NEONATAL RESPIRATORY FAILURE

RESPIRATION IN ANESTHESIA: PATHOPHYSIOLOGY AND CLINICAL UPDATE

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NEONATAL RESPIRATORY FAILURE Current Ventilator Management Strategies Alison B. Froese, MD, FRCPC

The current challenge in neonatal ventilatory care is to select among proliferating options that include extracorporeal membrane oxygenation (ECMO), highfrequency ventilation (HFV), and partial liquid ventilation (PLV). More and more options in pressure and flow waveforms, triggering sensors, synchronization options, and breath-by-breath pressure, flow, and volume monitoring are available on conventional ventilators. All of these new options offer value over the ventilatory modes of the 1970s and 1980s that were executed without real understanding of the impact of ventilatory pattern on the evolution of the lung injury process. These novel therapies raise both the therapeutic potential and the complexity of neonatal ventilation to new levels. Such developments make it imperative that we as anesthesiologists understand the individual roles, risks, and benefits of these new approaches. IMPORTANT PHYSIOLOGIC CONSIDERATIONS

Several physiologic characteristics of the neonate influence both its vulnerability to respiratory dysfunction and therapeutic management. These include an immature respiratory control system, an unstable functional residual capacity (FRC) and chestwall, the small size of the airways, incomplete alveolarization of lung parenchyma, and immaturity of surfactant production.*, A heightened propensity to apnea complicates ventilatory management. It has been postulated that these apneas represent inadequate summation of afferent stimuli at the medullary respiratory centres, presumably because the den-

From the Departments of Anaesthesia, Physiology, and Pediatrics, Queen’s University, Kingston, Ontario, Canada

ANESTHESIOLOGY CLINICS OF NORTH AMERICA

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dritic arborization that provides the necessary neuronal network connections takes place during the last trimester of fetal development.'" Such apneas are exacerbated by concurrent hypoxemia, hypothermia, rapid eye movement (REM) sleep, and muscle fatigue.'" The neonate also fights a continuous battle to maintain end-expiratory lung volume. In neonates, the lung is relatively stiff and the chest wall extremely compliant. Based on these passive characteristics of lung and chest wall, one would predict the neonate's FRC would be only approximately 15% of total lung capacity (TLC).2These passive mechanical properties indicate that the neonate is predisposed to develop diffuse lung collapse even in the absence of lung disease. In actuality, FRC is maintained at approximately 40% of TLC in the normal neonatea by a variety of active maneuvers, including laryngeal braking,6I maintenance of postinspiratory tone in the muscles of the chest and use of respiratory rates fast enough for the usual expiratory time to be less than the expiratory time constant of the respiratory system. Because FRC is dynamically determined in the neonate through these active mechanisms, successful management at the weaning stages of ventilatory support requires attention to all of these components to optimize FRC and thereby minimize the work of breathing. Fortunately, low levels of nasal continuous positive airway pressure (CPAP) can compensate for inadequacies in all three areas while recovery occurs. The extremely compliant chest wall also impedes the neonate's ability to generate an adequate tidal volume. Any force generated by the respiratory muscles to drop pleural pressure acts in parallel on the lung and chest wall. In the adult, compliances of the lung and chest wall are similar, and about half the force generated by the respiratory muscles expands the lungs while half drives the chest wall. In the full-term neonate, the ratio of chest wall to lung compliance is 41; in premature neonates with normal lungs, it is 6:1.12Superficially, such a compliant chest wall might seem advantageous to reduce the work of breathing. In practice, any such theoretical benefit is outweighed by the problem of chest wall distortion. For any given change of pleural pressure, the premature has six times the chance of sucking in ribs rather than fresh air because motion is determined by the passive properties of the system. This physiologic characteristic can present problems during weaning from ventilator support. Rib cage distortion can inhibit respirati~n?~ increase the work of contribute to muscle and accentuate growth r e t a r d a t i ~ n . ~ ~ This physiologic property has a useful aspect, however. When adjusting ventilator settings to reverse atelectasis and improve lung compliance, one can use the degree of intercostal retraction during the baby's spontaneous unassisted breaths as a guide to the adequacy of lung re-expansion. As atelectasis reverses and compliance improves, the degree of distortion decreases visibly. One can then confirm one's clinical estimate with a chest radiograph. The neonate's small airways also complicate care. The selection of optimal tube size, avoidance of endobronchial intubation, and maintenance of tube patency require careful attention to detail. These anatomic dimensions preclude the application of techniques such as intratracheal O2 insufflation to the very low birth weight premature. Physiologic Impact of Ventilation on Other Organ Systems

Neonatal mechanical ventilation is complicated by the neonate's vulnerability to intracerebral injury. The fragile support of subependymal capillaries, particularly in the premature baby, puts these infants at high risk of developing

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intraventricular hemorrhage (IVH) with possible long-term deficits in cognitive and motor function.%Any event that generates a surge in cerebral perfusion pressure or period of venous congestion puts the neonatal brain at risk for IVH.67Clearly, this means that many activities essential to respiratory care, such as laryngoscopy and endotracheal intubation, suctioning, position changes, and virtually any procedure that can induce the infant to "fight" the ventilator or in some other way perturb cerebral perfusion, carries a modicum of risk. Many current treatment protocols in neonatal units represent attempts to minimize such risks while maintaining necessary respiratory care.34,41, 74 It has become clear, however, that an even greater risk of long-term cerebral dysfunction arises from hypoperfusion of the infant brain. Areas of periventricular leukomalacia (PVL), which represent actual neuronal loss, carry a much higher risk of permanent neurologic deficit than N H per ~ e . 5PVL ~ appears to result from exposure of the developing brain to periods of hypotension, hypoxemia, or the two in combination-that is, a failure of oxygen delivery. One important determinant of cerebral blood flow and therefore oxygen delivery in 51, Several studies the preterm newborn is the arterial COz tension (Paco2).36, have reported an association between hypocarbia and the occurrence of neurodevelopmental deficit^.^, 33*37 Therefore, continuous PcoZmonitoring using transcutaneous electrodes remains an important aid to Pacoz regulation during the acute phases of neonatal lung disease. It is now clear that respiratory failure in the neonate is not an independent risk factor for long-term cerebral deficits. The apparent association of the two conditions is, in fact, secondary to the frequency with which cerebral perfusion and/or oxygen delivery can be deranged during the management of respiratory failure.53 The reactivity of the circulatory system in the immediate postnatal period can lead to severe pulmonary hypertension and persistence of or abrupt reversal to fetal circulatory pathways with massive right-to-left shunting at the level of the ductus or foramen ovale. In this context, a brief period of arterial hypoxemia that may have an undetectable impact on an adult in respiratory failure can, in a neonate, cause reopening of a ductus arteriosus and trigger an acute sustained deterioration that may be difficult to reverse once initiated. This vulnerability to pulmonary hypertension substantially complicates the management of meconium aspiration syndrome, infant respiratory distress syndrome (IRDS), and other conditions. Whereas too little oxygen can exacerbate pulmonary hypertension, too much is hazardous to the immature retina of the premature.= Like Pace?, the target Paoz must be controlled within a rather narrow range. The goals of mechanical ventilation in the neonate are therefore (1) to maintain gas exchange without damage to the lungs, brain, or eyes and (2) to facilitate weaning to respiratory self-sufficiency with a normal growth potential. These goals can only be attained in so far as we succeed in avoiding ventilatorrelated lung injury. To do so, it is not enough just to become familiar with a variety of special techniques such as HFV or ECMO or PLV. It is essential to understand what constitutes the lung-protective features of these various approaches and how to apply them optimally. @

VENTILATOR-RELATED LUNG INJURY CURRENT CONCEPTS

The goal of ventilator management in the 1970s was relatively simple: Minimize the peak pressures applied to the lung in an attempt to prevent the

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development of bronchopulmonary dysplasia. Life is now more complex. We now recognize that both ongoing atelectasis and alveolar overdistention induce progressive lung injury. Therefore, both extremes of lung volume must be avoided while supporting gas transport (Fig. 1). Much of the interinstitutional variance in ventilator management protocols that one encounters today can be traced to variations in the relative weighting given to these two danger zones by the individual practitioner. In general, the hazards of excessive pressurization or distention of lung units are readily accepted in neonatology, where airleak syndromes have been a constant concern for decades. The hazards of ongoing atelectasis are not as widely grasped. However, solid experimental evidence from both adult and premature lungs now indicates that failure to reverse atelectasis depletes endogenous surfactant,26potentiates lung fluid acc~mulation,~~ stimulates neutrophil accumulation and activation in the 1ung44. 76 (Fig. 2), structurally damages the epithelial cells of small airways,56and diminishes the effectiveness of exogenous surfactant the rap^^^,^^ (Fig. 3). These deleterious effects occur even in the absence of overdistention but are accelerated by concurrent exposure to large volume cycles. The first evidence that ongoing atelectasis potentiates the progression of lung injury came from a study using high-frequency oscillatory ventilation (HFO

Figure 1. Pressure-volume (P-V) curve of a moderately diseased lung, showing the danger zones at both extremes of lung volume. The low volume-pressure zone contributes to lung injury in several ways: through the direct trauma of repeated closure and re-expansion of airways and alveoli, by stimulation of the inflammatory response, through the effects of local hypoxemia on the lung, and by the damage generated through compensatory overdistension of remaining lung units as the lung shrinks. The high volume-pressure zone induces injury by potentiating lung fluid accumulation, enchancing surfactant degradation, and causing physical disruption of overstretched tissues. Note that any such singular P-V representation is highly approximate since both overdistension and atelectasis will have heterogeneous distribution patterns. (Reprinted from Froese AB. A reappraisal of highfrequency ventilation in the critical care setting. Current Opinion in Grit Care 2 5 4 , 1996; with permission.)

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Figure 2. Levels of platelet-activatingfactor (PAF), thromboxane B, and 6-keto-prostaglandin F,, (PGF,,) recovered from final lung lavage. Error bars indicate SD. Adult rabbits were surfactant-depleted by lavage and then ventilated for 4 hours using either controlled mechanical ventilation (CMV) at a mean pressure of 15 cm H,O and fraction of inspired oxygen (FIo,) of 1.0, or high-frequency oscillatory ventilation (HFO) at 15 Hz at a mean pressure of 15 cm H,O. HFO was applied either at the same FIO, as CMV (HFO, 100%) or the same arterial oxygen tensions (HFO, 21%) using a strategy designed to achieve optimal aeration of the lung. NS = not significantly different. (From lmai Y, Kawano T, Miyasaka K, et al: Inflammatorychemical mediators during conventional ventilation and during high frequency oscillatory ventilation. Am J Respir Crit Care Med 150:1550, 1994; with permission.)

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Figure 3. Phospholipid recovered from the lavage fluid (A) and lung lamellar bodies (B)of rabbits in whom surfactant deficiency had been induced by repeated lavage and then treated by instillation of bovine lipid extract surfactant. Animals were then randomized to ventilation for 4 hours with HFO or CMV at either a high end-expiratory volume (i.e., atelectasis reversed; PaO, > 350 mm Hg) or low end-expiratory volume (i.e. ongoing atelectasis; PaO, 70 to 100 mm Hg). Phospholipid recovery was significantly better from both lavage fluid and lamellar bodies following ventilation with the high end-expiratory lung volume strategy, particularlywhen small tidal volumes were applied to the re-expandedlung using HFO. HFO = high-frequency oscillatory ventilation. CMV = conventional mechanical ventilation; CC = cage control animals; LC = animals who have been lavaged and then sacrificed; PL = phospholipid; open bar = 0.4 M band; hatched bar = 0.5 M band; horizontal line bar = 0.75 M band. (From Froese AB, McCulloch PR, Sugiura M, et al: Optimizing alveolar expansion prolongs the effectiveness of exogenous surfactant therapy in the adult rabbit. Am Rev Respir Dis 148569, 1993; with permission.)

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or HFOV) in the surfactant-depleted adult rabbit in which the degree of alveolar re-expansion was a controlled variable.56A rigorously standardized model of an atelectasis-prone lung was produced and animals were randomized to receive HFO at either a relatively high mean lung volume at which alveolar re-expansion was maintained (Pao2 > 350 mm Hg) or a lower mean volume with ongoing atelectasis ( P a 9 70-100 mm Hg). Both groups were ventilated at 15 Hz (900 bpm) and an inspired oxygen fraction (FIo,) of 1.0. Another group was ventilated using conventional tidal volumes of approximately 15 mL/kg and positive end-

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Figure 4. A, Respiratory system pressure volume curves obtained at the end of experimental periods of ventilation of saline-lavaged rabbits. Pressure volume curves were the same for all animals at the time of randomization. Note the significant differences in total respiratory system compliance and hysteresis after 7 hours in the HFO groups or 3.9 hours of CMV. HFO-NHI animals were ventilated to achieve alveolar re-expansion and a PaO, > 350 mm Hg. In animals ventilated with HFO-NLO and CMV PaO, was kept in 70 to 100 mm Hg range. HFO = high-frequency oscillatory ventilation; CMV = conventional mechanical ventilation. Illustration continued on following page

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Figure 4 (Continued). B, Histograms of injury scores from lung tissue sections. For each rabbit, 40 small airways were scored for epithelial injury and 80 high power fields were examined for hyaline membranes (HM) 0 = normal epithelium; 1 + = slight injury; 2+ = moderate injury; 3+ = severe injury; 4 + = complete exfoliation of epithelium. For HM, units are percentage of fields with HM present. Values are mean f SEM. (From McCulloch PR, Forkerl PG, Froese AB: Lung volume maintenance prevents lung injury during high frequency oscillatory ventilation in surfactant deficient rabbits. Am Rev Respir Dis 137:1185, 1988; with permission.)

expiratory pressure (PEEP) such that Pao, was again in the 70 to 100 nun Hg range. Significant differences in lung mechanics (Fig. 4) and histology developed over 4- to 7-hour periods in animals that all started with the same primary injury. This study demonstrated that ongoing atelectasis is an independent risk factor for progressive structural lung injury, even in the absence of overdistention. It also demonstrated the importance of the timing of any therapeutic intervention. Clearly, serious lung damage evolved very rapidly in these animal models of lung disease such that any delay in instituting optimal therapy would markedly decrease the potential benefit.

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Ventilator pattern also evidenced a powerful effect in the premature baboon model of respiratory distress syndrome (RDS) investigated by deLemos and colleagues.'" If the premature baboon was treated from birth using HFO at mean distending pressures deliberately set high enough to achieve alveolar aeration, then a strikingly different disease course emerged over the next 24 hours than was seen in animals randomized to conventional mechanical ventilation.58These differences included decreased oxygen requirements, improved lung compliance, decreased lung wet weight/dry weight ratios, decreased levels of cytokines such as platelet-activating factor, and decreased morphologic evidence of cell damage (Fig. 5 ) . Delayed intervention produced much diminished benefit.I9 Again, the unarguable conclusion was that prevention of lung injury requires reversal of and avoidance of atelectasis. Unfortunately, much of this experimental evidence was available in only rudimentary form when the National Institutes of Health (NIH) funded a large multicenter randomized controlled trial of HFO for primary ventilator managein the mid-1980s. At the time it was planned, lowment of RDS (HIFI pressure "rescue" applications dominated the collective clinical experience. A small handful of plus a growing number of surfactant-depleted adult rabbits and premature baboons, constituted the total evidence for the efficacy, safety, and essential role played by lung volume optimization in the prevention

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Figure 5. Static volume pressure curves (from functional residual capacity) measured after 24 hours of ventilation of premature baboons using either high-frequency oscillatory ventilation (HFOV) or conventional positive pressure ventilation (PPV). Note marked difference in lung mechanics after 24-hour ventilator management. HFOV was initiated at mean airway pressures of 18 to 19 cm H,O to achieve early alveolar re-expansion. PPV was used at settings that had been found to minimize air leak complications in this model. (From Meredith KS, deLemos RA, Coalson JJ, et al: Role of lung injury in the pathogenesis of hyaline membrane disease in premature baboons. J Appl Physiol 66:2150, 1989; with permission.)

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of injury in the RDS-type lung. Not surprisingly, the NIH trial selected a cautious protocol in which HFO was used at mean pressures similar to those on conventional mechanical ventilation (CMV), and pressures were weaned before 30 Not surprisingly, this protocol failed to demonstrate any significant FIO~.~, benefit to HFO and in fact suggested possible increased neurologic risk. A negative trial of such numeric and economic magnitude sent shock waves throughout the field of clinical and laboratory investigation that might have eliminated HFV from the scene if not for the growing body of evidence that the strategy with which one used a high-frequency device was an extremely powerful variable.", 56, 58 The type of management protocol used in the HIFI trial was clearly also ineffective in but protocols that placed a priority on early establishment and maintenance of alveolar re-expansion produced substantial 56, 58 Therefore, cautious, carebenefit both physiologically and morphologically.40, ful, controlled investigation continued and rebuilt the framework for the clinical use of HFV.I5,32, 42,

Emergence of Pathophysiologically Based Strategies of Ventilator Support in the 1990s

One beneficial byproduct of the turbulent 1980s was a growing realization that ventilator protocols must be carefully tailored to the specific pathophysiology of each patient. McCulloch and colleagues' study56showed that the same device (i.e., HFO), used at exactly the same operating frequency and tidal volume, could produce two significantly different outcomes over 7 hours in exactly the same "patient" population with only one important change in ventilator protocol-the choice of mean operating lung volume. Clearly, how one uses a device matters, not just what one uses. In the early 1990s, the wealth of clinical HFO experience accumulated by the group of neonatologists at Wilford Hall began to appear, expressed in an extremely useful format as pathophysioThe initial formulations of these logically based strategies of ventilator strategies came out of experience using HFO relatively late in the course of ventilatory support, after hours or days of CMV. In these circumstances, the settings being used during CMV, including the mean airway pressure, could be used as convenient reference points for selecting one's initial HFO settings. The nature of the underlying pathophysiologic process had been identified by the time one was starting HFO. Ancillary information about volume status and cardiac reserve was available. At that stage, the primary issue was whether to pursue an optimized or "high" lung volume strategy or a low-pressure app r ~ a c h That . ~ ~ decision can only be made once one has defined the dominant pathophysiologic process affecting a given infant's lungs. Moreover, because the pathophysiology is constantly changing over time, this initial decision must be repeatedly re-assessed and modified accordingly. It is useful to review these treatment strategies as an example of how to develop an overall conceptual approach to individual ventilator decisions. The strategies are discussed with reference to HFO because experience using both approaches goes back to the early 1980s with HFO. It has since been demonstrated that an open lung strategy can also be achieved using highfrequency jet ventilation (HFJV),and clinical trials of early lung volume o p t h i zation with HFJV are now appearing." Because the specifics of ventilator adjustments and terminology differ for the two high-frequency modes, I use HFO to illustrate the principles involved.

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Open Lung Applications: Management of Disease Characterized by Diffuse Alveolar Collapse

In essence, achievement of even and complete aeration of alveoli has become the primary goal of ventilatory support with HFO. It is relinquished primarily when existing or developing complications introduce a competing priority. For example, conditions characterized by diffuse alveolar involvement, such as infant RDS, group B streptococcal pneumonia, pulmonary hemorrhage, or adulttype RDS, all have common pathophysiologic mechanisms of edema, atelectasis, decreased lung compliance, and ventilation-perfusion mismatch. These lungs have unstable alveoli that tend to atelectasis. The therapeutic goal of HFO in such circumstances is to re-expand these atelectasis-prone lungs by applying plus or minus specific volume recruitappropriate mean airway pressure, ( M ) ment maneuvers, and then to maintain ventilatory support in this "open lung" state while the underlying pathophysiologic process resolves over time. In such clinical applications, HFO is usually initiated at PZG levels 2 to 3 cm H20higher than those being used on CMV. The patient's initial response is assessed in terms of oxygen requirements, heart rate, and blood pressure. Then stepwise increases in Paw are pursued every 5 to 10 minutes until one begins to see signs of alveolar re-expansion. Effective alveolar expansion is reflected by a decrease in F I Orequirements, ~ disappearance of intercostal retractions during spontaneous breaths, and reversal of the usual opacifications on chest radiograph with diaphragms down to the level of the eighth to ninth rib posteriorly. Once there is evidence of alveolar re-expansion, the Paw should be maintained at that level until its full impact can develop. Experience has shown that once reversal of atelectasis begins, it often continues to progress over several hours at those same mean pressure settings, a process probably related to the alveolar interdependence phenomena described by Mead et al.57Therefore, one must allow time for the response to plateau, reassess lung inflation radiologically, and then decide what further PZG adjustments are needed. The actual mean pressure requirement varies markedly from infant to infant depending on the severity of the underlying disease process. Once alveolar aeration is achieved, the first priority of the open lung approach is to reduce the inspired oxygen tension. Mean airway pressures are reduced only when this can be accomplished without a resultant deterioration in oxygenation (i.e., recurrence of atelectasis). Usually, PZG levels can be weaned gradually, guided by radiographic evaluation of the overall level of lung inflation, as the underlying condition of the lung improves. It must be stressed that this process of optimizing alveolar expansion is an extremely dynamic process, which must be carried out interactively at the bedside during its initial phases. It is not uncommon to see F I O ~requirements decrease from 100% to 30% over a few hours with such a management strategy. At other times, response is seen over days, not hours. Therefore, management must be tailored to each case and based on repeated clinical, radiologic, and gas exchange reassessments. The rate of response may be predictive of outcome. Patients with recruitable lung volume respond quickly and recover. In contrast, patients with severely damaged lungs respond more slowly and are less likely to recover, particularly without sequelae. Low-Pressure Applications

Pure low-pressure applications of HFO are relatively rare. Some infants with persistent pulmonary hypertension and large right-to-left shunts have fairly normal alveolar stability. Correction of hypercarbia and acidosis at low

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transrespiratory pressures may improve the relative balance of systemic and pulmonary resistances, increase pulmonary perfusion, and facilitate resolution of the problem. This application depends on the ability of HFV to transport CO, effectively using low peak and mean pressures. Most low-pressure HFV applications represent a compromise in which some pulmonary or cardiovascular complication must be given priority over the usual desire to achieve optimal alveolar expansion. In each individual case, the relative priority of the competing pathophysiologic problems must be determined. Infants with pulmonary interstitial emphysema (PIE) or recurrent air leaks form a substantial part of this population. In each case, one must first decide if the predominant problem is poor lung inflation or air leak. If severe air leak is the primary problem, then one uses the lowest mean pressure that allows adequate gas exchange, accepting higher F I O requirements ~ to buy time while the parenchymal leakage sites seal off. This can occur even with mean pressures equal to those present during CMV when the complications developed because the small volume cycles of HFV mean that the peak distending pressures and volumes are less than the peak inspiratory pressures and volumes of CMV. However, if the primary problem in an infant is poor lung inflation, then the primary goal should be to re-expand the lung despite evidence of air leak. An example of this would be the premature infant, in whom the radiologic picture of widespread focal bubbles of PIE surrounded with diffuse atelectasis develops while on CMV. In this situation, HFO management would be the same as that outlined earlier for diffuse disease. In these lungs, the best way to prevent rupture of those "bubbles" of dilated distal airways is to open up the atelectactic parenchyma around them and improve overall lung compliance. Here again, the small tidal volumes of HFV allow one to achieve and maintain such alveolar expansion safely and remove the shear stresses from the terminal bronchioles. If the PIE is more advanced and there are extensive interstitial cystic accumulations of gas acting as an "internal" tension pneumothorax, that becomes the priority and dictates step-by-step decrease in mean pressures until a level is reached at which signs of air leak resolution appear. This can often be achieved at mean pressures the same as or only slightly less than those previously used on CMV. It is interesting to recognize the subtle shift in low-pressure HFO usage that has evolved over the past 5 to 10 years as clinical experience has moved toward earlier intervention. In the early days of protocols with the Food and Drug Administration (FDA) approval only for use in imminently life-threatening situations, by definition neonates all had severe air leak problems. The air leak was itself the predominant problem, and lung re-expansion had to take second place to the use of the lowest possible mean airway pressures compatible with maintaining adequate gas exchange. Since the introduction of exogenous surfactant and early applications of HFO, severe air leak is an uncommon problem. As a result, the "low-pressure" approach has moved steadily toward more balanced priorities of achieving lung inflation while also resolving the air leak. Hypoplastic Lungs

The best way to avoid overdistention of individual lung units is to distribute a given tidal volume over as large a number of units as possible. If the number of available units is limited (i.e., the lung is small), then decrease the tidal volume. That is simple physics. Therefore, one can theorize that any hypoplastic lung would be most safely managed using high rates and small volume cycles. Such predictions are remarkably difficult to test rigorously in clinical practice,

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however. The problem is that the only available predictors of outcome are based on measurements made during a reference period of conventional ventilation? However, accumulating animal and human data have demonstrated that even a few minutes of large-volume mechanical ventilation can initiate lung injury. Thus, there has been a move toward early initiation of HFV in at-risk populations such as infants with congenital diaphragmatic hernia (CDH). Several centers have organized therapeutic approaches that include prenatal diagnosis of CDH, delivery room intubation and initiation of HFO, stabilization on HFO for hours to days preoperatively, followed by HFO for ventilatory support during the intraoperative and postoperative period (R Stoddard, personal communication). Several such series have been published or reported, with very commendable survival rates compared with retrospective outcome data.60However, the low incidence of the condition, variation in patient-related factors, and sporadic occurrence of such births make randomized controlled studies difficult to conduct. Therefore, gold-standard definitive data remain unavailable. The lack of such data currently represents a significant impediment to the wider use of such management protocols, which are based on sound rationale but nonetheless need appropriate clinical evaluation. Primary HFV Intervention for Hypoplasia

The disease-specific HFV treatment strategy for the hypoplastic unilateral lung (e.g., CDH) focuses on finding a mean distending pressure that achieves radiologic evidence of reasonable aeration of the contralateral, more normal lung. With bilateral hypoplasia, this intrinsic reference is unavailable and one must depend on radiologic estimation of appropriateness of expansion. One then maintains ventilation at this level while providing time for the multiple cardiorespiratory adaptations to extrauterine life to occur before introducing the stress of anesthesia and surgery. When a hypoplastic lung is managed in this way, experience suggests that this early postnatal period can be accompanied by considerable gradual expansion of the hypoplastic lung and decrease in reactivity of the pulmonary circulation. Rescue HFV for Hypoplasia

Many infants with lung hypoplasia have also been managed with HFV as a rescue intervention when serious complications threaten management on CMV. In this circumstance, a therapeutic trial of HFV may prove effective and avoid the need for ECM0.I7However, ECMO should be available in such cases because cardiac dysfunction is often a limiting factor at this stage and HFV may not be tolerated. Increased Airways Resistance

The most common example of high airways resistance pathophysiology in the neonate is meconium aspiration syndrome. The natural history of this disease is dominated in the early phase by patchy obstruction and consolidation by particulate matter. The development of ball-valve obstructions with regions of hyperinflation is a constant underlying risk. Many of these aspiration syndromes have been going on for some time in utero, and pulmonary artery hyperplasia with persistent pulmonary hypertension is a frequent concomitant problem. In the early phase, HFV is of arguable benefit, largely because of the risk of trapping gas behind plugs of meconium. Laboratory models of the syndrome in

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piglets have not demonstrated consistent benefit.83However, after 1 to 2 days, neonates with meconium aspiration often present with a secondary diffuse adult RDS-like picture. In this phase, HFV, used for the management of diffuse lung disease with or without air leak, may prove useful and should be tried prior to instituting ECM0.65 Lung-Protective Conventional Ventilatory Techniques

Over the last decade of heightened awareness of ventilator-related lung injury, ”conventional” ventilatory techniques have also undergone substantial modification. Efforts have been directed toward reducing the complications arising from adverse patient/ventilator interactions during conventional ventilation. Active expiration against ventilator breaths has been associated with de74 increased barotrauma,34and increased cerebral blood creased oxygenation,41* flow ~ a r i a b i l i t yAlthough .~~ muscle paralysis can guarantee synchrony, it is not without disadvantage^.^^, 73 Recent technologic improvements in methods of breath detection and synchronization have led to increased exploration of patient-triggered ventilation in either an assist control (AC) mode or synchronized to a selected number of patient breaths per minute (synchronized intermittent mandatory ventilation [SIMV]).4, A recent multicentred trial of SIMV vs intermittent mandatory ventilation (IMV) in 306 infants randomized at 7.5 6 hours of age showed improvements in oxygenation, a decrease in duration of ventilatory support in infants larger than 2000 g, and a reduction in chronic lung disease in infants less than 1000 g 6 In this study, synchronization was given a priority rather than optimization of lung volume. Clearly, what we now need are randomized comparisons of early intervention with SIMV compared with HFO with an optimized lung volume strategy because both approaches are demonstrably better than conventional IMV but have not yet been compared directly with each other. An alternative lung-protective conventional strategy has been advocated for many years by Jen-Tien Wung et aP4 of Columbia University. The priority with this regimen has been to minimize barotrauma by limiting peak inspiratory pressure and allowing hypercarbia (long before the concept became fashionable) if necessary to minimize the risk of lung overdistention. This approach was noted in 1984 to be associated with a significantly lower incidence of bronchopulmonary dysplasia (BPD) than that found in nine other centers participating in a multicenter trial? The ventilation strategy uses neither muscle paralysis nor patient synchronizing technology. Data from Columbia Babies’ Hospital support the efficacy of such an approach, even in the presence of persistent fetal circulation,% and have led to the increasing use of pressure-limited ventilation and permissive hypercapnia strategies for the preoperative stabilization and postoperative management of infants with CDH.85It has become common to delay the surgical repaitas 71 The relative timing of surgery and the initiation of ECMO have shifted,”,85and overall outcome appears to be improving as lung-protective ventilatory strategies are increasingly being pursued using conventional ventilator~.*~ Again, we lack direct randomized comparisons of these various “improved ventilatory regimens. All of these approaches are driven by the desire to reduce ventilator-related lung injury and associated complications in other organ systems, particularly the brain. Each approach is championed vigorously by individuals highly experienced in that technique. All have different constellations of advantages, limitations, and potential for complications during misuse. Each

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carries its own learning curve. For example, the first trial of the early application of HFJV in RDS was terminated prematurely because of increased neurologic adverse events in the jet ventilation group.82Subsequent evaluation of patterns of HFJV usage within a study population using an optimized lung volume strategy revealed that adverse neurologic outcomes correlated with the occurrence of liypocarbia secondary to inappropriately low PEEP levels for this new "optimized volume" Adverse neurologic outcomes accompany hypocarbia with any ventilator and are not specific for HFJV.7,33, 37 In many ways, this story is a repeat of the 1980s learning curve with HFO and the adverse neurologic events that accompanied the HIFI Trial.", 78 Its occurrence reemphasizes the importance of each member of the team understanding the "why" of the ventilator settings rather than just how to use the machine. Randomized comparisons of these new treatment options are now urgently needed. Such studies require participants who are knowledgeable in the optimal use of all the treatment options under investigation, who are prepared to supervise protocol compliance for all infants enrolled in the study, who have available all necessary monitoring equipment (such as transcutaneous CO, electrodes), and who are committed to the rigorous discipline required for clinical investigation in such a complex milieu. Only then will the pitfalls of earlier trials be avoided." Partial Liquid Ventilation

In recent years, the technical complexities of liquid ventilation using high 0,-carrying capacity chemical compounds14,35 have been strategically simplified by combining cyclic gas transport with perfluorocarbon (PFC) filling of the This approach changes the problem of re-establishing an air/tissue interface with each inspiration in each collapsed, surfactant-unprotected airway and alveolus to a very different force-distribution problem of expanding the area of a gas/perfluorocarbon liquid interface with each inspiration through a complex tubular structure. Experimentally, PLV has been shown to improve gas exchange and survival and decrease lung injury in animal models of RDS5"and hypoplastic lungs.81The first phase I and I1 trials of PLV in premature infants has established its basic efficacy and fea~ibility.4~ However, much more information is needed about the optimal balance between the amount of liquid instilled and the pattern of the superimposed mechanical ventilation. Cox et a1,I8 using a lavaged rabbit model, encountered high rates of air leak using the combinations of PFC volume and tidal volume (VT) that have been introduced clinically. Smaller PFC filling volumes coupled with more PEEP and smaller VT were as effective at oxygenation with fewer complications.'8 INTERACTIONS AMONG THERAPIES Nitric Oxide

Inhaled nitric oxide (iNO) was introduced as a selective pulmonary vasodilator that relaxed pulmonary vessels without deleterious systemic effects because it was delivered via the airways to its desired site of action and was inactivated before reaching the systemic vessels. Not surprisingly, for this delivery system to work the alveoli must be expanded. Both Kinsella and Abman4' in neonates and Puybasset et aP9 in adults have presented evidence relating the efficacy of

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iNO therapy to the pretreatment degree of lung recruitment (Fig. 6). Nonresponders can be turned into responders by changing ventilator parameters in such a way as to increase the amount of lung to which the NO is delivered, by adjustment of conventional settings or by use of HFV.

Exogenous Surfactant

Although exogenous surfactant replacement therapy (ESRT) has revolutionized the management of infant RDS over the past 10 years, it has not abolished the need for ongoing ventilatory support in all cases. A complex interaction occurs between ventilator pattern and surfactant therapy. The therapeutic response to ESRT was better using HFO with respect to gas exchange;1, 27, 45 duration of resp0nse,2~and lung edema formation45in adult rabbitz1,27 and premature monkeyl5 models of IRDS (Fig. 7) than using conventional ventilation with PEEP. The observations in the premature monkey concur with the clinical experience of several centers that report need for fewer repeat doses of exogenous surfactant in babies managed on HFO using an optimal lung volume strategy.32 These findings are not surprising. We know that the distribution of exogenous surfactant is somewhat nonuniform, particularly when given after the first breath. In animal experiments we found it impossible to maintain a PEEP high enough to prevent all derecruitment in the surfactant-treated lung consistently without encountering cardiac and respiratory complications of relative overdist e n t i ~ nBoth . ~ ~ exogenous surfactant and HFO are techniques with major effects on alveolar aeration. Exogenous surfactant works by reducing the retractive forces arising from the surface tension of the alveolar lining layer; HFV works by splinting the lung open mechanically while avoiding extremes of lung volume. It is not surprising that they would work well in combination. Some centers have actually decreased their use of exogenous surfactant, finding that they can achieve equivalent alveolar expansion and reduction in Fro2 using HFO without exposing the infant to the foreign proteins and transient perturbations associated with surfactant administration, and simply wait for endogenous surfactant production to become sufficient.

HFV and ECMO

Ever since the introduction of HFO as a therapeutic option lying between CMV and ECMO, the Wilford Hall group of neonatologists have been notable for their cautious, systematic assessment and reassessment of the impact of this therapeutic choice on short- and long-term outcome.17,ffi Very early it became clear that, within populations of very sick infants who were meeting ECMO criteria while on CMV, many infants could be managed successfully with HFO. There were also nonresponders who went on to require ECMO. These investigators were the first to look systematically at outcome patterns, asking an extremely important question germane to any new therapy: Has the use of this new therapy (HFV) prejudiced the chances for the patient to obtain a good result from another therapeutic option (ECMO)? These studies recommend that patients who persist as nonresponders after 24 hours of HFO should proceed to ECMO while still within the "window" for optimal ECMO outcome.ffi

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Figure 6. A, Arterial Po, (PaO,) versus age in an infant with congenital diaphragmatic hernia and persistent pulmonary hypertension. Although the infant had an initial response to inhaled nitric oxide (iNO) during conventional mechanical ventilation (CMV), the response was not sustained. Oxygenation did not improve during the first hour of high-frequency oscillatory ventilation (HFOV), but lung volume improvements were noted on the chest radiograph. At that point, reintroduction of iNO produced a marked and sustained improvement in oxygenation. 13,Radiographic changes in lung inflation associated with HFOV. Improvement in oxygenation with iNO occurred only after adequate lung expansion was achieved with HFOV. (From Kinsella JP, Abman SH: Recent developments in the pathophysiology and treatment of persistent pulmonary hypertension of the newborn. J Pediatr 126:853, 1995; with permission.)

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Figure 7. Oxygenation index, radiograph score, lung injury score, and volume fraction of alveolar debris after 6 hours of ventilatory support in four groups of premature Macaca nemesfrina monkeys. CMV = conventional mechanical ventilation; HFOV = high-frequency oscillatory ventilation. Survanta", a modified bovine surfactant, was instilled over the first few minutes of life in half the animals (SURF). The inspired 0, fraction (Fto2) was 1.0 in all animals. Significant improvements in all outcome measures were seen with the combination of HFOV, used with the goal of early optimization of the alveolar expansion pattern, plus surfactant. **P< 0.0001 (compared with HFOV and SURF) *P < 0.015 (compared with HFOV and SURF). (From Jackson JC, Truog WE, Standaert TA, et al. Reduction in lung injury after combined surfactant and high-frequency ventilation. Am J Respir Crit Care Med 150:534, 1994; with permission).

ADDITIONAL CONSIDERATIONS The Time Factor

Throughout the 1980s, there was a clear dichotomy between the timing of intervention with HFV in laboratory investigations and clinical applications. In the laboratory, randomization to ventilator therapies tends to occur at "time zero" and consequently yields data on their use for primary ventilator management to prevent lung injury. In the neonatal or pediatric ICU, treatment used to

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occur only late in the course of disease when FDA criteria for rescue intervention were met for experimental therapies and lung injury was well-established. The mindset of late rescue still persists in many centers. Although this is a cautious, ethical, and appropriate route to follow early in the introduction of a new therapy, it must be reassessed as experience accumulates. All animal studies, in both adult models of ARDS and premature models of IRDS, demonstrate powerful time effects.I9,40,56, 58, 76 It takes very little time to initiate cell damage, death, and inflammatory reaction in a vulnerable lung. Such changes, when severe, have life-long implications with respect to the final alveolarization of the lung.16 Therefore, the emphasis has moved from rescue to prevention. It appears that the earlier the initiation of protective care with HFO, the greater the benefit that becomes apparent with respect to the quality of the survivors’ Selection of Ventilator Frequency

Ever since it became clear that gas transport could be supported adequately over an amazingly wide range of respiratory frequencies, we have wrestled with the question of “optimal” frequencies. A major advance in our understanding of how patient pathophysiology should influence our selection of ventilator settings has been provided by Venegas and FredbergaOThey formulated the “optimization” question as a problem of achieving adequate alveolar ventilation at minimal pressure cost. This was subdivided into (1)the pressure cost per unit of oscillatory flow and (2) the convective flow cost necessary to achieve a unit of alveolar ventilation. Their approach is powerful because it addresses the whole lung, not just a tube. They incorporate important elements such as alveolar recruitment and derecruitment into the cost functions, the effects of lung inflation and frequency on dead space volume, and the volume dependence of lung compliance. Venegas and FredbergsO express their results as three-dimensional plots of ”safe” combinations of PEEP and frequency for different clinical scenarios. “Safe” is defined as settings that result in a peak alveolar distention of less than 90% of total lung capacity. This analytic approach provides graphic depictions of the shifting boundary conditions for ”safe” ventilator settings with varying lung pathology (Fig. 8). The three-dimensional plots demonstrate that the normal lung can be ventilated safely with respect to peak distention over a very wide range of ventilator frequencies and PEEP levels. In contrast, the lung with poor compliance but relatively normal airways (i.e., the infant or child with RDS) has a very limited ”safe” zone of frequency-PEEP combinations. In this case the selection of PEEP is critical, particularly at lower frequencies, with penalties in pressure cost for both too low and too high a PEEP. At higher frequencies the safe PEEP zone becomes somewhat wider as tidal volume decreases. These graphs help one understand why ventilator protocols aimed at optimizing alveolar expansion are simpler and safer to achieve using HFO than using modified conventional techniques such as that reported in rabbits by Sandhar et al.” This formulation demonstrates the importance of using high frequencies and optimizing the amount of PEEP (which is done through optimizing Paw during HFO) in infant respiratory distress syndrome. It also demonstrates graphically a principle learned the hard way through extensive animal and clinical investigation: When the lungs are in a derecruited state, the combinations of PEEP, tidal volume, and frequency that can support Co, transport without overdistention (and therefore eventual hjury) of open alveoli are extremely limited. Once the alveoli are recruited, the range of ‘’safe’’ settings broadens immediately This

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0.4

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B Figure 8. 3-dimensional plots of normalized peak alveolar distension (Dalv) plotted against frequency (f) and positive end-expiratory pressure (PEEP) for a normal infant (A) and one with respiratory distress syndrome (RDS). (B) Normalized peak alveolar distension (Dalv) is defined as lung volume at end-expiration (VEE)plus tidal volume (VT) normalized by total lung capacity (TLC). The safe zone for peak alveolar distension was set at 90% of TLC. The combinations of frequency and PEEP that are within this limit are given by the shaded zones projected onto the x-z plane. For clarity, combinations of f and PEEP producing alveolar distension exceeding this safe level are arbitrarily set to unity. In the normal infant, the range of safe f-PEEP choices is very wide. However, because of the tendency to atelectasis in the infant with RDS, lung peak distension encroaches on TLC for all but a small range of f-PEEP combinations. The width of the safe zone becomes greater as frequency increases. This formulation depicts graphically the twin dangers of both too little and too much PEEP. Both lead to potentially damaging alveolar overdistension. (Reprinted from Venegas JG, Fredberg JJ: Understanding the pressure cost of ventilation: Why does high-frequency ventilation work? Crit Care Med 22(suppl 9):S49-S57,1994; with permission.)

theoretic prediction, backed by extensive in vivo experience, has immense practical therapeutic significance in our critical care units. When abnormalities of airways resistance are introduced into their model, the resultant plots shift to lower optimal frequencies. These predictions fit well with the clinical experience of early postnatal treatment of meconium aspiration syndrome. Volume Recruitment Methods

Although the small volume cycles of HFV are advantageous for avoiding alveolar overdistention, they lack the high peak pressure often needed to exceed the opening pressures of atelectatic alveoli and re-expand the lung. Therefore, some type of maneuver is needed to achieve alveolar re-expansion during HFV. Brief, discrete recruitment maneuvers have been used extensively and successfully in animal laboratories9,13, 56 and in a few babies.= Most clinical HFO has achieved alveolar re-expansion by progressive increases in mean airway

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pressure without discrete sustained inflations in an attempt to avoid potentially damaging fluctuations in venous and intracranial 32 Many HFJV protocols use background IMV breaths to reverse a t e l e c t a ~ i s .This ~ ~ , area ~ ~ needs further clarification of the risk/benefit ratios of the various options in use, particularly for the very small premature infant.

Monitoring Issues Transcutaneous CO,

One unfortunate side effect of the replacement of transcutaneous oxygen tension monitoring by hemoglobin saturation monitors (pulse oximetry) has been the concurrent abandonment of transcutaneous CO, monitoring in the neonatal intensive care unit. Online CO, monitoring remains vital during periods of potential rapid fluctuations in lung compliance and ventilation, as during initiation of a high-frequency modality, because of the potential for cerebral hypoperfusion if hypocarbia ensues.7,33, 37 Lung Volume Monitoring

Our current electronic information explosion provides an amazing amount of breath-by-breath data. Nevertheless, we still lack a practical, nonradiologic on-line estimate of the "appropriate" degree of alveolar expansion, a high priority therapeutic goal. Currently, therapeutic decisions are made on the basis of on-line oxygenation information (FIo, and pulse oximetry) with periodic radiologic evaluation of overall lung inflation. Undoubtedly, better tools can and will be devised. Gauge of Evenness of Aeration

We also need a practical way to evaluate the evenness of aeration in the critical care setting. Much of the diffuse air space consolidation evident in the usual anteroposterior chest radiograph is actually heterogeneously distributed when evaluated by techniques such as CT scans.66Regions that develop both reduced ventilation and perfusion are not detected by evaluation of oxygenation but nevertheless contribute to overall lung injury risk. We need a better way to assess the therapeutic goal of alveolar aeration in order to fine tune our management. Validation of FQ Targets

No firm basis yet exists for selection of FIO, targets in critical care. The rationale behind treatment protocols of the past few decades has been avoidance of oxygen toxicity. In that context, targets of 60% (or lower) inspired oxygen were commonly deemed acceptable. Now, the driving rationale is to prevent the progression of lung injury through optimization of alveolar expansion. Such "protection" is seen experimentally even with ongoing exposure to 100% 0,. Therefore, it is not due to mere avoidance of 0, toxicity. This distinction is crucial. With both rationales, the patient receives a "lower" FIO,, but for very different reasons. What we now need is objective testing of a target for alveolar reexpansion. Is it enough to reduce the FIO, requirement to 50%? Or 40%? Or

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less? We need clarification of this endpoint for proper weighing of the risk/ benefit ratio in individual cases in which alveolar re-expansion proves difficult.

REVISING OUR CONTINUUM OF CARE

The current challenge in neonatal ventilatory care is to organize our burgeoning array of treatment options into a practical sequence that can be applied over the wide range of disease entities and severity encountered in clinical practice. The fundamental decision points are (1) What modality do I initiate now? (2) When do I rule that a modality has failed and switch to an alternative? and (3) When do I say that a modality is no longer needed? Important variables influencing these decisions include gestational age, birth weight, diagnosis, and prognosis. These questions must be addressed with the recognition that we are in the midst of a paradigm shift in mechanical ventilation. During the 1980s, if supportive care with continuous positive airway pressure and O2 supplementation proved inadequate, primary ventilator care was automatically delivered using CMV at modest frequencies. Only when the condition was deemed ”severe” or specific indications such as air leak syndrome developed were modalities such as HFV or ECMO introduced into the continuum of care. What emerged was a shifting boundary condition whereby the decision to initiate ”novel therapies” reflected numerous local factors, including availability of and familiarity with equipment plus physician preferences and experience. Now, the dominant requirement is to maintain alveolar expansion while supporting CO, elimination. In such a paradigm, the treatment choice is driven by a desire to prevent possible ventilator-related lung injury (VRLI), rather than treating it after it has developed. Because one cannot identify in advance precisely which infant is most at risk of developing VRLI, one would treat all infants prophylactically based on the evidence accumulating from randomized controlled trials. For example, based on current data from premature animals and human trials, CMV might be used only in larger babies with a good exogenous surfactant response in whom ventilator support is unlikely to be needed for longer than 12 to 24 hours. However, the very low birth weight baby, who developmentally has a relatively hypoplastic and therefore vulnerable lung, could be managed using HFV based on VRLI considerations, even in the presence of a good surfactant response and low FIO, requirement. Currently, only HFV and CMV have an appropriate risk/benefit ratio for primary care of respiratory failure. ECMO and PLV remain reserved for the treatment failures because these modalities carry significant risks along with their greater efficacy. Neonatal ventilatory care is in a dynamic stage of development. Systematic training and evaluation of outcomes are needed at every stage of the process. Either rash innovation or determined maintenance of the status quo can expose patients to unnecessary risk. In an era of strident cost containment, we need to choose our course wisely as we optimize ventilatory care for the neonate.

ACKNOWLEDGMENT Saulina Almeida provided invaluable secretarial support for the preparation of this manuscript.

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Address reprint requests to Alison B. Froese, MD, FRCPC Department of Anaesthesia Kingston General Hospital 76 Stuart Street Kingston, ON K7L 2V7 Canada