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There are several proposed advantages of volume-targeted ventilation over pressure control ventilation in neonates, which include: controlled minute ventilation to avoid hypercarbia and hypocarbia, reduction in ventilator-induced lung injury with changes in lung compliance, a lower risk of lung de-recruitment associated with variable respiratory drive in neonates, reduced work of breathing, and automatic weaning of ventilator settings.

Despite the positive findings in the Cochrane review, 2 widespread acceptance and implementation of volume-targeted ventilation has been slow in the neonatal ICU setting. In addition, differences in ventilator performance related to accuracy and the location of volume monitoring and flow triggering, ability to appropriately target V T and pressure when endotracheal tube ETT leaks are present, complexity in the mode operation, and lack of standardized protocols may help explain low clinical use of volume-targeted ventilation.

These proposed improvements may have important clinical implications for low birthweight infants that require invasive ventilation. The ability to provide consistent and accurate V T and triggering has recently been evaluated across different volume-targeted modes and ventilator brands by using neonatal lung simulators with simulated ETT leaks. We hypothesized that there would be no differences in ventilation parameters, gas exchange, triggering, or effort of breathing in surfactant-deficient, lung-injured, spontaneously breathing juvenile rabbits with and without an ETT leak among 3 different volume-targeted modes that monitor V T at different locations and regulate PIP based on inspiratory, expiratory, or leak adapted compensated V T.

A recent meta-analysis showed that volume-targeted modes of ventilation may improve outcomes when compared with pressure control modes in premature infants. Differences in performance among the different brands of volume-targeted ventilation modes were shown in artificial lung models adapted with simulated endotracheal tube ETT leaks, but it was unclear whether these differences may have any physiologic impact on gas exchange or work of breathing.

In surfactant-deficient, spontaneously breathing rabbits, aside from triggering and minute ventilation, 3 commonly used ventilators provided similar lung support without an ETT leak. When a moderate ETT leak was present, volume-targeted modes that use proximal triggering and volume monitoring with adaptive leak compensation capabilities seemed more effective in providing ventilation support than did a ventilator that uses measurements obtained from the expiratory limb of the ventilator and does not have leak compensation.

The study was designed, measurements obtained, data reduced, and manuscript written by the investigators, with no input from the grantor. Ventilator brand selection was based on differences in volume-targeted mode operation, specifically, as they relate to 1 location of V T monitoring and breath triggering, 2 ability to stabilize pressure in the expiratory phase in the presence of a leak, and 3 differences in V T input required for PIP adjustment.

The different triggering locations, V T measurement inputs, and leak compensation variables related to the specific brand of volume-targeted modes are shown in Table 1. The neck and upper chest were shaved. Cetacaine spray 0. Local anesthesia was provided around the trachea with lidocaine before tracheal isolation and oral intubation. The trachea was dissected, isolated, and intubated with a 2. After intubation, a strand of umbilical tape was used to anchor the trachea and the ETT, to prevent displacement, gas leakage, and saline solution leakage during lavage, and to allow investigators the ability to control the magnitude of the ETT leak.

We chose 6. A gauge angiocatheter was placed in the right jugular vein for administration of fluids and medications. Sedation and analgesia were maintained to minimize pain and promote spontaneous breathing by using continuous intravenous infusion of ketamine and xylazine 3 and 0. A gauge angiocatheter was placed in the right carotid artery for heart rate and blood pressure monitoring and sampling for blood-gas analyses. The F IO 2 was increased to 1.

The animals were allowed to stabilize for 30 min. A 6 French esophageal balloon catheter Cardinal Healthcare, Dublin, Ohio was positioned in the lower esophagus, and proper placement was confirmed by using the occlusion technique. A ventilator circuit leak test and a circuit calibration were performed per manufacturer's recommendation.

Proprietary proximal flow sensors were used for each of the different ventilators. Ventilators were configured to display measured V T based on a body temperature pressure saturated condition calculation. The spontaneously breathing, surfactant-deficient animals served as their own controls and were supported in a randomized crossover block sequence so that each animal was supported with and without an ETT leak by using each of the 3 ventilator's volume-targeted assist-control modes for 30 min.

A schematic of the animal procedures and experimental conditions is shown in Figure 1. The flow or pressure trigger setting was carefully adjusted with the most-sensitive triggering setting that allowed the animals' ability to optimize ventilator triggering based on intrinsic efforts without creating an autocycling condition confirmed by esophageal monitoring. Diagram of experimental procedures and testing conditions with each of the ventilator's volume-targeted modes.

Blood gas measurements were obtained and blood pressure, heart rate, airway pressure, flow, and esophageal pressure were recorded for 45 s at Hz after 30 min of support with each ventilator and leak condition in all the animals. Ventilation settings and measured parameters were also obtained at this time. We compared differences in mean variables between ventilator brands for the ETT leak and no ETT leak conditions independently.

We then compared differences within the individual ventilator brand to assess differences between the leak and no leak conditions. Frequencies and percentages were calculated for ventilator and leak assignment to assess data completeness. A linear-mixed effects model, an extension of 2-way analysis of variance that accounts for the repeated measures taken on the rabbits, was used to evaluate the association of ventilator and leak status on each continuous outcome variable.

In these linear mixed-effects models, ventilator type, and leak status were treated as fixed effects. A compound symmetric covariance matrix was used in this model, which assumes that the correlation between measurements was equal for any 2 measurements taken on the same rabbit. All models were assessed for convergence, and the modeling assumptions of homogeneity of variance and normality were verified by using 2 residual diagnostics: residuals versus predicted values and normal probability plots.

Differences in outcome variables for each ventilator and leak status were estimated from the model. Bonferroni correction was used to adjust for multiple comparisons. SAS 9. After saline solution lavage, lung compliance decreased from 1.

Heart and blood pressure were not different among the different ventilator modes or leak conditions. There were no differences in P aO 2 among the different volume-targeted modes under no leak and ETT leak conditions Fig. When no leak was present, P aCO 2 was not different among the 3 ventilator brands. The pressure-rate product measurements were similar among all 3 ventilators when there was no ETT leak Fig. There was no difference in the pressure-rate product between the leak and no leak conditions when using the Servo-i ventilator.

Graphic PIP and esophageal pressure waveforms in one animal, which was representative of most animals, and highlighted differences in trigger efforts among ventilator brands and leak conditions are shown in Figure 4. Effect of each ventilator's volume-targeted mode with and without ETT leak on pressure-rate product A and percentage of triggered breaths B. Airway upper and esophageal lower pressure in cm H 2 O recorded over a s period in one animal.

The arrows represent the efforts being made without a corresponding ventilator-assisted breathe being delivered. To our knowledge, these were the first physiologic data by using a spontaneously breathing animal model of surfactant-deficiency and respiratory distress syndrome to show associations between specific volume-targeted modes across ETT leak and non-leak conditions. The major finding of this study was that different volume-targeted modes may exhibit different levels of ventilator assistance and respiratory support under specific conditions.

All 3 of the different volume-targeted modes supported oxygenation and ventilation similarly in a juvenile rabbit model of severe respiratory distress syndrome when there was no ETT leak. Because uncuffed ETTs are frequently used in neonatal patients, ETT leak is a common occurrence in the neonatal ICU setting, and this may result in the need for reintubation to upsize the tube, especially when ventilator volume-targeted modes are not able to provide adequate support.

We speculated that a primary reason why the AVEA and Babylog VN were able to provide greater support with an ETT leak is related to the fact that V T and flow measurements at the proximal airway are used to achieve the target V T and provide flow triggering, respectively.

Also, because these ventilators adjust PIP based on either expiratory or an adaptive leak corrected V T , both ventilators are capable of compensating for volume loss to the atmosphere through moderately sized ETT leaks and will increase PIP to achieve the pre-set V T. Also, because these volume-guarantee modes add additional flow to maintain PEEP and triggering expiratory leak compensation , this additional flow may reduce the amount of inspired CO 2 during exhalation, which may further improve ventilation when an ETT leak is present.

Similar mechanisms of gas exchange have been described with increasing flows and pressure when using heated high-flow nasal cannula. Additional studies are needed to determine if fewer patients may need to be reintubated with a larger-sized ETT for clinical deterioration when selecting these modes over others that are not leak compensated. As mentioned previously, the Servo-i PRVC mode differs from the other 2 ventilators in that it uses the inspiratory V T measurement acquired back at the ventilator in its algorithm to adjust PIP levels to achieve goal V T during volume-targeted ventilation.

The Servo-i has a proprietary disposable pneumotachometer that can be placed at the proximal airway to measure V T and flow; however, these values are not used to guide the PRVC algorithm or assist with inspiratory-flow triggering. Circuit compliance compensation has been shown to improve the accuracy and precision of ventilator-displayed V T when compared with having no circuit compliance compensation. As such, the major limitation of the PRVC mode with an ETT leak is that using V T delivery and compliance is overestimated, which may lead to undesirable reductions in PIP, which may also result in hypercapnia and lung de-recruitment.

This excessive V T delivery may lead to hypocarbia and air leak. With the Babylog VN, these problems have been reduced because the volume-guarantee assist-control mode adjusts PIP based on a V T that is estimated and compensated for based on the magnitude of the calculated inspiratory and expiratory leak.

After implementation of the ETT leak, V T within the lung model was not able to be measured accurately due to an inability of the lung model to effectively trigger a minimum of 5 consecutive breaths with the Servo-i PRVC mode.

Another study reaffirms the importance of proximal V T monitoring location for accurate V T delivery with ETT leak in infants with low lung compliance. Although short-term studies evaluating patient-ventilator interaction are lacking in premature infants, there are 2 phenomena related to triggering that may contribute to poor gas exchange and asynchrony. These include: 1 an inability of the ventilator to sufficiently detect a flow or pressure signal when a patient inspiratory effort is made, and 2 auto-triggering when an ETT leak is present.

In the past, an inability to provide patient-synchronized ventilation was associated with major consequences and often required muscle paralysis and heavy sedation, and was associated with prolonged respiratory support. We noted that triggering was more successful in our animal model when flow input for triggering was measured in the proximal airway and when using a mode that provided expiratory leak compensation. Expiratory leak compensation algorithms may help with ETT leaks by adding flow during exhalation, which stabilizes the PEEP levels and provides a sufficient bias flow from which to flow trigger breaths when respiratory efforts are being made.

This may be due to a lack of expiratory leak compensation as well as the flow-triggering measurement located back at the ventilator. We believed that minute ventilation was negatively impacted due to an inability of the animals to effectively trigger PRVC breaths from the Servo-i. This could be a major contributing reason why ventilation was compromised when the animals were supported with the Servo-i with and without a leak.

In a previous study that used a spontaneously breathing lung model of a premature infant 1—2 kg with respiratory distress syndrome, the Servo-i PRVC assist-control mode was shown to have greater asynchrony index than Babylog VN and AVEA volume-guarantee modes. We observed that animals frequently made 2 inspiratory efforts before a breath could be triggered in PRVC with the Servo-i Fig. However, it is interesting to note that triggering did improve with the Servo-i after the ETT leak.

We speculated that the presence of a leak actually benefited the signal-to-noise ratio of the patient flow because the flow sensor at the ventilator was no longer required to measure near-zero flow, thus, all flows measured by the Servo-i may be biased by the ETT leak.

Future ventilator improvements are needed to reduce ventilator response times and improve triggering because these may contribute to ventilator asynchrony, 25 which leads to negative outcomes, including prolonged intubation, 26 , 27 increased sedative use, 28 — 30 and higher mortality. The major limitations of the present study derived from the use of an animal model with different pulmonary anatomies than are found in prematurely born human infants, along with mature lung structure undergoing active surfactant metabolism.

This limited the ability of the lavage procedure to provide a stable surfactant-deficient model, which, in turn, limited our ability to study the long-term effects of the different modes of respiratory support studied. This was why we randomized the mode and leak order, and were only able to study short-term physiologic outcomes. We used a research pneumotachometer in series with each of the testing conditions.

This may have added some dead space and resistance, and inversely impacted some physiologic measurements. However, we attempted to overcome these deleterious effects by using a flow sensor with extremely low dead space and resistance as well as increased the pre-set V T to overcome any issues related to compressible volume loss that resulted in hypoventilation. It should be noted that we chose to evaluate performance beyond some manufacturers' recommendations, similar to previous bench studies.

As such, it is important to not extrapolate findings from the current study with the Servo-i PRVC mode and assume a similar performance with the Servo U ventilator. Future studies are needed to determine if there are physiologic differences related to ventilator performance between PRVC modes offered with these 2 ventilators.

Increased work of breathing and poor gas exchange are 2 important clinical factors that may contribute to respiratory failure and the ongoing need for mechanical ventilation in premature infants. Differences in ventilator brands' performance and the ability to appropriately deliver V T and PIP, and allow effective triggering with volume-targeted ventilation may have several important clinical implications in the pre-term neonatal patient population.

The Servo-i uses inspiratory V T and provides triggering and V T measurements based on values acquired back at the ventilator and not proximal to the patient, as with the other ventilators, during volume-targeted ventilation. Also, unlike the other ventilators, the Servo-i targets a calculated inspired V T based on tubing compliance and not expiratory or adaptive leak-compensated V T , thus, it is likely that combined inadequate triggering and reduced PIP with an ETT leak condition were major contributing factors that explained some of the observed differences in minute ventilation, the effort of breathing pressure-rate product , and gas exchange between the Servo-i and the other ventilators tested.

Based on our observations, we believed that clinical success and future research of volume-targeted modes in neonates should use ventilators with algorithms that incorporate expiratory V T or leak-corrected V T measured at the proximal airway because these ventilators may deliver better ventilation support by compensating for the leak of air around an ETT. The remaining authors have disclosed no conflicts of interest. It destroys the part of the brain that controls all of the body's automatic functions.

Coronavirus, on the other hand, primarily affects the respiratory system, in severe cases resulting in pneumonia. The primary symptoms are fever, coughing, and shortness of breath. The book also describes a virus that has an incubation period of just four hours, whereas coronavirus incubates for several days to two weeks.

Finally, to the disappointment of conspiracy theorists, it turns out that in the first edition of The Eyes Of Darkness, the virus was originally called 'Gorki', after the Russian city where Koontz originally wrote the bioweapons lab. After the Soviet Union fell in , Koontz apparently changed later editions to make China the villain. The views expressed in the contents above are those of our users and do not necessarily reflect the views of MailOnline.

Argos AO. Privacy Policy Feedback. Share this article Share. Share or comment on this article: Dean Koontz's thriller about a deadly virus from Wuhan is now a bestseller e-mail 2. Comments Share what you think. View all. More top stories. Bing Site Web Enter search term: Search. Retired tennis star confirms she is expecting a baby girl with her husband David Lee Sweet 'I'm going to be a first time dad at 51 with my absolute soulmate': EastEnders star Michael Greco shares baby scan That is oarsome!

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