Activity of afatinib in patients with NSCLC harboring novel uncommon EGFR mutations with or without co-mutations: a case report.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) represent first-line standard of care in unresectable EGFR mutation-positive (EGFRm+) non-small cell lung cancer (NSCLC). However, 10-20% of patients with EGFRm+ NSCLC have uncommon EGFR variants, defined as mutations other than L858R substitutions or exon 19 deletions. NSCLC harboring uncommon EGFR mutations may demonstrate lower sensitivity to targeted agents than NSCLC with L858R or exon 19 deletion mutations. Prospective clinical trial data in patients with NSCLC uncommon EGFR mutations are lacking. Afatinib is a second-generation TKI and the only Food and Drug Administration-approved drug for some of the more prevalent uncommon EGFR mutations. We present a series of seven case reports describing clinical outcomes in afatinib-treated patients with NSCLC harboring a diverse range of extremely rare mutations with or without co-mutations affecting other genes. EGFR alterations included compound mutations, P-loop αC-helix compressing mutations, and novel substitution mutations. We also present a case with NSCLC harboring a novel EGFR::CCDC6 gene fusion. Overall, the patients responded well to afatinib, including radiologic partial responses in six patients during treatment. Responses were durable for three patients. The cases presented are in line with a growing body of clinical and preclinical evidence that indicating that NSCLC with various uncommon EGFR mutations, with or without co-mutations, may be sensitive to afatinib.

Evaluation of the Prognostic Impact of SP263-Evaluated PD-L1 Expression in Patients with Stage III Non-Small Cell Lung Cancer (NSLC) Treated with Radio-Chemotherapy.

BACKGROUND: The PACIFIC study showed that after radio-chemotherapy, patients with NSCLC derived a benefit in PFS and OS when treated with durvalumab. This effect was limited to patients with a PD-L1 expression of >1%, partly because the outcome in the observational control arm was surprisingly favorable. Thus, it could be speculated that a lack of PD-L1 expression confers a favorable outcome for patients with stage III NSCLC. METHODS: Clinical data, PD-L1 expression, predictive blood markers, and the outcomes of 99 homogeneously treated patients with stage III NSCLC were retrospectively captured. Statistical analyses using the log rank test were performed. RESULTS: The median OS of patients with an expression of PD-L1 < 1% was 20 months (CI 10.5-29.5) and the median OS of patients with an expression of PD-L1 ≥ 1% was 28 months (CI 16.5-39.2) (p = 0.734). The median PFS of patients with an expression of PD-L1 < 1% was 9 months (CI 6.3-11.6) and the median PFS of patients with an expression of PD-L1 ≥ 1% was 12 months (CI 9.8-14.2) (p = 0.112). CONCLUSIONS: The assumption that the lack of PD-L1 expression represents a favorable prognostic factor after radio-chemotherapy vs. PD-L1 expression > 1% was not confirmed.

The Combined Therapy of Cabozantinib, Crizotinib, and Osimertinib in a Lung Cancer Patient with Acquired MET Amplification and Resistance Mutations.

EGFR-mutant lung cancers develop a wide range of potential resistance alterations under therapy with the third-generation EGFR tyrosine kinase inhibitor osimertinib. MET amplification ranks among the most common acquired resistance alterations and is currently being investigated as a therapeutic target in several studies. Nevertheless, targeted therapy of MET might similarly result in acquired resistance by point mutations in MET, which further expands therapeutic and diagnostic challenges. Here, we report a 50-year-old male patient with EGFR-mutant lung adenocarcinoma and stepwise acquired resistance by a focal amplification of MET followed by D1246N (D1228N), D1246H (D1228H), and L1213V (L1195V) point mutations in MET, all detected by NGS. The patient successfully responded to the combined and sequential treatment of osimertinib, osimertinib/crizotinib, and third-line osimertinib/cabozantinib. This case highlights the importance of well-designed, sequential molecular diagnostic analyses and the personalized treatment of patients with acquired resistance.

Fluctuation of Acquired Resistance Mutations and Re-Challenge with EGFR TKI in Metastatic NSCLC: A Case Report.

Osimertinib has become the preferred first-line therapy for epidermal growth factor receptor (EGFR) mutation-positive metastatic non-small cell lung cancer (NSCLC) in recent years. Originally, it was approved for second-line treatment after epidermal growth factor receptor EGFR tyrosine kinase inhibitors (TKIs) of the first and second generations had failed and EGFR T790M had emerged as a mode of resistance. Osimertinib itself provokes a wide array of on- and off-target molecular alterations that can limit therapeutic success. Liquid biopsy ctDNA (circulating tumor DNA) analysis by hybrid capture (HC) next-generation sequencing (NGS) can help to identify alterations in a minimally invasive way and allows for the detection of common as well as rare resistance alterations. We describe a young female patient who was initially diagnosed with metastatic EGFR L858R-positive NSCLC. She received EGFR TKI therapy at different timepoints during the course of the disease and developed sequential EGFR resistance alterations (EGFR T790M and C797S). In the course of her disease, resistance alteration became undetectable, and the tumor was successfully rechallenged with the original first-generation EGFR TKI as well as osimertinib and altogether showed prolonged response despite a prognostically negative TP53 alteration. To date, the patient has been alive for more than seven years, though initially diagnosed with a heavy metastatic burden.

Development of the NOGGO GIS v1 Assay, a Comprehensive Hybrid-Capture-Based NGS Assay for Therapeutic Stratification of Homologous Repair Deficiency Driven Tumors and Clinical Validation.

The worldwide approval of the combination maintenance therapy of olaparib and bevacizumab in advanced high-grade serous ovarian cancer requires complex molecular diagnostic assays that are sufficiently robust for the routine detection of driver mutations in homologous recombination repair (HRR) genes and genomic instability (GI), employing formalin-fixed (FFPE) paraffin-embedded tumor samples without matched normal tissue. We therefore established a DNA-based hybrid capture NGS assay and an associated bioinformatic pipeline that fulfils our institution's specific needs. The assay´s target regions cover the full exonic territory of relevant cancer-related genes and HRR genes and more than 20,000 evenly distributed single nucleotide polymorphism (SNP) loci to allow for the detection of genome-wide allele specific copy number alterations (CNA). To determine GI status, we implemented an %CNA score that is robust across a broad range of tumor cell content (25-85%) often found in routine FFPE samples. The assay was established using high-grade serous ovarian cancer samples for which BRCA1 and BRCA2 mutation status as well as Myriad MyChoice homologous repair deficiency (HRD) status was known. The NOGGO (Northeastern German Society for Gynecologic Oncology) GIS (GI-Score) v1 assay was clinically validated on more than 400 samples of the ENGOT PAOLA-1 clinical trial as part of the European Network for Gynaecological Oncological Trial groups (ENGOT) HRD European Initiative. The "NOGGO GIS v1 assay" performed using highly robust hazard ratios for progression-free survival (PFS) and overall survival (OS), as well a significantly lower dropout rate than the Myriad MyChoice clinical trial assay supporting the clinical utility of the assay. We also provide proof of a modular and scalable routine diagnostic method, that can be flexibly adapted and adjusted to meet future clinical needs, emerging biomarkers, and further tumor entities.

Assessment of a SARS-CoV-2 population-wide rapid antigen testing in Italy: a modeling and economic analysis study.

BACKGROUND: This study aimed to compare the cost-effectiveness of coronavirus disease 2019 (COVID-19) mass testing, carried out in November 2020 in the Italian Bolzano/Südtirol province, to scenarios without mass testing in terms of hospitalizations averted and quality-adjusted life-year (QALYs) saved. METHODS: We applied branching processes to estimate the effective reproduction number (Rt) and model scenarios with and without mass testing, assuming Rt = 0.9 and Rt = 0.95. We applied a bottom-up approach to estimate the costs of mass testing, with a mixture of bottom-up and top-down methodologies to estimate hospitalizations averted and incremental costs in case of non-intervention. Lastly, we estimated the incremental cost-effectiveness ratio (ICER), denoted by screening and related social costs, and hospitalization costs averted per outcome derived, hospitalizations averted and QALYs saved. RESULTS: The ICERs per QALY were €24 249 under Rt = 0.9 and €4604 under Rt = 0.95, considering the official and estimated data on disease spread. The cost-effectiveness acceptability curves show that for the Rt = 0.9 scenario, at the maximum threshold willingness to pay the value of €40 000, mass testing has an 80% probability of being cost-effective compared to no mass testing. Under the worst scenario (Rt = 0.95), at the willingness to pay threshold, mass testing has an almost 100% probability of being cost-effective. CONCLUSIONS: We provide evidence on the cost-effectiveness and potential impact of mass COVID-19 testing on a local healthcare system and community. Although the intervention is shown to be cost-effective, we believe the initiative should be carried out when there is initial rapid local disease transmission with a high Rt, as shown in our model.

Response of an HER2-Mutated NSCLC Patient to Trastuzumab Deruxtecan and Monitoring of Plasma ctDNA Levels by Liquid Biopsy.

HER2-targeted therapy is currently the subject of several studies in lung cancer and other solid tumors using either tyrosine kinase inhibitors (TKI) or targeted-antibody-drug conjugates. We describe a 61-year-old female patient with HER2 mutated adenocarcinoma of the lungs who received chemo-immunotherapy, followed by trastuzumab deruxtecan (T-DXd) and third-line Ramucirumab/Docetaxel at disease progression. Plasma ctDNA monitoring was obtained at 12 timepoints during therapy and revealed HER2 mutation allele frequencies that corresponded to the clinical course of disease. HER2-targeted T-DXd therapy resulted in a profound clinical response and may be an option for NSCLC patients carrying an activated HER2 mutation. Longitudinal liquid biopsy quantification of the underlying driver alteration can serve as a powerful diagnostic tool to monitor course of therapy.

Do newborn infants exhale through the CPAP system? Secondary analysis of a randomised cross-over trial.

BACKGROUND: During nasal continuous positive airway pressure (nCPAP) treatment in neonates, leakage is inevitable and can lead to reduced distending pressure in the lungs of the infant. In current practice, neither leakage nor expiratory flow is measured, which makes it difficult to assess if exhalation is through the device or entirely through leakages. OBJECTIVE: To examine if infants treated with nCPAP exhale through the CPAP system. DESIGN AND SETTING: Secondary data analyses from the ToNIL trial on leakages during nCPAP treatment. We retrospectively examined respiratory curves for the 50 infants included in the trial, using NI LabVIEW 2015. Each infant was measured with both prongs and nasal masks. A flow recording was classified as exhalation through the system if more than 50% of all expirations showed reverse flow, each for a minimum duration of 0.1 s. PATIENTS: 50 infants were included, born with a mean gestational age (GA) of 34 weeks, median birth weight of 1948 g and mean age at measurement 6.5 days. Inclusion criteria were CPAP treatment and a postmenstrual age (PMA) of 28-42 weeks. RESULTS: In our measurements, 32/50 infants exhaled through the CPAP system in at least one recording with either nasal mask or prongs. Leakages exceeding 0.3 L/min were seen in 97/100 recordings. CONCLUSIONS: During nCPAP treatment, infants can exhale through the CPAP system and leakage was common. Measuring expiratory flows and leakages in clinical settings could be valuable in optimising CPAP treatment of infants. TRIAL REGISTRATION NUMBER: NCT03586856.

Acquired G2032R Resistance Mutation in ROS1 to Lorlatinib Therapy Detected with Liquid Biopsy.

Lorlatinib, a third-generation anaplastic lymphoma kinase (ALK)/receptor tyrosine kinase inhibitor (ROS1), demonstrated efficacy in ROS1 positive (ROS1+) non-small cell lung cancer (NSCLC), although approval is currently limited to the treatment of ALK+ patients. However, lorlatinib-induced resistance mechanisms, and its efficacy against the resistance mutation G2032R in ROS1, respectively, have not yet been fully understood. Furthermore, concomitant tumor suppressor gene p53 (TP53) mutations occur in driver alteration positive NSCLC, but their prognostic contribution in the context of ROS1 inhibition remains unclear. Here we report a ROS1+ NSCLC patient who developed an on target G2032R resistance mutation during second-line lorlatinib treatment, indicating the lack of activity of lorlatinib against ROS1 G2032R. The resistance mutation was detected in plasma-derived ctDNA, signifying the clinical utility of liquid biopsies.

Simulated Acute Hypobaric Hypoxia Effects on Cognition in Helicopter Emergency Medical Service Personnel - A Randomized, Controlled, Single-Blind, Crossover Trial.

OBJECTIVE: To evaluate, under replicable, blinded and standardised conditions, the effect of acute exposure to hypobaric hypoxia (HH) (equivalent to 200 or 3000 or 5000 m above sea level (asl)) on selected cognitive domains and physiological parameters in personnel of helicopter emergency medical service (HEMS). METHODS: We conducted a randomized clinical trial using a single-blind crossover design in an environmental chamber (terraXcube) to induce HH in 48 HEMS personnel. Participants performed cognitive tests (CT) before the ascent, after 5 min at altitude, and after simulated cardiopulmonary resuscitation (SCR). CT evaluated: sustained attention using the psychomotor vigilance test (PVT) that included measurement of reaction time (RT); risky decision making using the balloon analogue risk task (BART), and attention and speed of processing using the digit symbol substitution test (DSST). CT performance was subjectively rated with a visual analogue scale (VAS). Physiological data were recorded with a physiological monitoring system. Data were analysed using a linear mixed model and correlation analysis. RESULTS: Mean reaction time was significantly slower (p = 0.002) at HH (5000 m asl), but there were no independent effects of HH on the other parameters of the PVT, BART or DSST. Participants did not detect subjectively the slower RT at altitude since VAS performance results showed a positive correlation with mean RT (p = 0.009). DSST results significantly improved (p = 0.001) after SCR. CONCLUSION: Acute exposure of HEMS personnel to HH induced a slower RT but no changes in any other investigated measures of cognition. The reduced RT was not detected subjectively by the participants. Trial number 3489044136, ClinicalTrials.gov trial registration.

Hypothermia Induced Impairment of Platelets: Assessment With Multiplate vs. ROTEM-An In Vitro Study.

Introduction: This experimental in vitro study aimed to identify and characterize hypothermia-associated coagulopathy and to compare changes in mild to severe hypothermia with the quantitative measurement of rotational thromboelastometry (ROTEM) and multiple-electrode aggregometry (MULTIPLATE). Methods: Whole blood samples from 18 healthy volunteers were analyzed at the target temperatures of 37, 32, 24, 18, and 13.7°C with ROTEM (ExTEM, InTEM and FibTEM) and MULTIPLATE using the arachidonic acid 0.5 mM (ASPI), thrombin receptor-activating peptide-6 32 µM (TRAP) and adenosine diphosphate 6.4 µM (ADP) tests at the corresponding incubating temperatures for coagulation assessment. Results: Compared to baseline (37°C) values ROTEM measurements of clotting time (CT) was prolonged by 98% (at 18°C), clot formation time (CFT) was prolonged by 205% and the alpha angle dropped to 76% at 13.7°C (p < 0.001). At 24.0°C CT was prolonged by 56% and CFT by 53%. Maximum clot firmness was only slightly reduced by ≤2% at 13.7°C. Platelet function measured by MULTIPLATE was reduced with decreasing temperature (p < 0.001): AUC at 13.7°C -96% (ADP), -92% (ASPI) and -91% (TRAP). Conclusion: Hypothermia impairs coagulation by prolonging coagulation clotting time and by decreasing the velocity of clot formation in ROTEM measurements. MULTIPLATE testing confirms a linear decrease in platelet function with decreasing temperatures, but ROTEM fails to adequately detect hypothermia induced impairment of platelets.

TP53 co-mutations as an independent prognostic factor in 2nd and further line therapy-EGFR mutated non-small cell lung cancer IV patients treated with osimertinib.

BACKGROUND: The negative prognostic and predictive value of TP53 co-mutations (TP53 mt+) in EGFR mutated (EGFR mt+) non-small cell lung cancer (NSCLC) is increasingly being acknowledged. Data consistently show that TP53 mt+ impact negatively on 1st line objective response rate (ORR), progression free survival (PFS) and overall survival (OS) with 1st and 2nd generation tyrosine kinase inhibitors (TKI). However, a negative predictive impact has not been shown for the 3rd generation TKI Osimertinib. Therefore, we investigated the impact of TP53 mt+ in EGFR mt+ NSCLC carrying a T790M resistance mutation and treated in 2nd/further lines with Osimertinib. METHODS: A total of 77 EGFR mt+ NSCLC IV patients carrying a T790M resistance mutation from two institutions were analyzed for TP53 mt+. Clinical data including sex, age, presence of CNS metastases, etc., as well as types of EGFR and TP53 mt+ were captured. PFS and OS were calculated from the start of Osimertinib. RESULTS: TP53 mt+ were found in 32/77 patients (42%). TP53 mt+ was a statistically significant independent negative predictive factor for PFS and OS. PFS for TP53 mt+ patients were 9 months vs. 14 months for patients with TP53 wild-type (TP53WT) (P<0.008). OS for TP53 mt+ patients was 16 months vs. 24 months patients with TP53WT (P<0.025). CONCLUSIONS: TP53 mt+ have a negative impact on PFS and OS in a group of patients carrying a sensitizing EGFR mt+ and a T790M resistance mutation treated with Osimertinib. These data, together with the data for 1st/2nd generation TKI in 1st line treatment call for additional therapeutic and management concepts for this subgroup of patients.

Outcome of Ordinary Polymorphous Adenocarcinomas of the Salivary Glands in Comparison With Papillary and Cribriform Subtypes.

BACKGROUND/AIM: Polymorphous adenocarcinoma (PAC) is a low-grade salivary gland malignancy in contrast to variants with papillary (PAP) or cribriform (CASG) architecture and confers the second most common malignancy of minor salivary glands. Our study aimed to identify prognostic factors and to evaluate histomorphological and molecular diagnostic criteria of PACs. PATIENTS AND METHODS: A series of 155 PACs, including 10 PAPs and 12 CASGs from the population-based Cancer Registry of North Rhine-Westphalia (LKR-NRW) and the Hamburg Salivary Gland Reference Centre (HRC) were analyzed. RESULTS: One fifth of the tumors were located in the major salivary glands and PACS/CASGS invariably lacked p40 expression. Fifty-two percent of PACs showed a PRKD1 E710D mutation. Ordinary PACs had a disease-specific 10-year survival probability of 97% compared to 90% when combining PAPs and CASGs. T-stage at diagnosis was a prognostic factor with 98% for stages T1/T2 versus 75% for T3/T4. CONCLUSION: Diagnostic algorithms for the PAC/CASG spectrum of tumors need to be improved and should include molecular markers.

CPR with restricted patient access using alternative rescuer positions: a randomised cross-over manikin study simulating the CPR scenario after avalanche burial.

BACKGROUND: The aim of this manikin study was to evaluate the quality of cardiopulmonary resuscitation (CPR) with restricted patient access during simulated avalanche rescue using over-the-head and straddle position as compared to standard position. METHODS: In this prospective, randomised cross-over study, 25 medical students (64% male, mean age 24) performed single-rescuer CPR with restricted patient access in over-the-head and straddle position using mouth-to-mouth ventilation or pocket mask ventilation. Chest compression depth, rate, hand position, recoil, compression/decompression ratio, hands-off times, tidal volume of ventilation and gastric insufflation were compared to CPR with unrestricted patient access in standard position. RESULTS: Only 28% of all tidal volumes conformed to the guidelines (400-800 ml), 59% were below 400 ml and 13% were above 800 ml. There was no significant difference in ventilation parameters when comparing standard to atypical rescuer positions. Participants performed sufficient chest compressions depth in 98.1%, a minimum rate in 94.7%, correct compression recoil in 43.8% and correct hand position in 97.3% with no difference between standard and atypical rescuer positions. In 36.9% hands-off times were longer than 9 s. CONCLUSIONS: Efficacy of CPR from an atypical rescuer position with restricted patient access is comparable to CPR in standard rescuer position. Our data suggest to start basic life-support before complete extrication in order to reduce the duration of untreated cardiac arrest in avalanche rescue. Ventilation quality provided by lay rescuers may be a limiting factor in resuscitation situations where rescue ventilation is considered essential.

Lockdown effects on Parkinson's disease during COVID-19 pandemic: a pilot study.

The coronavirus-disease 2019 (COVID-19) outbreak precipitated prolonged lock-down measures. The subsequent social distancing, isolation, and reduction in mobility increased psychological stress, which may worsen Parkinson's disease (PD). Therefore, telemedicine has been proposed to provide care to PD patients. To evaluate the effects of lock-down on motor and nonmotor symptoms in PD patients during the COVID-19 pandemic and the feasibility of telemedicine. Motor and nonmotor aspects were longitudinally assessed using structured questionnaires at baseline (in-person, February 2020) and at follow-up (remote web-based video, lock-down) evaluation. Of the seventeen PD patients evaluated at baseline, fourteen agreed to participate in, and completed follow-up evaluations. There was an impairment of nonmotor aspects measured with the MDS-UPDRS part I (p < 0.001) during lock-down. Nine patients participated independently in the telemedicine evaluation while five needed help from relatives. Our preliminary findings suggest an impairment of nonmotor symptoms in PD patients and support the feasibility and need for telemedicine in monitoring PD patients during the COVID-19 pandemic, to guarantee optimal assistance with reducing the burden of infection. Our findings also suggest that movement disorder clinics should be carefully considering socio-demographics and clinical features when developing telemedicine programs.

Mucoepidermoid carcinoma of the salivary glands revisited with special reference to histologic grading and CRTC1/3-MAML2 genotyping.

Mucoepidermoid carcinoma (MEC) is the most common carcinoma of the salivary glands. Here, we have used two large patient cohorts with MECs comprising 551 tumors to study clinical, histological, and molecular predictors of survival. One cohort (n = 167), with known CRCT1/3-MAML2 fusion status, was derived from the Hamburg Reference Centre (HRC; graded with the AFIP and Brandwein systems) and the other (n = 384) was derived from the population-based Cancer Registry of North Rhine-Westphalia (LKR-NRW; graded with the AFIP system). The reliability of both the AFIP and Brandwein grading systems was excellent (n = 155). The weighted kappa for inter-rater agreement was 0.81 (95% CI 0.65-0.97) and 0.83 (95% CI 0.71-0.96) for the AFIP and Brandwein systems, respectively. The 5-year relative survival was 79.7% (95% CI 73.2-86.2%). Although the Brandwein system resulted in a higher rate of G3-MECs, survival in G3-tumors (AFIP or Brandwein grading) was markedly worse than in G1/G2-tumors. Survival in > T2 tumors was markedly worse than in those with lower T-stage. Also, fusion-negative MECs had a worse 5-year progression-free survival. The frequency of fusion-positive MECs in the HRC cohort was 78.4%, of which the majority (86.7%) was G1/G2-tumors. In conclusion, the AFIP and Brandwein systems are useful in estimating prognosis and to guide therapy for G3-MECs. However, their significance regarding young age (≤ 30 years) and location-dependent heterogeneity of in particular G2-tumors is more questionable. We conclude that CRTC1/3-MAML2 testing is a useful adjunct to histologic scoring of MECs and for pinpointing tumors with poor prognosis with higher precision, thus avoiding overtreatment.

Comparison of Resistance Spectra after First and Second Line Osimertinib Treatment Detected by Liquid Biopsy.

Since 2009, several first, second, and third generation EGFR tyrosine kinase inhibitors (TKI) have been approved for targeted treatment of EGFR mutated metastatic non-small lung cancer (NSCLC). A vast majority of patients is improving quickly on treatment; however, resistance is inevitable and typically occurs after one year for TKI of the first and second generation. Osimertinib, a third generation TKI, has recently been approved for first line treatment in the palliative setting and is expected to become approved for the adjuvant setting as well. Progression-free survival (PFS) under osimertinib is superior to its predecessors but its spectrum of resistance alterations appears significantly more diverse compared to first and second generation EGFR TKI. As resistance mechanisms to osimertinib are therapeutically targetable in some cases, it is important to comprehensively test for molecular alterations in the relapse scenario. Liquid biopsy may be advantageous over tissue analysis as it has the potential to represent tumor heterogeneity and clonal diversification. We have previously shown high concordance of hybrid capture (HC) based next generation sequencing (NGS) in liquid biopsy versus solid tumor biopsies. In this study, we now present real-word data from 56 patients with metastatic NSCLC that were tested by liquid biopsy at the time of disease progression on mostly second line treated osimertinib treatment. We present examples of single and multiple TKI resistance mechanisms, including mutations in multiple pathways, copy number changes and rare fusions of RET, ALK, FGFR3 and BRAF. In addition, we present the added value of HC based NGS to reveal polyclonal resistance development at the DNA level encoding multiple EGFR C797S and PIK3CA mutations.

Neonatal Resuscitation With T-Piece Systems: Risk of Inadvertent PEEP Related to Mechanical Properties.

Background: Resuscitation of infants using T-piece resuscitators (TPR) allow positive pressure ventilation with positive end-expiratory pressure (PEEP). The adjustable PEEP valve adds resistance to expiration and could contribute to inadvertent PEEP. The study indirectly investigated risk of inadvertent peep by determining expiratory time constants. The aim was to measure system expiratory time constants for a TPR device in a passive mechanical model with infant lung properties. Methods: We used adiabatic bottles to generate four levels of compliance (0.5-3.4 mL/cm H2O). Expiratory time constants were recorded for combinations of fresh gas flow (8, 10, 15 L/min), PEEP (5, 8, 10 cm H2O), airway resistance (50, 200 cm H2O/L/sec and none), endotracheal tube (none, size 2.5, 3.0, 3.5) with a peak inflation pressure of 15 cm H2O above PEEP. Results: Low compliances resulted in time constants below 0.17 s contrasting to higher compliances where the expiratory time constants were 0.25-0.81 s. Time constants increased with increased resistance, lower fresh gas flows, higher set PEEP levels and with an added airway resistance or endotracheal tube. Conclusions: The risk of inadvertent PEEP increases with a shorter time for expiration in combination with a higher compliance or resistance. The TPR resistance can be reduced by increasing the fresh gas flow or reducing PEEP. The expiratory time constants indicate that this may be clinically important. The risk of inadvertent PEEP would be highest in intubated term infants with highly compliant lungs. These results are useful for interpreting clinical events and recordings.

Interface leakage during neonatal CPAP treatment: a randomised, cross-over trial.

OBJECTIVE: To determine leakage for two neonatal continuous positive airway pressure (CPAP) interfaces and evaluate leak-corrective manoeuvres. DESIGN: The ToNIL (Trial of NCPAP Interface Leakage) study was a randomised, clinical, cross-over trial with data collection between August 2018 and October 2019. The primary outcome was blinded to the treating staff. SETTING: One secondary, 8-bed neonatal intensive care unit (NICU) and three larger (>15 beds), academic NICU referral centres. PATIENTS: Newborn infants with CPAP were screened (n=73), and those with stable spontaneous breathing, low oxygen requirement, postmenstrual age (PMA) over 28 weeks and no comorbidities were eligible. In total, 50 infants were included (median PMA 33 completed weeks). INTERVENTIONS: Leakage was measured for both prongs and nasal mask, before and after leak-corrective manoeuvres. Interface application was performed in a randomised order by a nurse, blinded to the measured leakage. MAIN OUTCOME MEASURES: 30 s average leakage, measured in litres per minute (LPM). RESULTS: Analyses showed a significantly lower leakage (mean difference 0.86 LPM, 95% CI 0.07 to 1.65) with prongs (median 2.01 LPM, IQR 1.00-2.80) than nasal mask (median 2.45 LPM, IQR 0.99-5.11). Leak-corrective manoeuvres reduced leakage significantly for both prongs (median 1.22 LPM, IQR 0.54-1.87) and nasal mask (median 2.35 LPM, IQR 0.76-4.75). CONCLUSIONS: Large leakages were common for both interfaces, less with prongs. Simple care manoeuvres reduced leakage for both interfaces. This is the first report of absolute leakage for nasal interfaces and should encourage further studies on leakage during CPAP treatment.