care unit (ICU) according to obesity status.

Methods

We conducted a retrospective single-center study of prospectively collected data of all ARDS patients admitted consecutively to a mixed medical-surgical adult ICU from January 2009 to May 2017. Plateau pressure, compliance of the respiratory system (Crs) and driving pressure of the respiratory system within 24 h of ARDS diagnosis were compared between survivors and non-survivors at day 90 and between obese (body mass index?≥?30 kg/m²) and non-obese patients. Cox proportional hazard modeling was used for mortality at day 90.

Results

Three hundred sixty-two ARDS patients were included, 262 (72%) non-obese and 100 (28%) obese patients. Mortality rate at day 90 was respectively 47% (95% CI, 40–53) in the non-obese and 46% (95% CI, 36–56) in the obese patients. Driving pressure at day 1 in the non-obese patients was significantly lower in survivors at day 90 (11.9?±?4.2 cmH₂O) than in non-survivors (15.2?±?5.2 cmH₂O, p?<?0.001). Contrarily, in obese patients, driving pressure at day 1 was not significantly different between survivors (13.7?±?4.5 cmH₂O) and non-survivors (13.2?±?5.1 cmH₂O, p?=?0.41) at day 90. After three multivariate Cox analyses, plateau pressure [HR?=?1.04 (95% CI 1.01–1.07) for each point of increase], Crs [HR?=?0.97 (95% CI 0.96–0.99) for each point of increase] and driving pressure [HR?=?1.07 (95% CI 1.04–1.10) for each point of increase], respectively, were independently associated with 90-day mortality in non-obese patients, but not in obese patients.

Conclusions

Contrary to non-obese ARDS patients, driving pressure was not associated with mortality in obese ARDS patients.

     

Pharmacokinetics of rivaroxaban in children using physiologically based and population pharmacokinetic modelling: an EINSTEIN-Jr phase I study

Background

The EINSTEIN-Jr program will evaluate rivaroxaban for the treatment of venous thromboembolism (VTE) in children, targeting exposures similar to the 20 mg once-daily dose for adults. A physiologically based pharmacokinetic (PBPK) model for pediatric rivaroxaban dosing has been constructed.

Methods

We quantitatively assessed the pharmacokinetics (PK) of a single rivaroxaban dose in children using population pharmacokinetic (PopPK) modelling and assessed the applicability of the PBPK model. Plasma concentration–time data from the EINSTEIN-Jr phase I study were analysed by non-compartmental and PopPK analyses and compared with the predictions of the PBPK model. Two rivaroxaban dose levels, equivalent to adult doses of rivaroxaban 10 mg and 20 mg, and two different formulations (tablet and oral suspension) were tested in children aged 0.5–18 years who had completed treatment for VTE.

Results

PK data from 59 children were obtained. The observed plasma concentration–time profiles in all subjects were mostly within the 90% prediction interval, irrespective of dose or formulation. The PopPK estimates and non-compartmental analysis-derived PK parameters (in children aged ≥6 years) were in good agreement with the PBPK model predictions.

Conclusions

These results confirmed the applicability of the rivaroxaban pediatric PBPK model in the pediatric population aged 0.5–18 years, which in combination with the PopPK model, will be further used to guide dose selection for the treatment of VTE with rivaroxaban in EINSTEIN-Jr phase II and III studies.

Trial registration

ClinicalTrials.gov number, NCT01145859; registration date: 17 June 2010.

     

Exploratory evaluation of pharmacodynamics,pharmacokinetics and safety of rivaroxaban in children and adolescents: an EINSTEIN-Jr phase I study

Background

The EINSTEIN-Jr program will evaluate rivaroxaban for the treatment of venous thromboembolism (VTE) in children, targeting exposures similar to the 20 mg once-daily dose for adults.

Methods

This was a multinational, single-dose, open-label, phase I study to describe the pharmacodynamics (PD), pharmacokinetics (PK) and safety of a single bodyweight-adjusted rivaroxaban dose in children aged 0.5–18 years. Children who had completed treatment for a venous thromboembolic event were enrolled into four age groups (0.5–2 years, 2–6 years, 6–12 years and 12–18 years) receiving rivaroxaban doses equivalent to 10 mg or 20 mg (either as a tablet or oral suspension). Blood samples for PK and PD analyses were collected within specified time windows.

Results

Fifty-nine children were evaluated. In all age groups, PD parameters (prothrombin time, activated partial thromboplastin time and anti-Factor Xa activity) showed a linear relationship versus rivaroxaban plasma concentrations and were in line with previously acquired adult data, as well as in vitro spiking experiments. The rivaroxaban pediatric physiologically based pharmacokinetic model, used to predict the doses for the individual body weight groups, was confirmed. No episodes of bleeding were reported, and treatment-emergent adverse events occurred in four children and all resolved during the study.

Conclusions

Bodyweight-adjusted, single-dose rivaroxaban had predictable PK/PD profiles in children across all age groups from 0.5 to 18 years. The PD assessments based on prothrombin time and activated partial thromboplastin time demonstrated that the anticoagulant effect of rivaroxaban was not affected by developmental hemostasis in children.

Trial registration

ClinicalTrials.gov number, NCT01145859.

     

Anti-Anginal Effectiveness and Tolerability of Trimetazidine Modified Release 80 Mg Once Daily in Stable Angina Patients in Real-World Practice

Introduction

Trimetazidine (TMZ) was shown to reduce angina symptoms and increase the exercise capacity in stable angina (SA) patients. A new formulation allowing a once-daily (od) dosage could improve patients’ satisfaction and adherence.

Methods

ODA was a 3-month, observational, multicenter, prospective Russian study in SA patients with persistent symptoms despite therapy. Angina attack frequency, short-acting nitrate (SAN) consumption, adherence to antianginal medications, and overall efficacy and tolerability of TMZ 80 mg od were assessed in a real-world setting.

Results

A total of 3066 patients were included (mean age 62.8, 48% male). After 3 months, TMZ 80 mg od treatment led to a significant (p?<?0.001) decrease in angina attack frequency (from 4.7?±?3.5 to 0.9?±?1.3/week) and SAN use (from 4.5?±?3.9 to 0.7?±?1.3/week). Overall tolerability and effectiveness were rated as “very good” by the majority of physicians. Medication adherence improved significantly, with good adherence reported by 56% of patients (vs. 24% at baseline, p?<?0.0001) and non-adherence by 3% (vs. 36% at baseline, p?<?0.0001) at month 3. Patient satisfaction with TMZ od was 9.5 [on a scale of 1 to 10 (very satisfied)]. Patients reported improved physical activity: more patients reported no limitations (15% vs. 1% at baseline p?<?0.01), slight limitation (46% vs. 5% at baseline, p?<?0.001) or moderate limitation (30% vs. 23%, p?<?0.01) and fewer patients reported substantial limitation (8% vs. 52% at baseline, p?<?0.001) or very marked reduction (1% vs. 19% at baseline, p?<?0.01) at month 3.

Conclusion

In this prospective, observational study, TMZ 80 mg od effectively reduced angina attacks and SAN consumption, improved physical activity and adherence and was well tolerated in chronic SA patients.

Trial Registration

ISRCTN registry Identifier, ISRCTN97780949.

Funding

Servier.

Plain Language Summary

Plain language summary available for this article.

     

Terlipressin versus norepinephrine as infusion in patients with septic shock: a multicentre,randomised, double-blinded trial

Purpose

Recent clinical data suggest that terlipressin, a vasopressin analogue, may be more beneficial in septic shock patients than catecholamines. However, terlipressin’s effect on mortality is unknown. We set out to ascertain the efficacy and safety of continuous terlipressin infusion compared with norepinephrine (NE) in patients with septic shock.

Methods

In this multicentre, randomised, double-blinded trial, patients with septic shock recruited from 21 intensive care units in 11 provinces of China were randomised (1:1) to receive either terlipressin (20–160 µg/h with maximum infusion rate of 4 mg/day) or NE (4–30 µg/min) before open-label vasopressors. The primary endpoint was mortality 28 days after the start of infusion. Primary efficacy endpoint analysis and safety analysis were performed on the data from a modified intention-to-treat population.

Results

Between 1 January 2013 and 28 February 2016, 617 patients were randomised (312 to the terlipressin group, 305 to the NE group). The modified intention-to-treat population comprised 526 (85.3%) patients (260 in the terlipressin group and 266 in the NE group). There was no significant difference in 28-day mortality rate between the terlipressin group (40%) and the NE group (38%) (odds ratio 0.93 [95% CI 0.55–1.56]; p?=?0.80). Change in SOFA score on day 7 was similar between the two groups: ??7 (IQR ??11 to 3) in the terlipressin group and ??6 (IQR ??10 to 5) in the NE group. There was no difference between the groups in the number of days alive and free of vasopressors. Overall, serious adverse events were more common in the terlipressin group than in the NE group (30% vs 12%; p?<?0.001).

Conclusions

In this multicentre, randomised, double-blinded trial, we observed no difference in mortality between terlipressin and NE infusion in patients with septic shock. Patients in the terlipressin group had a higher number of serious adverse events.

Trial registration

This trial is registered at ClinicalTrials.gov: ID NCT01697410.