Rapid arterial O2 desaturation during apnea in the preterm infant has obvious clinical implications but to date no adequate explanation for why it exists. Understanding the factors influencing the rate of arterial O2 desaturation during apnea () is complicated by the non-linear O2 dissociation curve, falling pulmonary O2 uptake, and by the fact that O2 desaturation is biphasic, exhibiting a rapid phase (stage 1) followed by a slower phase when severe desaturation develops (stage 2). Using a mathematical model incorporating pulmonary uptake dynamics, we found that elevated metabolic O2 consumption accelerates throughout the entire desaturation process. By contrast, the remaining factors have a restricted temporal influence: low pre-apneic alveolar causes an early onset of desaturation, but thereafter has little impact; reduced lung volume, hemoglobin content or cardiac output, accelerates during stage 1, and finally, total blood O2 capacity (blood volume and hemoglobin content) alone determines during stage 2. Preterm infants with elevated metabolic rate, respiratory depression, low lung volume, impaired cardiac reserve, anemia, or hypovolemia, are at risk for rapid and profound apneic hypoxemia. Our insights provide a basic physiological framework that may guide clinical interpretation and design of interventions for preventing sudden apneic hypoxemia.
Apnea and its accompanying arterial O2 desaturation are common clinical complications in preterm infants, occurring in more than 50% of very low birth weight infants [1]. In preterm infants, apnea causes a reduction in heart rate [2] and cerebral perfusion [3], often requires mechanical ventilation, and is associated with neurodevelopmental impairment [4]. Apnea-related hypoxemia is of major concern in light of evidence that repetitive hypoxia in newborn animals results in irreversibly-altered carotid body function [5], raising the possibility of impaired ventilatory control, and causes neurocognitive and behavioural deficits [6]. Respiratory arrest and hypoxemia are also strongly implicated in sudden infant death syndrome (SIDS) [7], [8] where the speed at which hypoxemia develops is considered to be particularly dangerous. In preterm infants, the rate of arterial O2 desaturation () can be highly variable and rapid, with average rates as high as 4. 3% s−1 during isolated apneas [9]. An earlier framework to describe proposed that metabolic O2 consumption relative to alveolar volume determines the speed at which alveolar falls [10]; it was envisaged that is then a function of falling and the slope of the oxy-hemoglobin dissociation curve. However, such a model assumes that the rate of alveolar depletion of O2, denoted pulmonary O2 uptake (), is equal to tissue O2 consumption during apnea (see Methods – Theory). Previous studies in adults have shown that falls from metabolic consumption during apnea [11], and our previous modeling studies in lambs showed that the difference between and metabolic O2 consumption has a crucial role in determining during recurrent apneas [12]. We found that apneic changes in cause desaturation to occur in 2 stages. During stage 1, lung O2 stores are depleted, and falls below metabolic consumption. During stage 2, is close to zero, and tissue O2 needs are provided by depletion of blood O2 stores. To date, no complete theoretical analysis of the factors influencing desaturation during apnea has been published. The only available study [13] has a number of critical limitations. First, the model incorporated a constraint of a fixed difference between and mixed-venous saturation; thus dynamic changes in could not occur and their influence on could not be examined. Second, no assessment was made of the impact of cardiorespiratory factors on the two stages of O2 desaturation. Third, in focusing on adults, the study did not examine profound desaturation to levels well below 60% as can often occur in preterm infants [9], [14]. Accordingly, the aim of the current study was to quantify the importance of cardiorespiratory factors relevant to during apnea, with particular reference to the preterm infant. Using a model that permits variation of during apnea, we examine a number of factors known to influence, such as lung volume [15], metabolic O2 consumption [16] and pre-apneic arterial oxygenation [17] as well as factors that are particularly pertinent for the developing newborn, including anemia, hypovolemia, reduced O2 affinity, and chronically and acutely reduced cardiac output. We use the results to develop a conceptual framework for the interpretation of mechanisms underlying rapid during apnea.
To determine the independent influence of clinically relevant cardiorespiratory factors on during a single isolated apnea, we used a two-compartment lung-body mathematical model which incorporated realistic blood O2 stores and gas exchange dynamics (Figure 1), as described in Methods – Mathematical model (a full list of symbols is provided in Table 1). We used published parameters for healthy preterm infants born at ∼30 wk gestational age (Table 2); the values represent measurements taken at approximately term equivalent age when surprisingly rapid desaturation has been observed [9]. We also derive analytic solutions for to quantify the importance of cardiorespiratory factors on to obtain a detailed view of the arterial O2 desaturation process, as described in Methods – Theory. To examine changes in O2/CO2 exchange during apnea, a single apnea was imposed on the model. During apnea, changes in alveolar O2 and CO2 stores are not constant (Figure 2); importantly, alveolar () did not continue to fall at its initial rate as governed by metabolic O2 consumption (), but instead the rate of fall in was reduced as it approached mixed venous (), an observation also reflected in the falling. As a result, two distinct phases for O2 depletion can be seen, which we refer to as stage 1 and stage 2 [12]. During stage 1, fell rapidly and decreased and became dissociated from; during stage 2, with greatly reduced, both and fell together at a reduced rate. The two distinct phases were also observed for alveolar and arterial (,) although stage 1 for CO2 was substantially shorter than that for O2. Such an effect results from the earlier fall in pulmonary CO2 uptake () relative to the fall in (Figure 2A) and is reflected in the reduction in respiratory exchange ratio () (Figure 2B). Consequently, a more rapid fall in was observed compared with the rise in (see Methods – Derivation of equations), such that fell by 100 mmHg in the time rose by just 14 mmHg (Figure 2C). The time-course of is complex (Figure 3), a consequence of the nonlinear O2-dissociation curve in combination with the fall in. At apnea onset, started to fall with a rate equivalent to that predicted by Equation 12, where (Figure 3). During apnea, changes in the slope of the O2-dissociation curve () and dominated the time-course of desaturation as hypoxemia progressed. As started to fall after apnea onset, increased with little change in, resulting in a proportional increase in. However, as arterial hypoxemia developed, there was a concurrent decline in. As is directly proportional to the product (Equation 11) it follows that during apnea, the peak of 3. 5% s−1 occurred when reached a maximum. This occurred when neither nor was at its maximum (both ∼50% of peak). Finally, with greatly reduced during stage 2, remained at a constant level (), close to that predicted by Equation 13 (1. 8% s−1). The following parameters were individually varied from their ‘normal’ values to quantify their influence on: resting, lung volume (), metabolic O2 consumption (), blood hemoglobin content (Hb), cardiac output (), R-L shunt fraction (Fs), and the at 50% saturation (P50). All other parameters were kept constant to remove confounding effects, unless specified otherwise. To quantify we used 3 different measures. First, since apnea is considered clinically significant if it lasts for >10 s and is accompanied by bradycardia or O2 desaturation [18], we calculated the average rate of fall in between apnea onset and 10 s later (); such a measure describes the immediacy of onset of desaturation and is analogous to the practical measurement of average used in many clinical studies [9], [15], [19], [20]. Second, we determined the peak instantaneous during apnea (), the value during the linear portion of arterial desaturation [10], [21] which we find is not confounded by resting. Third, we report a measure of during stage 2 apnea (). To quantify the sensitivity of to changes in each cardiorespiratory factor, we defined the term impact ratio as the ratio of proportional increase in to a small increase from the normal value of each factor. For example, an impact ratio of 1 indicates a one-to-one increase in with an increase in the factor, and a negative ratio indicates an inverse relationship. The impact of each cardiorespiratory factor on, , and is summarised in Table 3.
To evaluate the independent effects of cardiorespiratory factors on we used a two-compartment model, incorporating both alveolar and blood gas stores. The inclusion of a realistic blood store was crucial to reveal that changes in occur as a consequence of arterial and mixed-venous saturation falling asynchronously during apnea (Figure 3). Our approach allowed us to extend the previous framework based on the assumption of constant [23], which prevented the recognition that a steep O2-dissociation curve and low lung volume do not accelerate beyond stage 1. Furthermore, the varying permitted recognition that cardiac output, hemoglobin content, and blood volume have a major influence on. In the current study, the typical value of found using our model was 3. 5% s−1 whereas Poets and Southall [9] using beat-by-beat oximetry in preterm infants reported a mean value for during isolated apneas. Reasons for our lower value may lie with our simplifying assumptions. Notably, we assumed a homogenous lung compartment and complete gas mixing and as such, the model incorporated neither limitation of alveolar-capillary diffusion nor an uneven ventilation-perfusion distribution, two factors that could cause an increase in. In addition, we assumed a constant lung volume during apnea, equal to published values of functional residual capacity, whereas it is known that lung volume can fall during apnea [15], [24]; based on our data, a fall in lung volume to 15. 5 ml min−1kg−1 immediately after apnea onset would achieve of 4. 3% s−1 (Figure 5B). A final assumption implicit in our model is that all O2 transfer to the blood occurs via the pulmonary circulation. However, in very preterm infants there is evidence of percutaneous respiration in the first few days of life in both room air and with supplemental O2 [25]. With whole body exposure of 90% O2 to the newborn skin, it has been calculated that can be reduced by 8–10% [26], likely via an increased resting mixed-venous saturation; our study demonstrates that such an effect would decrease during apnea. Our study is consistent with previous observations that and rapidly decline during apnea from their steady-state values [11], with falling faster than. The relatively low blood capacitance for O2 compared with that for CO2 results in the resting alveolar–mixed-venous partial pressure difference being ∼12-fold greater for O2 than for CO2. Consequently, when apnea begins ∼12 times more O2 than CO2 must diffuse across the lung to obliterate the alveolar–mixed-venous partial pressure difference. The slower fall in vs. provides for a faster depletion of alveolar O2 vs. CO2 stores; such an effect results in complete desaturation of arterial blood in the time rises by just 14 mmHg. These findings lead us to conclude that short-term O2 homeostasis is more unstable than CO2 homeostasis and thus that the danger of isolated apneas in infants is likely to be mediated via hypoxemia rather than hypercapnia. Our study provides for the first time a comprehensive analysis of the factors that determine arterial desaturation during apnea in preterm infants. We show that resting oxygenation in the form of alveolar has the greatest influence on desaturation at apnea onset. When apnea begins at an increasingly lower alveolar, more quickly reaches its maximum because rapidly arrives at the steepest part of the O2-dissociation curve. This effect explains the inverse relationship between mean and pre-apneic during apnea [17], but as we show the peak slope itself is negligibly affected by reduced resting within the normal range. We demonstrate that is inversely related to lung volume during stage 1 of apnea as a result of the greater reduction in alveolar in poorly inflated lungs per unit of O2 transferred into the pulmonary capillaries. This analysis is consistent with the inverse correlation between and lung volume [15], with the view that active upper airway closure maintains lung volume and slows [27], [28], and with our recent report that the application of continuous positive airway pressure effectively slows in lambs [29]. However, once stage 2 begins, the blood becomes the principal source of O2 and thus the only store which influences. A novel finding from our study is that reduced resting mixed-venous saturation, caused by either a reduced cardiac output or reduced hemoglobin content, strongly elevates peak, independent of metabolic O2 consumption. We show that reduced resting mixed-venous saturation accelerates via an increase in the peak value of; in other words, low mixed-venous saturation provides for a greater pulmonary O2 uptake even in the presence of a developing arterial hypoxemia, and thereby increases. A role for hemoglobin in determining is consistent with the finding that elevated hemoglobin content in adults slows during apnea [21]. In contrast, blood transfusion to raise hemoglobin content in anemic preterm infants, a common clinical therapy, has little or no impact on the severity of apneic desaturation [30]. Our proposed explanation for the lack of benefit of raising hemoglobin content via transfusion is that it also reduces heart rate [30] and cardiac output. Thus, in the newborn, the rise in mixed-venous saturation expected after transfusion is counteracted by a tendency for mixed-venous saturation to fall as a result of reduced cardiac output. An investigation that failed to find an effect of cardiac output on [23] did not account for our finding that pre-apneic and transient changes in cardiac output have opposing influence on. Importantly, we find that a transient fall in cardiac output, characteristic of bradycardia during apnea in preterm infants [2], conserves alveolar O2 via reduced and thus reduces (see Equations 10 and 11). Consistent with this finding, apneic bradycardia prevents a rapid fall in in adults [21]. We found that each of the factors examined exerts a unique and therefore recognisable influence on the time course of the desaturation process (Figure 10). Low alveolar can be recognised by a left-shift of the desaturation trajectory so that desaturation begins sooner following the onset of apnea. A steep desaturation slope in the early phase of stage 1 points to a low ratio of lung volume to metabolic O2 consumption. In the late phase of stage 1, when desaturation proceeds in a linear fashion, a low resting mixed-venous saturation accelerates and leaves the fingerprint of a low inflection point in arterial O2 desaturation; low resting mixed-venous saturation reflects low cardiac output or hemoglobin content with respect to O2 consumption. Lastly rapid during stage 2 signifies a low total blood O2 capacity with respect to O2 consumption which would point to either low blood volume or anemia. The presence of a constant R-L shunt, while having no influence on, causes a parallel downwards shift in the desaturation trajectory. The unique impact of different factors on the desaturation curve may be used to guide preventive clinical intervention. We show theoretically that the lower lung volume [31] and higher metabolic O2 consumption [32] of preterm compared to term infants predisposes to a rapid onset and progression of desaturation during apnea. Two reports offer support for this view. First, rapid desaturation occurs in infants with low functional residual capacity [15], a finding that may help to explain the more frequent O2 desaturation events during active sleep [33] when functional residual capacity is reduced. Second, frequent desaturation is characteristic of preterm infants with bronchopulmonary dysplasia (BPD) [34] whose O2 consumption is 25% greater [35], and functional residual capacity is 25% less [36], than in preterm infants without BPD; Equations 11 and 12 predict that such differences increase both immediate and peak by ∼70%. In addition, hypoventilation and reduced resting in infants with BPD, as inferred from elevated [37], further increase desaturation at apnea onset. Our finding that each rise of 1% in inspired O2 provides ∼1 s of delay (right-shift) in the onset of apneic desaturation (Equation 15) may guide the titration of supplemental O2 for the prevention of apneic hypoxemia while minimising the well known side-effects of long-term exposure to hyperoxia. Our study has implications for the management of infants in clinical care. Metabolic O2 consumption can be elevated after feeding [38], with reduced ambient temperature [39], and via the adminstration of methylxanthines [40]. Despite the success of methylxanthines in reducing the frequency of apnea and bradycardia, such treatment has surprisingly little impact on hypoxemic episodes [41]; we suggest that the elevated O2 consumption and the absence of bradycardia are likely to increase during those apneas that persist despite treatment. The severity of hypoxemic episodes is reduced by switching preterm infants from supine to prone [42], which may increase functional residual capacity [43] and improve diaphragm function, increase tidal volume and increase resting alveolar [44]. Our finding that low cardiac output leads to increased during apnea leads to the suggestion that judicious adjustment of inotropic support in infants with cardiac abnormalities could improve resting mixed-venous saturation and reduce apneic hypoxemia. Hypoxemic events become less frequent between infancy and childhood, despite an unchanged apnea frequency [28], perhaps as a result of a fall in O2 consumption per body weight. However, before this occurs, infants experience a period of susceptibility to rapid desaturation during apnea as a result of a fall in hemoglobin content and O2 affinity [22] and a rise in O2 consumption [45]. The implications for SIDS are obvious in that these changes coincide with the peak incidence for SIDS at 2–3 months [46]. SIDS also occurs disproportionately in preterm infants [46], who manifest severe anemia [22] and greater O2 consumption. Infants resuscitated from apparent life threatening events have been found to have lower hemoglobin content [47], pointing to a potential role for rapid in the progression of such events. It is possible that the rapid development of apneic hypoxemia initiates prolonged hypoxic cardiorespiratory depression that in turn leads to SIDS. We have provided a mathematical framework for quantifying the relative importance of key cardiorespiratory factors on the rate of arterial O2 desaturation during apnea, with particular relevance to preterm infants. For the first time we have demonstrated that each of the factors examined has a signature influence on the trajectory of desaturation, providing quantitative insight into the causes of rapidly developing hypoxemia during apnea.
Here we derive the explicit equations used within the current study to encapsulate key relationships pertaining to gas exchange and arterial desaturation during apnea.
When breathing stops, the flow of O2 into and the flow of CO2 out of the body cease. Such an event, termed an apnea, can be especially dangerous in preterm infants in whom it can lead to a rapid decline in arterial O2 saturation, reaching rates of 3–8% per second, rapidly reducing O2 to a level that could lead to neurological damage. Despite extensive experimental research, we have a poor mechanistic understanding of the causes of rapidly developing hypoxemia. We describe a new mathematical model that allows examination of the importance of the major cardiorespiratory factors that are likely to influence the speed at which arterial hypoxemia worsens during apnea. We found that high metabolic rate as well as reduced pre-apneic ventilation, lung volume, cardiac output, hemoglobin content, blood O2 affinity, and blood volume accelerate the development of hypoxemia during apnea. Importantly, the cardiorespiratory factors that contribute to rapid hypoxemia are all pertinent to the preterm infant during early postnatal development. Thus the newborn is highly susceptible to rapid and severe desaturation, potentially explaining the propensity of preterm infants, particularly those with apnea, to neurological impairment.
respiratory medicine/sleep and ventilation disorders
physiology/respiratory physiology
physiology/cardiovascular physiology and circulation
mathematics
physiology/integrative physiology
respiratory medicine/respiratory pediatrics
computational biology/systems biology
respiratory medicine/respiratory failure
A Model Analysis of Arterial Oxygen Desaturation during Apnea in Preterm Infants