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PEDIATRIC ANESTHESIA: CRITICAL CARE AND TRAUMA

Factors Determining the Onset and Course of Hypoxemia During Apnea: An Investigation Using Physiological Modelling

Hardman, Jonathan G. FRCA; Wills, Jonathan S. FRCA; Aitkenhead, Alan R. FRCA

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doi: 10.1097/00000539-200003000-00022
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Abstract

The hypoxemia caused by apnea after the induction of anesthesia is potentially dangerous and has been the subject of previous investigations (1). However, the impact of the factors determining the onset and course of hypoxemia has been poorly identified and quantified. These factors include the duration of pulmonary denitrogenation, oxygen consumption, functional residual capacity (FRC), and ventilatory minute volume before apnea (2–5). The profile of hypoxemia during apnea may also be affected by airway obstruction, preventing passive entry of fresh gas. In addition, desaturation of oxyhemoglobin is significantly delayed by breathing oxygen-enriched gas mixtures before the induction of anesthesia in a tidal or vital capacity manner (1,6–10). The relative importance of these factors in determining the profile of hypoxemia during apnea after denitrogenation has not been adequately clarified by clinical investigations, and no quantitative relationship between these factors and the safe duration of apnea has been established. We used the Nottingham Physiology Simulator (NPS) to investigate the effect of various factors on the onset and course of hypoxemia during apnea after denitrogenation.

Methods

The NPS is a digital computer simulation of advanced, original, multicompartmental, physiological models and is described in detail elsewhere (11–14). The respiratory models include anatomical and equipment dead spaces and 100 parallel pulmonary compartments with independent compliance curves and ventilation/perfusion ratios. It has been validated in investigating hypoxemia, apnea, and denitrogenation by successfully reproducing the methods and results of previous studies (14).

The model was set to simulate a healthy, 70-kg man. Several factors were considered as potential determinants of the oxyhemoglobin desaturation profile during apnea. These are listed in Table 1 with the standard value assigned to each. One factor at a time was varied while the other factors were kept constant at the standard values. The examination of each factor was performed as a “clean” run, with the NPS initialized with new data before each examination. For each set of conditions generated, the modelled patient was denitrogenated by breathing 100% oxygen (in a nonrebreathing fashion) and was then “rendered” apneic until arterial oxygen saturation (SaO2) decreased to 50%. Each set of conditions was examined with the modelled airway closed and open during apnea. The ambient gas during apnea with an open airway was air. The modelled patient made no respiratory efforts during apnea with a closed airway, which would otherwise have caused fluctuating intrathoracic pressures and elevated oxygen consumption. Finally, the model was set with the standard values given in Table 1, an open airway, and 100% oxygen as the ambient gas during apnea, and the time taken to reach 50% arterial oxyhemoglobin saturations was examined.

Results

Figures 1–5 show the onset and course of hypoxemia (the hypoxemia profile) from the start of denitrogenation to the achievement of an arterial oxyhemoglobin saturation of 50% under a variety of conditions. All the curves showed a rapid increase in PaO2 during denitrogenation that slowed as its maximum approached. Apnea with an open airway resulted in a linear decline of PaO2 until oxygen began to unload from hemoglobin, at which point the rate of decline slowed. Apnea with a closed airway resulted in a more rapid decrease in PaO2. The rate of decline increased during apnea until oxygen began to be extracted from hemoglobin (Figure 1). Progression of oxyhemoglobin saturations from 90% to 50% was rapid and was associated with a brief reduction in the rate of decrease of PaO2 in all the situations examined.

Figure 1
Figure 1:
The effect of varying the pulmonary venous admixture on the hypoxemia profile during apnea with a closed airway and an open airway. The dashed, vertical line marks the start of apnea, and the open, square markers show the point of 90% oxyhemoglobin saturation. All curves terminate at the point of 50% oxyhemoglobin saturation. The ambient gas during apnea is air.
Figure 2
Figure 2:
The effect of varying the duration of denitrogenation on the hypoxemia profile during apnea with a closed airway and an open airway. The dashed, vertical line marks the start of apnea, and the open, square markers show the point of 90% oxyhemoglobin saturation. All curves terminate at the point of 50% oxyhemoglobin saturation. The ambient gas during apnea is air.
Figure 3
Figure 3:
The effect of varying the oxygen consumption on the hypoxemia profile during apnea with a closed airway and an open airway. The dashed, vertical line marks the start of apnea, and the open, square markers show the point of 90% oxyhemoglobin saturation. All curves terminate at the point of 50% oxyhemoglobin saturation. The ambient gas during apnea is air.
Figure 4
Figure 4:
The effect of varying the functional residual capacity on the hypoxemia profile during apnea with a closed airway and an open airway. The dashed, vertical line marks the start of apnea, and the open, square markers show the point of 90% oxyhemoglobin saturation. All curves terminate at the point of 50% oxyhemoglobin saturation. The ambient gas during apnea is air.
Figure 5
Figure 5:
The effect of varying the ventilatory minute volume preceding apnea on the hypoxemia profile during apnea with a closed airway and an open airway. The dashed, vertical line marks the start of apnea, and the open, square markers show the point of 90% oxyhemoglobin saturation. All curves terminate at the point of 50% oxyhemoglobin saturation. The ambient gas during apnea is air.

Table 1 shows the time taken from the start of apnea to reach 50% oxyhemoglobin saturation. An open airway allowed more prolonged apnea than a closed airway (11 min 37 s vs 8 min 13 s), and provision of 100% oxygen to the open airway greatly extended the “safe” duration of apnea (66 min 20 s) when other factors were normal. Duration of denitrogenation, ventilatory minute volume preceding apnea, respiratory quotient, fractional venous admixture, and hemoglobin concentration had only small effects on the time taken to reach 50% oxyhemoglobin saturation, although the profile of PaO2 during apnea was affected by all the factors. However, FRC and oxygen consumption had significant effects on the course of hypoxemia in the apneic patient model with both closed and open airways.

Table 1
Table 1:
Values of Physiological Factors Used in the Investigation and Apnea Times to 50% Oxyhemoglobin Saturation with Either a Closed or an Open Airway

During apnea, PaCO2 increased at approximately 0.43 kPa/s, and arterial pH decreased at approximately 0.02/s, initially. The rate of change of arterial pH reduced during apnea, so that arterial pH decreased to 6.7 kPa after 66 min apnea with an open airway and 100% oxygen delivered as the ambient gas. Airway obstruction during apnea reduced the rate of rise of PaCO2 and the rate of decrease of pH by approximately 2%.

Extending the duration of denitrogenation from 1 to 2 min (Figure 2) increased the maximal PaO2 from 69.6 to 82.9 kPa. A further increase to 3 min (Figure 2) increased the maximal PaO2 to 85.8 kPa. The rate of rise of PaO2 during denitrogenation was reduced by a reduction in ventilatory minute volume (Figure 5) and by an increase in FRC (Figure 4).

Discussion

We considered the NPS to be an appropriate tool for examining this complex, physiological scenario. Its previous validation (11,13,14) provides assurance that conclusions based on an investigation using the NPS should be reliable, although it should be stressed that it is impossible to validate the model fully at the extremes which are modelled in this study.

Our findings agree with the findings of previous studies in the effect of the various factors studied (2,3,5). Unlike previous studies, ours allows analytical separation of the contributing factors, enabling an evaluation of the importance and individual behavior of each. We examined apnea after denitrogenation because apnea at FRC without denitrogenation produces a rapid hypoxemia (15,16) that is more difficult to analyze than the more gradual hypoxemia after denitrogenation. In addition, examination of apnea after denitrogenation answers more clinically relevant questions because patients receiving anesthesia usually have oxygen-enriched inspired gas and often their lungs have been denitrogenated.

We used an arbitrary end-point of 50% arterial oxyhemoglobin saturation. It may be seen in Figures 1–5 that the desaturation of hemoglobin is rapid and occurs late in hypoxemia after denitrogenation. The use of higher saturation end-points would have produced a predictably earlier termination, whereas use of lower end-points may have stretched the credibility and validity of the NPS too far. Validation of the NPS did not extend to its use in examining the profile of severe hypoxemia. Thus, predictions of physiological behavior at these extremes are more tentative. In addition, the NPS models do not include the possibility of a transfer from aerobic to anaerobic metabolism, but assume that oxygen consumption remains constant during desaturation, so predictions of behavior during severe hypoxemia are less confident. The results of simulations of physiological scenarios can only predict the behavior of the population mean. These predictions should thus be applied with caution to individuals, particularly if physiological data concerning the individual is incomplete.

Other investigators have attempted to produce mathematical models of the hypoxemia of apnea, but they made assumptions that render their conclusions difficult to support. Farmery and Roe (17) assumed that CO2 enters the alveoli as quickly as it is produced during apnea, just as O2 is extracted from the alveoli as quickly as it is consumed. However, the high water solubility of CO2 (18) ensures that, during obstructive apnea, lung volume decreases at a rate almost equal to the rate of O2 consumption and at lung volumes below FRC, negative intrathoracic pressures are produced, consequently increasing the rate of decrease of PaO2 and reducing the rate of increase of PaO2. The compliance of the chest wall may thus have an important effect on the course of hypoxemia during obstructive apnea. The NPS includes detailed modelling of dynamic thoracic compliance. If lung volume is reduced as far as residual volume, intrathoracic pressure decreases even more rapidly for a given reduction in volume. This may be seen in Figures 1–5, where the rate of decrease of PaO2 increases as lung volume passes residual volume. It may also be noted that these curves have a second (positive) inflection near their end. This reduction in the rate of decrease of PaO2 is caused by the beginning of extraction of oxygen from hemoglobin in significant amounts. The desaturation of hemoglobin is a relatively rapid, terminal event during apnea after denitrogenation, and for this reason, curves of PaO2 over time are shown rather than of saturation against time. Markers on each figure show the point of 90% oxyhemoglobin saturation. In all cases, this only slightly precedes the termination of the curves at 50% oxyhemoglobin saturation.

During apnea, the open airway prevents the development of negative intrathoracic pressures by allowing ingress of ambient gas. The metabolic demand for oxygen can be almost satisfied if the ambient gas is 100% oxygen (19) and apneic oxygenation has been demonstrated in vivo (20). Previous clinical work (21) examining hypoxemia during the apneic part of testing for brainstem death supports the finding that air as the ambient gas provides a much shorter duration of safe apnea. The provision of 100% oxygen to the apneic patient with an open airway seems to provide a prolonged period safe from hypoxemia. However, in these circumstances, the NPS prediction indicates that by the time hemoglobin is becoming significantly desaturated (approximately 60 min), PaCO2 has increased to 34 kPa and pH has decreased to 6.7. These modelled changes of PaCO2 and pH are similar to those found clinically (15,16). Hypercapnia and consequent acidemia may be more dangerous than hypoxemia during prolonged apnea. However, during the brief apnea after the induction of anesthesia, delivery of 100% oxygen to the lungs via a clear airway may avoid hypoxemia and relief of airway obstruction while 100% oxygen is delivered will be accompanied by ingress of gas into the lungs, reducing the rate of desaturation of hemoglobin.

All of the factors examined had a greater effect on the time to desaturate during apnea with an open airway than during apnea with a closed airway. Factors that had little effect on the time to desaturate were:

  • Reduced hemoglobin concentration: If oxygen stores are limited (e.g., reduced FRC), increased blood stores may have a significant effect.
  • Increased respiratory quotient: This had minor effects related to shift of the oxyhemoglobin saturation curve. Even during large increases in respiratory quotient, there is little dilution of alveolar oxygen caused by the great water solubility of CO2.
  • Increased pulmonary venous admixture (Figure 1): It is of interest that the hypoxemic patient presenting for surgery will not necessarily desaturate more quickly than a healthy patient. Compared with the healthy patient, the “shunting” patient will show a smaller increase in PaO2 but a similar increase in PaO2 during denitrogenation. However, many patients with elevated shunt fractions also have a reduced FRC (e.g., pulmonary edema) and will thus have an accelerated onset of hypoxemia compared with those with “isolated” shunt (e.g., intracardiac right to left shunt).

Factors that had a moderate effect on the time to desaturate were:

  • Reduced ventilatory minute volume preceding apnea (Figure 5): Accelerated desaturation after hypoventilation during denitrogenation is caused by a combination of hypercapnia (shifting the oxyhemoglobin dissociation curve), mild initial hypoxemia, and inadequacy of denitrogenation.
  • Reduced duration of denitrogenation (Figure 2): When the duration of denitrogenation is reduced to 60 seconds the maximal PaO2 achieved is only 69.6 kPa, while a 3-minute denitrogenation achieves a maximal PaO2 of 85.8 kPa. It is known that a small number of vital capacity breaths provide adequate denitrogenation in certain clinical situations (10,22), although physiological variation may make this method unreliable (23). It is likely that the time to maximal denitrogenation is related to the oxygen consumption, the FRC volume, and the rate of oxygen addition to the alveoli. This study indicates that extension of the duration of denitrogenation from one to three minutes extends the time to desaturation by 31 seconds in obstructive apnea and by 134 seconds in nonobstructive apnea. The eventual desaturation in the patient with a closed airway may be related to the development of negative intrathoracic pressure rather than simply “running out” of oxygen, in which case residual alveolar nitrogen may postpone development of negative intrathoracic pressures. This area requires further investigation.

Factors that had a large effect on the time to desaturate were:

  • Increased oxygen consumption (Figure 3): Major disturbances in this factor cause large changes in the safe duration of obstructive and nonobstructive apnea. This is of particular relevance in pyrexial or pregnant patients and in those patients with pharmacologically elevated oxygen consumption, such as those receiving suxamethonium.
  • Reduced FRC (Figure 4): Reducing the FRC reduces the reservoir of oxygen and hastens the development of negative intrathoracic pressure. This combination of effects makes the FRC volume fundamental in determining desaturation time. Patients with reduced thoracic compliance (e.g., kyphoscoliosis) or with increased intraabdominal pressure (e.g., pregnancy, ascites) may be observed to desaturate quickly (2,3,22,24), and the induction of anesthesia itself causes a 50% reduction in FRC volume (24).

This study would be impossible to perform clinically, because neither patients nor volunteers could be subjected to such degrees of hypoxemia, and the factors affecting the hypoxemia profile could not be identified and varied in isolation. The study has implications for clinical anesthesia. Hemoglobin desaturation during apnea is delayed by maintenance of an open airway and is delayed further by provision of oxygen to the open airway. Rapid desaturation should be anticipated in those situations that combine risk factors (risk of airway obstruction, high oxygen consumption, low FRC)—these situations include anesthesia for small children, and pregnant and obese patients.

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