Negative-Pressure Ventilation in the Pediatric ICU

Abstract

Negative-pressure ventilation (NPV) is a form of noninvasive ventilation that has been recently utilized in pediatric acute respiratory failure. Negative-pressure ventilators apply negative pressure onto the chest wall via a cuirass to recruit areas of atelectasis. Continuous negative extrathoracic pressure, the most common mode, is similar to CPAP, where negative pressure is maintained at a constant level throughout the respiratory cycle while patients initiate their own breaths and continue to breathe spontaneously throughout. Control mode, which is similar to bi-level positive airway pressure, alternates negative pressure with positive pressure and controls both phases of breathing at a mandatory frequency set higher than the patient’s spontaneous frequency. Supplemental oxygen is provided through a nasal cannula or face mask due of the lack of NPV devices’ interface with the mouth or nose. NPV can improve preload to the heart and cardiac output (CO) in patients with restrictive right-ventricular physiology requiring CO augmentation and those with Fontan physiology. The purpose of this article is to review the physiological principles of spontaneous and NPV, examine the evidence supporting the use of NPV, give practical and meaningful guidance on its clinical application in the pediatric ICU, and summarize areas for future studies on its uses.

Introduction

Physiologic breathing is an autonomic, unconscious process that takes very little thought or energy until it becomes insufficient during times of stress, such as during vigorous exercise or acute respiratory illness. In these instances, large amounts of energy are expended to ensure adequate gas exchange. This process requires the interplay of many complex components, including the central nervous system, the extrathoracic airways, the tracheobronchial tree, the chest wall, and the intrathoracic cavity.¹ In normal spontaneous breathing, gas movement is the result of negative-pressure change in the pleural space from respiratory muscle contraction. This creates a pressure gradient that results in gas flow into the lungs and exhalation is passive. Patients with acute respiratory failure are usually treated with positive-pressure ventilation (PPV) but can also be treated with negative pressure ventilation (NPV).

NPV utilizes the basic physiologic principles of spontaneous breathing to assist in noninvasive ventilation (NIV) through the cuirass system. NPV has been used for centuries, dating back to ancient times when the principles of creating a vacuum to assist breathing were first observed.² Over time, advancements in medicine and technology have led to the development of more sophisticated NPV techniques, from the iron lung of the early 20th century to modern negative-pressure ventilators used in critical care settings.² The aims of this review are to explore the history of assisted ventilation and NPV, review the physiological principles of spontaneous and NPV, examine the evidence supporting the use of NPV, give practical and meaningful guidance on its clinical application in the pediatric ICU (PICU), and summarize areas for future studies on its uses.

History of NPV

NPV has roots in the earliest documented forms of assisted ventilation. The first known negative-pressure ventilator was developed by John Mayow in 1673, who used bellows and a bladder to replicate the mechanics of the respiratory muscles.^2,3 The concept of widely used NPV was born out of the polio epidemic, with several iterations of negative-pressure ventilators in use from the 1920s to the 1950s.⁴ The Drinker respirator, or the original “iron lung,” became the predominant ventilator for the early part of the polio epidemic;² with the widespread availability of electricity, tank farms (which is a term used to describe dedicated units for patients with polio where care was centralized into one room that made it more efficient to care for the large numbers of patients) spread around the country as the epidemic raged. A competing negative-pressure ventilator was created in the 1931 by John Haven Emerson, an engineer, who created a more functional ventilator at cheaper costs using vacuum motors as the base for the design.² Throughout the 1940s and 1950s, as the polio epidemic raged on, newer and smaller versions of negative pressure developed including models that could be worn with chest plates, or cuirasses, that became the basis for today’s negative-pressure ventilators.^2,5

Physiology of NPV

Normal Spontaneous Ventilation

All physiological breathing is negative-pressure respiration. This is accomplished in large part by the diaphragm and the respiratory muscles contracting creating more negative pressure intrathoracically. Boyle law is fundamental to the mechanics of breathing such that within a system there is an inverse relationship between volume and pressure. As pressure decreases in the system, volume increases, and vice versa.⁶

The action of air flow into the lungs is dependent on the force of the respiratory muscles to overcome the elastic, flow-resistive, and inertial properties of the respiratory system.⁶ The most important muscle for spontaneous negative-pressure respiration is the diaphragm. The shape of the diaphragm in relaxation lends itself to this form of breathing. During inspiration, the diaphragm contracts and descends, increasing the vertical dimension of the chest cavity. Simultaneously, the diaphragm pushes the ribs outward, increasing the width of the chest wall. This motion is assisted by the external intercostal muscles of the ribs, which during inspiration contract and raise the ribs upward and outward, also aiding in the expansion of the chest cavity.¹ This increase in volume results in a decrease in intrathoracic pressure, creating a pressure gradient that allows air to flow from higher-pressure areas in the atmosphere into the lower-pressure area within the lungs. During expiration, the diaphragm and intercostal muscles relax, allowing the thoracic cavity to return to its resting volume. This decrease in volume results in an increase in intrathoracic pressure, creating a pressure gradient that allows air to flow out of the lungs and into the atmosphere.⁶ Mechanical ventilation alters these pressure differentials using external work applied to the respiratory system to assist in ventilation.

More succinctly, the flow of air into the respiratory system is dependent on pressure differentials applied to the system.⁶ The flow of air into the system occurs when the alveolar pressure becomes more negative than the pressure at the mouth (atmospheric) and air flows into the lungs. At the beginning of inspiration, the pressure in the respiratory system starts at atmospheric to a little positive (0–3 cm H₂O); and as inspiration continues, the pressure becomes more negative (−10 to 15 cm H₂O); and flow increases until inspiration ends and passive exhalation begins, driving the pressure less negative, and flow out of the system decreases until it is back at rest (0–3 cm H₂O).⁶

Noninvasive Ventilation

PPV operates in the opposite manner of spontaneous breathing. Pressure is applied to the airways, raising the airway pressure above the intrapleural pressure, and air flows into the lungs. Then through the use of breath cycling, flow ceases, and the lungs passively exhale using the normal physiologic mechanisms of ventilation back to atmospheric pressure, and the breath cycle begins again.

NIV has many uses in the pediatric population, helping reduce the work of breathing (WOB) across the spectrum of pathophysiology from neuromuscular disease to restrictive and obstructive processes.⁷ During CPAP, constant positive pressure is maintained throughout the respiratory cycle while the patient breathes spontaneously. CPAP recruits collapsed alveolar units and increases functional residual capacity (FRC) and lung compliance, improving oxygenation and the WOB.⁸

In bi-level positive airway pressure (BPAP) mode, clinicians set both an inspiratory positive airway pressure, an expiratory positive airway pressure, an inspiratory time, a rate, and the F_IO2. The difference between these 2 pressures helps in augmenting the tidal volume (V_T). This mode can increase mean airway pressure, improve oxygenation, increase ventilation, and unload fatigued respiratory muscles by increasing V_T. BPAP has been shown to be an effective NIV strategy for both hypoxic and hypercarbic respiratory failure.⁹

Negative-Pressure Noninvasive Ventilation

The concept of noninvasive NPV was born from the earlier models of NPV. As described above, the predominant assisted-ventilation strategy throughout the 19th and 20th centuries was NPV until advancements in PPV and endotracheal intubation gave way to its predominant use.⁹ New developments in NPV have renewed interest in its use as an alternative to PPV, particularly given the known complications of prolonged invasive mechanical ventilation in terms of airway complications such as endotracheal tube (ETT) displacement, vocal cord injury, ETT obstruction and incorrect placement, and subglottic stenosis. Additional challenges related to both invasive and noninvasive ventilation include poorly fitting interface, risk of barotrauma, patient discomfort,⁸ difficulty providing adequate nutrition, adverse cardiopulmonary interactions with decreased venous return, and compromised right-ventricular preload.¹⁰

Current negative-pressure ventilators make use of the chest shells, cuirasses, that are placed on the anterior chest wall to deliver continuous or biphasic negative pressure. During inspiration, the negative-pressure ventilator creates sub-atmospheric pressure (more negative) to mimic physiologic breathing, which allows for air flow into the lungs.⁹ Unlike physiologic breathing, exhalation is active, with the NPV device creating positive intra-alveolar pressure and air flow out of the lungs.^9,11

NPV may improve CO by lowering intrathoracic pressure and increasing right-ventricular preload. It also improves alveolar recruitment and increases FRC, which decreases pulmonary vascular resistance and right-ventricle afterload, thereby increasing pulmonary blood flow.¹¹ NPV may be an advantageous modality in patients with right-sided heart failure, passive pulmonary circulation (Fontan or Glenn physiology), and those with right-heart restrictive physiology to increase pulmonary blood flow and improve CO.^10,12,13

Settings and Technical Considerations

NPV is delivered using a unique type of ventilator. The Biphasic Cuirass Ventilator (BCV) (Hayek RTX Ventilator, Hayek Medical, London, United Kingdom)¹⁴ is cleared by the FDA as an external negative-pressure ventilator to support patients in need. It currently is the only commercially available device in the market.

Fitting of the Chest Cuirass

The cuirass shells come in 7 sizes for pediatric patients and 5 sizes for adults. Each cuirass has a corresponding foam seal, along with straps for the shell. Also needed are the cuirass pressure tubing and airway-pressure sensor tubing (Fig. 1). Wide-bore tubing connects from the cuirass to the ventilator (using a pediatric adapter for smaller pediatric circuit). All pieces are designed for single-patient use except for the shell that will be cleaned according to institution protocols. Using the sizing grids provided by the manufacturer gives a good starting point for what size cuirass to choose. Clinicians will consider the patient’s size and shape of the chest, then choose the largest cuirass possible to achieve the greatest therapeutic effect. It is important to place the cuirass over a patient gown or t-shirt rather than the skin directly to avoid hypothermia and skin bruising. The air flow used in creating the negative pressure within the cuirass can be cool to the patient, so a hospital gown made of cotton is used underneath the cuirass (Fig. 2). As long as the seal is maintained, the therapeutic effect will not be compromised.

Fig. 1.

Components of the commercially available negative-pressure ventilator. BCV = Biphasic Cuirass Ventilator; RTX = Hayek RTX Ventilator.

Fig. 2.

Photograph of the cuirass in place on a simulated patient.

It is worth noting that NPV is not an oxygen-delivering modality; patients on NPV will receive supplemental oxygen via low-flow nasal cannula, high-flow nasal cannula (HFNC), or face mask to keep their S_pO2 within the targeted range. As such, high F_IO2 requirements or persistent hypoxemia with the supplemental oxygen methods listed above may be a rate-limiting step in using NPV.

Modes

The BCV has 2 types of modes: ventilation modes and a secretion clearance mode. There are 4 ventilation modes: (1) continuous negative extrathoracic pressure (CNEP) mode, (2) control mode, (3) respiratory synchronized mode, and (4) respiratory triggered mode. CNEP is usually chosen as the initial support mode in patients undergoing NPV. CNEP works by recruitment of alveoli and improvement in ventilation/perfusion matching. Negative extrathoracic pressure of any sort provides a distending pressure on both airways and alveoli by increasing the transpulmonary pressure gradient.

CNEP is the NPV mode akin to CPAP. While using CNEP mode, the surface of the chest wall is exposed to sub-atmospheric (negative) pressures. This negative pressure is maintained at a constant level throughout the respiratory cycle while patients continue to breathe spontaneously throughout. The constant negative pressure leads to alveolar recruitment, FRC optimization, increased alveolar capillary perfusion, small airway dilation, and improvement in WOB.

When initiating CNEP, the only pressure to set up is the CNEP pressure, which is always a negative number (Fig. 3). The minimum CNEP support is −8 cm H₂O. A CNEP pressure of −14 cm H₂O at initiation is reasonable and provides a sufficient support for patients with acute respiratory failure. This usually is adjusted, mainly increased to a more negative number (eg, −18 cm H₂O) within the first few minutes of initiation. Support can be escalated to more negative pressures by increments of 2 (eg, −24 cm H₂O) as needed throughout the hospitalization course. Pressure as negative as −30 cm H₂O can be used before escalation to control mode or other forms of respiratory support.

Fig. 3.

Graph of pressure delivery in continuous negative extrathoracic pressure mode. This mode is akin to CPAP. CNEP = continuous negative extrathoracic pressure.

Control mode is the other commonly used NPV mode. When initiating the control mode, inspiratory pressure and expiratory pressure are set up in negative and positive numbers, respectively, while maintaining inspiratory to expiratory pressures as a 3:1 ratio (eg, −18, +6 cm H₂O). The “driving pressure,” which is the mathematical difference between inspiratory (I) and expiratory (E) pressures, determines the chest-wall excursion and, ultimately, the V_T. The I-E ratio is usually set at 1:1 but can be changed. The ventilator mandatory rate is set slightly above the patient’s breathing frequency but preferably not to exceed 60 breaths/min (eg, set ventilator rate at 38 breaths/min if patient breathing frequency is 36 breaths/min) (Fig. 4). This mode is akin to BPAP in PPV. Control mode delivers these pressures at a mandatory frequency set greater than the patients’ spontaneous breathing frequency and cannot synchronize with patients’ efforts.

Fig. 4.

Graph of pressure delivery in continuous negative extrathoracic pressure mode. This mode is akin to bi-level ventilation.

The control mode is typically initiated as an escalation from the CNEP mode in patients with acute respiratory failure secondary to lower respiratory tract infection (LRTI) such as bronchiolitis or pneumonia. It can be the initial mode of support in patients who are not able to initiate their own breaths effectively such as patients with neuromuscular disease and hypotonia. Table 1 shows a comparison between CNEP and control modes.

Table 1.

Comparison of Continuous Negative Extrathoracic Pressure and Control Modes

Respiratory triggered and respiratory synchronized are additional modes that are not commonly used. In the respiratory synchronized mode, breathing is fully synchronized to the patient’s own respiration, automatically adjusting the frequency and shape of breathing in line with the natural breathing adjustments being made by the patients themselves.

The patient’s inspiratory effort creates an initial trigger (ie, triggered inspiratory), which is followed by a further trigger effected by the initial expiratory effort (triggered expiratory). The trigger can be either through the airway or through the cuirass. I-E ratio will be calculated and displayed. This mode will enable patients to receive support both at their own rate and also to determine the shape of the wave forms that supply the support based on the duration and intensity of effort.

Respiratory triggered mode provides triggered ventilation, with the respiratory cycle triggered by the patient’s actual respiratory requirements. Frequency is determined by the patient’s breathing frequency or by the minimum frequency (6 breaths/min) set by the clinician. The trigger can be either through the cuirass (in cuirass triggered mode) or (in airway triggered mode) through the airway tube placed at or near the patient’s airway (eg, side of the nostril or mouth). Cuirass triggered mode will pick up more vigorous spontaneous breathing, whereas airway triggered mode can be triggered by smaller, more shallow respiratory effort.

As the respiratory cycle is triggered by the patient’s respiration, this allows better adjustment to the patient’s actual requirements. If the patient does not trigger a breath, the ventilator will deliver another cycle. If apnea is detected, a backup rate is initiated.

In addition to the previously mentioned ventilation modes, secretion clearance is the other mode available on the BCV device. Secretion clearance mode consists of 2 modes: vibration and assisted-cough modes. Both are used in sequence with one another. Vibration mode is considered the “chest physiotherapy” tool that enhances secretion mobilization and clearance. It consists of 240−1,200 cycles/min with an average of 800 to encourage clearance of secretions, with frequency decreased as tolerated for more tenacious secretions. Pressures used should be about −15 to −20 cm H₂O for pediatric patients and −20 to −30 cm H₂O for adults. The time for the vibration cycle is set for 3−4 min. For the assisted-cough mode, a huff cough is created by 8–60 cycles/min, using inspiratory pressures of −25 (up to −35) and expiratory pressures of +15 (up to +25) with a high I-E ratio of 4:1–6:1, using 20–40 cycles/min if patient is more comfortable or if a better effect is achieved. The patient can be coached to coordinate their effort with that of the device. The assisted cough should last for approximately 2 min. Completion of both modes (vibration and assisted cough) represents one cycle of secretion clearance mode. Each secretion clearance session lasts between 30–60 min with a minimum of 20 min. Figure 5 is a suggested algorithm to provide guidelines for clinician on how to initiate NPV for eligible patients.

Fig. 5.

Algorithm for negative pressure ventilation initiation and titration. EKG = electrocardiogram; CNEP = continuous negative extrathoracic pressure; PPV = positive-pressure ventilation; V̇/Q̇ = ventilation/perfusion; WOB = work of breathing; ENT = ear, nose, and throat; CO = cardiac output; P_aw = mean airway pressure; P_plat = plateau pressure. NPV = negative pressure ventilation

Studies of NPV in the Pediatric ICU

Clinical Studies in the Pediatric ICU

Bronchiolitis/respiratory failure/ARDS.

Like many areas in pediatrics, to date, there remains a relative deficit of data relating to the use of NPV in pediatric ARDS and bronchiolitis. In 1996, Samuels et al¹⁵ performed a prospective randomized controlled trial (RCT) in 244 neonates^7,13 where subjects were randomized to NPV and standard therapy (CPAP) for respiratory distress. In the study, the treatment group received CNEP of −24 to −26 cm H₂O in comparison with CPAP of 4 cm H₂O for the standard-of-care group. It is worth noting that the support used with CNEP was significantly higher and disproportionate to the CPAP group. Subjects in the NPV group also were shown to need oxygen therapy for fewer days compared with the control group (18.3 d vs 33.6 d, respectively).⁹ In a retrospective study of 2 PICUs, Al-Balkhi et al¹⁶ investigated the use of NPV versus PPV to reduce the rate of intubation in subjects with recurrent apnea secondary to bronchiolitis. In this study, the center that utilized NPV had lower rates of intubation and decreased PICU stay. In a commentary on this study, Henderson¹⁷ concedes that NIV (of all modalities) offers a potential advantage to avoid intubation in infants with bronchiolitis-associated apnea, but the easy availability of CPAP and BPAP may make NPV a less likely modality in most PICUs and calls for more RCTs to be done.

A recent Cochrane review found a decreased hospital stay and a decreased need for intubation in children who used NPV for acute respiratory failure.^9,18 In their review, there was one prospective case control study by Hartman^18,19 in which 33 children with bronchiolitis were studied, half in the control group and half in the NPV group. In the NPV group, there was reduction in the F_IO2 requirements within 1 h of initiation of NPV compared to the control group, and no subjects in the NPV group required intubation.¹⁸ In 2017, there was a large retrospective single-center study that looked at the use of NPV in 233 pediatric subjects with acute respiratory failure.^9,20 Viral bronchiolitis was the most common diagnosis (70% of the cases). Of those subjects, 163 (70%) had resolution of their acute respiratory failure while on NPV, while 63 subjects on NPV had to change to PPV modalities for respiratory support, including intubation. The authors reported a 28% reduction in the rate of intubation in these subjects across the 3-y study period in comparison to the 3 y prior.²⁰ Similarly, a case series demonstrated an improvement in clinical course and decrease for invasive ventilation in infants with acute respiratory failure.²¹ In subjects with cystic fibrosis (CF) and bronchiolitis who were not responding to maximal medical therapy, a small case series²² reported on the use of NPV to help avoid intubation or tracheostomy, and 2 of the cases showed improved compliance. Of note, the most recent Pediatric Acute Lung Injury Consensus Conference guidelines recommend a timed trial of NIV prior to intubation for pediatric ARDS (clinical recommendation), though they did not list NPV specifically in their data collection.

Neuromuscular disease.

NPV may be particularly useful in patients with chest-wall weakness either from neuromuscular disease or from prolonged mechanical ventilation. In preliminary adult studies, intermittent NPV has been shown to improve respiratory mechanics in subjects with progressive neuromuscular disease.² A review of NPV use for neuromuscular disorders²³ describes the lack of RCTs on the topic but that anecdotally subjects have seen improved quality of life, normalized blood gases, improved physical activity, and improved hemodynamics.²³ Splaingard et al²⁴ described home NPV use in subjects with neuromuscular disorders over a period of 20 y and the benefit of using NPV at night as an adjunctive measure to improve respiratory mechanics and rest respiratory muscles.

Central hypoventilation.

In central hypoventilation syndrome, children lack respiratory drive during sleep and are often mechanical ventilated via tracheostomy overnight. Hartmann et al²⁵ observed 9 children with central hypoventilation syndrome and their respiratory support at home over time. Seven subjects were successfully started on NPV while asleep at home and never progressed to needing tracheostomy. These subjects also were able to stay out of the hospital and when admitted did not stay longer than children with central hypoventilation syndrome who were managed with PPV or were mechanically ventilated.²⁵ Linton,²⁶ in a review of case series, discussed 2 subjects who he was able to convert from PPV via tracheostomy to only needing NPV at night, and the tracheostomy was ultimately closed.¹²

Cardiac surgery and heart failure.

The benefits of NPV on cardiac physiology, particularly the lowering of intrathoracic pressure and increasing venous return to the heart, make it potentially advantageous in certain cardiac patient populations. Additionally, NPV helps reduce right-ventricle afterload and decreases pulmonary vascular resistance by improving alveolar recruitment and FRC optimization.^9,10,27 In 2006, Shime et al¹³ studied 18 subjects divided into 2 groups after cardiac surgery, those who had undergone right heart bypass (group A) and those who had other types of cardiac surgery (group B), and applied continuous NPV to these subjects after weaning from PPV. Both groups saw significant changes in hemodynamic markers of CO including improved urine output and decreased central venous pressure. Similarly, Shekerdemian et al^10,27 demonstrated in one case series the effect of NPV on CO in the early postoperative period in 11 children who had undergone right heart surgery (eg, tetralogy of Fallot repair, Fontan surgery). Using the Fick method, the addition of NPV to PPV showed a statistically significant improvement in CO in these children. The addition of NPV also demonstrated significant improvements in stroke volume, mixed venous saturations, and pulmonary vascular resistance. In a subsequent study, looking specifically at subjects who had undergone tetralogy of Fallot repair, Shekerdemian et al²⁸ added NPV to 23 intubated children for either a short period, 15 min, or a longer period, 45 min, respectively. All subjects had improvements in pulmonary blood flow, and the greatest improvement was seen in those subjects who had undergone tetralogy of Fallot repair.

A case report from Deshpande et al²⁹ demonstrated improvement in the passive diastolic pulmonary blood flow through the Kawashima circuit (direct hemiazygos to left pulmonary artery connection and extracardiac hepatopulmonary connection to the right pulmonary artery completing total cavopulmonary connection in single-ventricle physiology) in a 9 month old subject through the addition of NPV to their mechanical ventilation. The subject was subsequently able to be weaned to extubation and discharged home. In a subsequent review of the effects of NPV on single-ventricle physiology, Deshpande and Maher³⁰ reviewed the physiological effects of NPV on the unique cardiopulmonary interactions seen in subjects who depend on passive diastolic blood flow to the lungs. They posit that the long-term use of NPV may effectively “rescue” the patient with failing Fontan physiology by improved pulmonary blood flow to the Fontan circuit that leads to decrease Fontan pressures, hepatic vein wedge pressure, and hepatic congestion. This results in improvement in hepatic function, decreased formation of ascites, and peripheral edema. Improving pulmonary flow stabilizes and even improves oxygen saturation and CO. To date, there have been no studies on the long-term use of NPV in this population of patients.

Animal Studies of NPV

In a study using anesthetized, surfactant-depleted rabbits, Grasso et al³¹ hypothesized that NPV would results in improved oxygenation and decreased lung injury in comparison to PPV due to its delivery globally to the thorax and abdomen compared to delivery to the airways in PPV. In the study, rabbits were ventilated in pairs (NPV with PPV) for 2.5 h, with matching V_T (12 mL/kg), F_IO2 1.0, and normocapnia was maintained using breathing frequency. They demonstrated several important findings. First, that for a given end-expiratory lung volume, NPV showed statistically significant improved oxygenation, P_aO2, and a decreased P_aCO2–end-tidal carbon dioxide gradient, which reflects less dead-space ventilation. Second, that perfusion (global and local) was not different between the 2 modalities, so the above findings could not be explained due to differences in perfusion alone. Lastly, the differences in the effects of PPV and NPV on end-expiratory lung volume may be due to the more even distribution of pressure applied to the system by NPV leading to lower transpulmonary pressure, increased thoracic pressure, leading to more compliant lungs and improved aeration.

In a recent study, Sattari et al³² demonstrated similar findings to Grasso using ex vivo porcine lungs and a high-speed, high-resolution camera to capture global and regional characteristics of the lungs as they were ventilated with PPV or NPV. The lungs were subjected to paired inflation-deflation cycles with matched total lung volumes and transpulmonary pressures. Despite these matched metrics, the mechanical characteristics between NPV and PPV were not the same. NPV demonstrated smoother pressure-volume curves, less hysteresis, and more homogenous tissue inflation. An editorial on the work,³³ focused on the differences between ex vivo healthy lungs and impaired or injured lungs in clinical practice that will demonstrate more mechanical and biological heterogeneity but praised the work for its novel physiologic methods and in demonstrating possible new avenues for lung protection in clinical practice.

Recommendations for Clinical Practice

NPV is used in pediatric respiratory failure to provide noninvasive respiratory support for children with a variety of underlying respiratory conditions including LRTI (eg, bronchiolitis, pneumonia), other forms of acute lower respiratory tract diseases (eg, atelectasis, pulmonary edema, acute chest syndrome), and status asthmaticus²⁰ (Table 2). Acute respiratory failure secondary to viral bronchiolitis is a common indication of NPV as an escalation modality of support from HFNC.²⁰ CNEP mode is the most commonly used mode at initiation with pressures −14 to −18 cm H₂O on average.

Table 2.

Proposed Indications for NPV Indications of NPV

The support is escalated, and pressures are adjusted to more negative number in increments of 2 cm H₂O if worsening respiratory status. CNEP pressures of −20 to −24 cm H₂O (up to −30 cm H₂O) are used throughout the course of respiratory support.

As mentioned earlier, control mode is used when CNEP mode is deemed inadequate, and escalation of respiratory support is warranted. Inspiratory and expiratory pressures of −21 cm H₂O and +7 cm H₂O, respectively; I-E ratio of 1:1; and breathing frequency of 60 are suggested initial settings (especially if CNEP pressure is −24 cm H₂O before conversion to control mode). Pressures up to −30 cm H₂O and +10 cm H₂O can be used before escalation to intubation and invasive mechanical ventilation (Table).

Children with neuromuscular disease who are presenting to the PICU with acute respiratory failure may also benefit from NPV. NIV has been the standard of care for children and adults with chronic respiratory failure associated with neuromuscular disease, including Duchenne muscular dystrophy and spinal muscular atrophy. As a clinical observation, NPV has been successfully used to support this patient population as a rescue in acute respiratory failure. NPV can be used either concomitantly with NIV (eg, BPAP) or by itself instead of NIV with additional supplemental oxygen via low flow or HFNC. A crucial benefit to patients with neuromuscular illness in respiratory failure receiving NPV is the advantage of using the secretion clearance mode (combination of vibration and cough modes) of the BCV ventilator. This allows frequent secretion clearance with the available vibration and cough modes without separating the ventilator from the patient.

As with NIV, we recommend early application of NPV in patients with neuromuscular diseases who are presenting with acute respiratory failure.

Patients with CF may also benefit from NPV.³⁴ NIV has been commonly used to support patient with CF-related acute and chronic respiratory failure. NPV has the potential application in patients with CF who are presenting to ICU with exacerbation of chronic respiratory insufficiency. Its noninvasive nature and ability to improve respiratory function and airway clearance make it a valuable tool in the management of CF-related lung disease. Both CNEP and control modes can be used according to patients’ respiratory status and previous respiratory support used. NPV can be used in tandem with BPAP to provide further recruitment. The secretion clearance mode is of a great benefit to patients with CF, and it can be solely utilized without the use of the ventilation modes of NPV, CNEP, and control modes. It is worth noting that the first patient to use NPV in the United States via the BCV was a patient with CF who suffered from acute respiratory failure secondary to bacterial pneumonia complicated by recurrent pneumothoraces while receiving NIV.

In patients with air leak (eg, pneumothorax, bronchopleural fistula), NPV use is beneficial and will allow lungs to heal while avoiding or minimizing PPV. This protective capability can be used as an adjunct to PPV (either invasive or noninvasive) to attenuate the delivered positive pressure while depending more on NPV devices for lung recruitment, maintaining FRC, and ventilation while minimizing risk of air-leak progression and allowing lung healing.³⁵

Nocturnal and home use of NIV is common in patients with chronic respiratory insufficiency secondary to various conditions, including restrictive lung disease, neuromuscular diseases (eg, spinal muscular atrophy, muscular dystrophies, poliomyelitis, nemaline myopathy), and CF. Despite lack of evidence to support NPV use in chronic respiratory insufficiency, unpublished data, at our previous institution, discovered successful use of NPV in children with neuromuscular disorders. Patients with spinal muscular atrophy and CF reported successful nocturnal use of NPV replacing NIV (ie, BPAP). Additionally, it has been used as a rescue therapy in case of acute respiratory illness. It has the potential to provide long-term respiratory support and improve quality of life. This is particularly relevant in children with progressive neuromuscular disorders such as spinal muscular atrophy, where early initiation of noninvasive respiratory support can delay the need for invasive ventilation.

Use of Other Respiratory Support While on NPV

Once a patient has been stabilized on NPV, it is reasonable to start weaning other respiratory support modalities (most likely to be HFNC). Once patient has one or 2 stable respiratory assessments, the flow of HFNC can be weaned rapidly, and F_IO2 is titrated to maintain S_pO2 92–97%.

Weaning NPV

Once patient respiratory status and serial respiratory assessments show improvement, NPV support can be weaned. While on CNEP mode, negative pressure can be weaned by increments of 2 cm H₂O every 4–6 h after each respiratory assessment. Once CNEP pressures reach −8 cm H₂O, the next step is to wean off the ventilator and take the cuirass off the patient’s chest. In control mode, the inspiratory pressure is the main weaning setting. Similar to CNEP, the weaning starts by reducing the negative inspiratory pressure in increments of 2 while maintaining the 3:1 ratio of the inspiratory and expiratory (eg, weaning control mode of −24/+8 cm H₂O to −22/+7, then to −20/+7 cm H₂O, then −18/+6 cm H₂O, and so on on). Once pressure is −10/+3 cm H₂O, then next step is to wean off the ventilator and take off the cuirass. Ventilator breathing frequency is weaned based on the patient’s breathing frequency during each respiratory assessment and maintain the rate at 2 breaths > the patient’s breathing frequency to a maximum of 60 breaths/min. Another way to wean control mode is to convert to CNEP mode with matching negative pressures (eg, weaning control mode of −24/+8 cm H₂O to CNEP mode with pressure of −24 cm H₂O) then start weaning CNEP pressures as described earlier.

Monitoring

Children requiring NPV support for acute respiratory failure are admitted to an ICU. Continuous monitoring of heart rate, breathing frequency, blood pressure (noninvasive), and pulse oximetry is necessary. Blood gas measurements add further information on gas exchange to help critical care providers guide escalation of therapy as needed. This is especially true for patients on control mode or high settings on the CNEP mode. Blood gas measurements should be assessed at initiation of control mode and serially as clinically necessary, though there is lacking evidence to support specific timing and frequency of blood gas draws. We recommend twice daily blood gases as a routine for these patients on control mode or escalating settings on CNEP mode and as needed based on the clinical course.

Hemodynamic monitoring during NPV is important to help guide fluid management and determine the need to escalate to intubation and mechanical ventilation. Similar to managing patients with other forms of NIV, judicious use of intravenous fluids to maintain appropriate intravascular volume is recommended despite lack of clear evidence guiding fluid management.

As with NIV, one of the main concerns of using NIV (NPV included) is delayed intubation in children whose respiratory compromise is failing to improve. There is no evidence in the literature to suggest when to intervene with intubation and mechanical ventilation in patients supported by NPV, but we recommend that intubation should be considered in patients receiving NIV who do not show clinical improvement or have worsening of the disease process within 6–8 h of NPV implementation.²⁰ Table 3 summarizes the advantages, disadvantages, contraindications and complications of negative pressure ventilation.

Table 3.

Advantages, Disadvantages, Contraindications, and Complications of NPV

Sedation

Sedation is used on several occasions at initiation of NPV and throughout its course of implementation. Dexmedetomidine has been commonly used for critical ill patients who are requiring NIV including NPV support.^20,36 Dexmedetomidine (Precedex) is a selective α₂-adrenergic agonist. It acts centrally in the locus ceruleus (sedation), in the spinal cord (analgesia), and in autonomic ganglia. Dexmedetomidine is ideal to use for these patients because of its minimal respiratory depression and predictable hemodynamic effects. Blood pressure and heart rate may fall slightly because of the reduced sympathetic activity. Doses from 0.1–0.5 μg/kg/h are usually sufficient to provide the needed sedation and analgesia without compromising the respiratory drive and hemodynamics.

Summary and Future Directions

The use of NPV as a modality of NIV respiratory support in pediatric acute respiratory failure has been expanding over the last decade. Its use is also promising in patients with neuromuscular illnesses with chronic respiratory insufficiency and in restrictive right-ventricular physiology following repair of tetralogy of Fallot and those with Fontan physiology.

Despite being the most ancient form of respiratory support known to humans, the paucity of evidence supporting its use is indecipherable. Except for one large single-center case series, most studies have been small case series or case reports without any case/control groups.

Although the impact on outcomes for any of these populations requires further investigation, the ease of use, its safety profile, and the initial promising experiences are encouraging. We believe that NPV has a promising role as an NIV respiratory support in the pediatric ICUs. That being said, further studies are needed to study the potential use and impact of NPV in pediatric population especially those with acute and chronic respiratory failure. Further efforts should focus on 3 main area: (1) studies to understand the physiology of NPV and finding the facts necessary to confirm or deny all the proposed benefits (eg, identifying the intrathoracic pressures while using different modes and pressures of NPV cuirass ventilator, measuring V_T while using control mode, and measuring V_T changes with changing the inspiratory and expiratory pressures in healthy subjects); (2) establish a national data registry where repository is created allowing tens and hundreds of data points to be stored. Having these data available to clinicians and researchers will improve our understanding of NPV and its application. One should remember the establishment of Extracorporeal Life Support Organization (ELSO) database in 1989 after extracorporeal membrane oxygenation (ECMO) became more popular and more clinicians brought this lifesaving technology to their own institutions. The establishment of ELSO was and remains to be one of the most impactful initiatives that led to the widespread of ECMO around the globe, and the ELSO data registry became a source of investigators’ collaboration leading to tens of thousands of publications. Both these areas will pave the road for the third focused area, which is (3) to design meaningful clinical trials, ideally RCT. RCTs are going to be extremely challenging to succeed for several reasons especially if survival rate is chosen as the primary outcome. As in many areas in pediatric critical care research, designing successful clinical trials (either prospective randomized or retrospective database outcome trials) should aim to achieve perceptible outcomes such as PICU and hospital stay, duration of oxygen therapy, avoidance of invasive interventions, improvement in hemodynamic measurements, patients’ comfort, cost reduction, complications rate, and ease of use.