Jörg Thomas

Sex-dependent differences in the in vivo respiratory phenotype of the TASK-1 potassium channel knockout mouse

TASK-1 potassium channels have been implicated in central and peripheral chemoreception; however, the precise contribution of TASK-1 for the control of respiration is still under debate. Here, we investigated the respiration of unrestrained adult and neonatal TASK-1 knockout mice (TASK-1-/-) using a plethysmographic device. Respiration in adult female TASK-1-/- mice under control (21% O2), hypoxia and hypercapnia was unaffected. Under acute hypoxia male TASK-1-/- mice exhibited a reduced increase of the respiratory frequency (fR) compared to wildtypes. However, the tidal volume (VT) of male TASK-1-/- mice was strongly enhanced. The volatile anesthetic isoflurane induced in male TASK-1-/- and male wild type mice (TASK-1+/+) a similar respiratory depression. Neonatal TASK-1-/- mice demonstrated a 30-40% decrease of the minute volume, caused by a reduction of the fR under control condition (21% O2). Under hypoxia, neonatal TASK-1-/- mice more frequently stopped breathing (apnea>3s) suggesting an increased hypoxia-sensitivity. As reported before, this increased hypoxia sensitivity had no influence on the survival rate of neonatal TASK-1-/- mice. In adult and neonatal mice, TASK-1 gene deletion induced a significant prolongation of the relaxation time (RT), which is a parameter for expiration kinetics. Additionally, screening for mutations in the human TASK-1 gene in 155 cases of sudden infant death syndrome (SIDS) was inconclusive. In conclusion, these data are suggestive for an increased hypoxia-sensitivity of neonatal TASK-1-/- mice, however, without causing an increase in neonatal lethality. In adult female TASK-1-/- mice respiration was unaffected, whereas adult male TASK-1-/- mice showed a modified breathing pattern. These results are suggestive for sex-specific mechanisms for compensating the inactivation of TASK-1 in mice.

Performance of adjustable pressure-limiting (APL) valves in two different modern anaesthesia machines.

The ability to gently ventilate a patients lungs using a self‐inflating bag requires a properly working adjustable pressure‐limiting (APL) valve. We compared the performance of the APL valves of the GE Aisys CS2 and the Draeger Fabius anaesthetic machines during closure and opening from 1‐20 and from 20‐1 cmH2O, using standardised experimental baby and adolescent patient lung models. Airway pressures and inspiratory tidal volumes were measured using an ASL‐5000 test lung and a GE Aisys CS2 near‐patient spirometry sensors. In both lung models, the GE Aisys CS2 APL valves demonstrated non‐linear behaviours for airway pressures and for inspiratory tidal volumes, with a sharp increase at set APL pressure levels of 8–10 cmH2O. With further closure of the GE Aisys CS2 APL valves up to 20 cmH2O, inspiratory tidal volumes decreased to ~50% of the highest values measured. Airway pressures in the Draeger Fabius APL valves demonstrated a near linear increase and decrease. Airway pressure values measured in the Draeger Fabius were never higher than those set by the APL valves, whereas in the GE Aisys CS2, they considerably exceeded set pressures (by up to 27 cmH2O). We conclude that the performance of the GE Aisys CS2 APL valve does not allow safe bag‐assisted ventilation of a patients lungs.

Impact of endotracheal tube shortening on work of breathing in neonatal and pediatric in vitro lung models

Work of breathing accounts for a significant proportion of total oxygen consumption in neonates and infants. Endotracheal tube inner diameter and length significantly affect airflow resistance and thus work of breathing. While endotracheal tube shortening reduces endotracheal tube resistance, the impact on work of breathing in mechanically ventilated neonates and infants remains unknown.

Arterial to end-tidal carbon dioxide difference in children undergoing mechanical ventilation of the lungs during general anaesthesia

Capnography (ETCO2) is routinely used as a non‐invasive estimate of arterial carbon dioxide (PaCO2) levels in order to modify ventilatory settings, whereby it is assumed that there is a positive gap between PaCO2 and ETCO2 of approximately 0.5 kPa. However, negative values (ETCO2 > PaCO2) can be observed. We retrospectively analysed arterial to end‐tidal carbon dioxide differences in 799 children undergoing general anaesthesia with mechanical ventilation of the lungs in order to elucidate predictors for a negative gap. A total of 2452 blood gas analysis readings with complete vital sign monitoring, anaesthesia gas analysis and spirometry data were analysed. Mean arterial to end‐tidal carbon dioxide difference was −0.18 kPa (limits of 95% agreement −1.10 to 0.74) and 71.2% of samples demonstrated negative values. The intercept model revealed PaCO2 to be the strongest predictor for a negative PaCO2‐ETCO2 difference. A decrease in PaCO2 by 1 kPa resulted in a decrease in the PaCO2‐ETCO2 difference by 0.23 kPa. This study demonstrates that ETCO2 monitoring in children whose lungs are mechanically ventilated may paradoxically lead to overestimation of ETCO2 (ETCO2 > PaCO2) with a subsequent risk of unrecognised hypocarbia.

Abnormal respiration under hyperoxia in TASK-1/3 potassium channel double knockout mice

Despite intensive research, the exact function of TASK potassium channels in central and peripheral chemoreception is still under debate. In this study, we investigated the respiration of unrestrained TASK-3 (TASK-3-/-) and TASK-1/TASK-3 double knockout (TASK-1/3-/-) adult male mice in vivo using a plethysmographic device. Ventilation parameters of TASK-3-/- mice were normal under control condition (21% O2) and upon hypoxia and hypercapnia they displayed the physiological increase of ventilation. TASK-1/3-/- mice showed increased ventilation under control conditions. This increase of ventilation was caused by increased tidal volumes (VT), a phenomenon similarly observed in TASK-1-/- mice. Under acute hypoxia, TASK-1/3-/- mice displayed the physiological increase of the minute volume. Interestingly, this increase was not related to an increase of the respiratory frequency (fR), as observed in wild-type mice, but was caused by a strong increase of VT. This particular respiratory phenotype is reminiscent of the respiratory phenotype of carotid body-denervated rodents in the compensated state. Acute hypercapnia (5% CO2) stimulated ventilation in TASK-1/3-/- and wild-type mice to a similar extent; however, at higher CO2 concentrations (>5% CO2) the stimulation of ventilation was more pronounced in TASK-1/3-/- mice. At hyperoxia (100% O2), TASK-1-/-, TASK-3-/- and wild-type mice showed the physiological small decrease of ventilation. In sharp contrast, TASK-1/3-/- mice exhibited an abnormal increase of ventilation under hyperoxia. In summary, these measurements showed a grossly normal respiration of TASK-3-/- mice and a respiratory phenotype of TASK-1/3-/- mice that was characterized by a markedly enhanced tidal volume, similar to the one observed in TASK-1-/- mice. The abnormal hyperoxia response, exclusively found in TASK-1/3-/- double mutant mice, indicates that both TASK-1 and TASK-3 are essential for the hyperoxia-induced hypoventilation. The peculiar respiratory phenotype of TASK-1/3 knockout mice is reminiscent of the respiration of animals with long-term carotid body dysfunction. Taken together, TASK-1 and TASK-3 appear to serve specific and distinct roles in the complex processes underlying chemoreception and respiratory control.

Thromboelastography to monitor the intra-operative effects of low-molecular weight heparin following bridging anticoagulation in a child with normal renal function*

Paediatric patients who require anticoagulation with therapeutic doses of low‐molecular weight heparin are at risk of having a residual anticoagulant effect at the time of surgery, even if managed according to current peri‐operative guidelines. Testing for residual effect is not currently recommended in such circumstances. A 15‐year‐old child with a mechanical aortic valve replacement requiring long‐term warfarin treatment, as well as underlying coagulation defects, was administered low‐molecular weight heparin for bridging anticoagulation before kyphoscoliosis surgery. Thromboelastography was used intra‐operatively to diagnose residual heparinisation, which was demonstrated by a prolonged reaction (R) time of 16.0 min in the plain cup, compared with 9.2 min in the heparinase cup. Subsequently, thromboelastography was also used to monitor haemostatic therapy, which consisted of protamine 2 mg.kg−1 and 500 IU cryoprecipitate. Thromboelastography was used intra‐operatively to allow rapid testing of coagulation status and guide therapy, thereby minimising use of blood products and reducing complications.

Work of breathing for cuffed and uncuffed pediatric endotracheal tubes in an in vitro lung model setting

Over the last decade, cuffed endotracheal tubes are increasingly used in pediatric anesthesia and also in pediatric intensive care. However, the smaller inner diameter of cuffed endotracheal tubes and, implicitly, the increased endotracheal tube resistance is still a matter of debate.

Accuracy of near-patient vs. inbuilt spirometry for monitoring tidal volumes in an in-vitro paediatric lung model

Spirometric monitoring provides precise measurement and delivery of tidal volumes within a narrow range, which is essential for lung‐protective strategies that aim to reduce morbidity and mortality in mechanically‐ventilated patients. Conventional anaesthesia ventilators include inbuilt spirometry to monitor inspiratory and expiratory tidal volumes. The GE Aisys CS2 anaesthesia ventilator allows additional near‐patient spirometry via a sensor interposed between the proximal end of the tracheal tube and the respiratory tubing. Near‐patient and inbuilt spirometry of two different GE Aisys CS2 anaesthesia ventilators were compared in an in‐vitro study. Assessments were made of accuracy and variability in inspiratory and expiratory tidal volume measurements during ventilation of six simulated paediatric lung models using the ASL 5000 test lung. A total of 9240 breaths were recorded and analysed. Differences between inspiratory tidal volumes measured with near‐patient and inbuilt spirometry were most significant in the newborn setting (p < 0.001), and became less significant with increasing age and weight. During expiration, tidal volume measurements with near‐patient spirometry were consistently more accurate than with inbuilt spirometry for all lung models (p < 0.001). Overall, the variability in measured tidal volumes decreased with increasing tidal volumes, and was smaller with near‐patient than with inbuilt spirometry. The variability in measured tidal volumes was higher during expiration, especially with inbuilt spirometry. In conclusion, the present in‐vitro study shows that measurements with near‐patient spirometry are more accurate and less variable than with inbuilt spirometry. Differences between measurement methods were most significant in the smallest patients. We therefore recommend near‐patient spirometry, especially for neonatal and paediatric patients.