Mechanical ventilation is a cornerstone in the treatment of respiratory failure in critically ill patients. Over the last decades the field of mechanical ventilation has developed from the use of monotonous methods of mechanical ventilation that dictate the breathing volume and frequency towards methods that support breathing while allowing the patient the freedom to attain a natural and variable breathing pattern. Another shift of paradigm is the increasing application of non-invasive ventilation, liberating the upper airways by avoiding endotracheal intubation. The present article will share the experiences of introducing neural control of mechanical ventilation.
by Dr Christer Sinderby and Dr Jennifer Beck
The Greek physician Galen of Pergamon (AD 129 – 199) argued that a muscle contraction was caused by fluid flowing into it. 1500 years later, Luigi Alyisio Galvani (1737 –1798) provided new understanding explaining that electrical energy, and not air or fluid, is the force behind muscle movement. In 1960 Petit et al  as well as Agostoni et al  published new work on trans-oesophageal measurements of electrical activity of the human diaphragm opening up a new avenue on how to monitor neural breathing efforts.
In 1999, we and coworkers  introduced the first method that allowed assisted breathing in critically ill patients to be controlled by their own diaphragm electrical activity. As the diaphragm electrical activity results from neural respiratory output signals coming from the brain, transferred via the phrenic nerves, it represents the neural effort to breathe and is regulated by input from multiple respiratory reflexes feeding back to the respiratory centres.
Neurally Adjusted Ventilatory Assist (NAVA)
The new technology to enable neural control of mechanical ventilation is named Neurally Adjusted Ventilatory Assist (NAVA). The main advantage of NAVA is that triggering, delivery and termination of the ventilator’s assist are "brain-controlled" by the same electrical signal that governs the contraction of the diaphragm. The electrical signals of the diaphragm are acquired via microelectrodes incorporated on an oro/naso-gastric tube, which is routinely used in critically ill patients. Consequently, NAVA differs substantially from other commercial modes of mechanical ventilation in that it use pneumatic signals (flow, volume and pressure) measured in the respiratory circuit to control assist delivery.
The advantages of neural control are that while the pneumatic signals controlling the ventilator are dampened by airway resistance, reduced lung compliance, intrinsic PEEP and weakened inspiratory muscles, control of the ventilator’s assist with the diaphragm electrical activity is not affected. Leaks in the respiratory circuit impair the control of assist delivery in conventional pneumatically-controlled modes, but leaks do not affect the diaphragm electrical activity and do not introduce any errors into the control of assist during NAVA.
The clinical advantage of NAVA to better synchronise the assist with patient inspiratory effort than conventional modes has been unanimously documented in patients of all age groups [4,5,6,7,8]. Since NAVA is directly influenced by respiratory reflexes from receptors of the entire respiratory system, the assist is modulated (by the respiratory drive) to automatically attain adequate blood gases  and to prevent excessive assist levels which would be injurious to the lung [4,10,11]. NAVA improves assist delivery compared to pressure support ventilation [4,5,6,12,13,14] allowing a more natural breathing pattern .
Monitoring electrical activity
The visualisation and quantification of diaphragm electrical activity during NAVA and during conventional modes introduce new unique features with regard to monitoring. First, monitoring the timing of diaphragm electrical activity in relation to the ventilator’s assist delivery allows detection of patient ventilator asynchrony in conventional modes. Second, the magnitude of the diaphragm electrical activity provides information about how much the neural respiratory drive is suppressed with increased assist levels, thus preventing excessive assist delivery in critically ill patients. The latter is associated with diaphragm atrophy and weakness and could delay weaning from mechanical ventilation.
The most recent development in NAVA is the introduction of the technology for non-invasive ventilation. Conventionally the intervention in acute respiratory failure has been to apply positive pressure that is used to assist respiration via an intrusive airway interface (endotracheal tube). Although invasive mechanical ventilation via the endotracheal tube protects the airway and allows better control of assist delivery, it is not without complications. Non-invasive ventilation, allowing more natural breathing, is gaining in popularity but its application is frequently limited by problems of adequately synchronising assist to breathing efforts  due to e.g. leaks in the interface between the patient and the ventilator circuit. In fact, there is a "catch 22" situation, where tighter fitting of the non-invasive interface over the face, which reduces the leak, increases development of pressure sores in the patient’s facial tissue.
As mentioned above, neural control of the ventilator’s assist using the diaphragm electrical activity overcomes the problems induced by leaks with conventional modes of ventilation using pneumatic sensors. Thus, during NAVA a leak will not affect the patient-ventilator synchrony regardless of its magnitude, and the appropriate assist will still be delivered as long as the magnitude of the leak can be compensated for by the servo-system, which continuously regulates flow to maintain the targeted assist level.
Clinical evidence of non-invasive delivery with NAVA was obtained by demonstrating synchronised assist and sufficient ventilation during non-invasive ventilation with a single nasal prong in premature babies of low birth weight . In fact, the leak associated with a single nasal prong (i.e. from the other nostril and mouth) is of a magnitude where pneumatic control (i.e. triggering and termination) of the ventilator’s assist cannot be relied upon. Because the respiratory rates in premature babies are high and irregular (40-50 breaths per minute) and tidal volumes are very small (3-4 mL), synchronising the assist and breathing effort during non-invasive ventilation in premature babies with a large leak represents the ultimate challenge and the success using NAVA has extended the limits of non-invasive ventilatory assist.
Overcoming the challenge of upper airway interference
Another challenge of non-invasive ventilation is that removing the endotracheal tube exposes the ventilatory assist delivery to interference from the upper airways. The upper airways constitute a crossroad between air and food passages controlled via a complex neural network with the aim of coordinating respiration with e.g. swallowing, speech, cough and vomiting such that no food or other substances aiming for the oesophagus enters the trachea, that no gastric content leaves the oesophagus, and that no air enters into the stomach. Apart from issues of leaks and interface, one common complication of non-invasive ventilation is air passing into the stomach, so-called gastric insufflation, which could lead to severe complications in newborns. It is suggested that gastric insufflation is caused by high pressures of assist but it is likely that it is also linked to poor synchrony of assist. As the act of swallowing occurs during a period of apnea, when the glottis is closed, and is typically followed by an expiration, no diaphragmatic activity occurs during swallowing. Hence, no assist delivery can occur during NAVA since the presence of diaphragm electrical activity is required for the breath to be delivered.
In contrast, a mode of ventilatory assist that terminates assist based on either pneumatic signals or by time criteria can also continue to deliver assist during swallowing. Since the upper oesophageal sphincter pressure (protecting reflux) is relaxed, little pressure should be required for air to enter into the food passage. An important feature of the upper airways is that they are synchronised to breathing and that the glottis and the upper airway passage widens during every inspiration. Delivery of assist in synchrony with the neural inspiration should thus result in a less resistive load. During exhalation, the glottis and upper airways can narrow and restrict flow, a function believed to be linked to maintained lung recruitment. Hence, asynchronous delivery of assist during the exhalation phase is unlikely to be favourable in terms of efficient assist delivery. The most efficient non-invasive assist delivery should hence occur when inspiratory muscles are active, such that the lowest possible pressure is required to inflate the lungs with the least interference of the upper airways. Cough is a complex three step activity initiated by 1) an inspiration, which when interrupted is followed by 2) an expiratory pressure generation against a closed glottis, and 3) opening of the glottis. The diaphragm is only active during the first two steps such that coughing is probably facilitated by NAVA, whereas a mode using a pneumatic controller or timer to terminate assist probably also delivers assist during the 3rd step and interferes with coughing. Another factor during non-invasive ventilation is that the patient actually has the ability to speak. Speech is a voluntary activity associated with rather arrhythmic contractions of the diaphragm. Due to its close neural integration, NAVA is not likely to interfere with speech, whereas a conventional mode using a pneumatic controller or timer to terminate assist introduces problems with timing of assist in synchrony with speech.
In summary, new developments in mechanical ventilation introducing neural control of assist delivery improve the quality of monitoring and assist delivery and open up great opportunities for extending ventilatory care in critically ill patients into previously untouched areas.
1. Petit JM, Milic-Emili G, Delhez L. J Appl Physiol 1960; 15:1101-6.
2. Agostoni E, Sant’Ambrogio, Del Portillo Carrasco H. J Appl Physiol 1960; 15:1093-7.
3. Sinderby C, Navalesi P, Beck J et al. Nat Med 1999; 5:1433-6.
4. Colombo D, Cammarota G, Bergamaschi V et al. Intensive Care Med 2008. 34:2010-18.
5. Spahija J, De Marchie M, Albert M et al. Crit Care Med 2010; 38:518-26
6. Piquilloud L, Vignaux L, Bialais E et al. Intensive Care Med 2011; 37:263-71.
7. Beck J, Reilly M, Grasselli G et al. Pediatr Res 2009; 65:663-8.
8. Alander M, Peltoniemi O, Pokka T et al. Pediatr Pulmonol 2011 Aug 9. doi: 10.1002/ppul.21519. [Epub ahead of print]
9. Karagiannidis C, Lubnow M, Philipp A et al. AIntensive Care Med 2010; 36:2038-44
10. Brander L, Leong-Poi H, Beck J et al. Chest 2009; 135:695-703
11. Sinderby C, Beck J, Spahija J et al. Chest 2007; 131:711-17
12. Coisel Y, Chanques G, Jung B et al. Anesthesiology. 2010; 113:925-35.
13. Breatnach C, Conlon NP, Stack M et al. Pediatr Crit Care Med 2010; 11:7-11
14. Terzi N, Pelieu I, Guittet L et al. Crit Care Med 2010; 38:1830-37.
15. Schmidt M, Demoule A, Cracco C et al. Anesthesiology 2010; 112:670-81.
16. Vignaux L, Tassaux D, Carteaux G et al. Intensive Care Med 2010; 36:2053-9.
Dr. Christer Sinderby, PhD1,2 and
Dr. Jennifer Beck, PhD1,3
1 Keenan Research Centre in the Li Ka Shing Knowledge Institute of St. Michael’s Hospital
6th floor, room 611
209 Victoria Street
Canada. M5B 1T8
30 Bond St
Canada M5B 1W8
2 Department of Critical Care Medicine, St-Michael’s Hospital
Department of Medicine
University of Toronto, Canada
Tel. +1 416 880-7507
3 Department of Pediatrics
University of Toronto
Tel. +1 416 880 3664