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© 2000 International Anesthesia Research Society
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionReferences |
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The aim of our study was to validate the Nottingham Physiology Simulator (NPS) for examining pulmonary denitrogenation and apnea by reproducing the methodology and results of previous clinical studies. Only four studies provided sufficient detail in their description of their methodology to allow accurate reproduction by using the NPS or provided a sufficiently detailed description of their subjects to allow accurate modelling. The results of the NPS recreation of the studies were within 13% of the values found clinically in all cases and were within 2% in the majority of cases. The four studies included healthy and morbidly obese patients, conscious and anesthetized patients, and included examination of the effect of denitrogenation and apnea on plasma pH and on lung and arterial oxygen and carbon dioxide tensions at various lung volumes.
Implications: We used mathematical, physiological models to recreate the methods and subjects of four clinical studies investigating oxygenation and low oxygen levels during cessation of breathing. Our aim was to validate the models, allowing theoretical investigations into this area. The blindly recreated results closely matched the clinical studies, validating the models.
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Apnea during anesthesia is common, and may produce dangerous hypoxemia (1). The relative importance of the factors determining the onset and progress of hypoxemia during apnea after pulmonary denitrogenation is unclear, and a quantitative relationship between these factors and the safe duration of apnea has not been established. An investigation of denitrogenation, hypoxemia, and apnea by using the Nottingham Physiology Simulator (NPS) will allow evaluation of the importance and individual behavior of each of the contributing factors, but may only be performed after validation of the NPS in this role. We aimed to validate the NPS in examining these complex relationships.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The NPS is an original, multicompartmental, iterative, physiological simulation and has been described in detail elsewhere (2–4). Some details of the respiratory models relevant to this modelling study are described in Figure 1.
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Validation
To validate the NPS as a tool for studying the effects of denitrogenation and apnea, the methodology of four previous, clinical studies were reproduced (5–8). These studies were selected based on their adequately detailed descriptions of their subjects (e.g., weight, functional residual capacity [FRC]), the reproducibility of their methods (e.g., standard timing points for arterial gas analysis), and the detail included in their results. Furthermore, these studies each varied different factors and used different end-points over different periods. The NPS was set to replicate the mean of the patient group described in each study (i.e., using the mean weight, mean FRC) and was subjected to the same intervention as the study subjects. The modelling of the subject group and reproduction of each study’s methodology were performed by an investigator blinded to the results of the clinical studies, and no further manipulation of the NPS was performed after the reproduction of each study.
Clinical Investigations
The four papers used in attempting to validate the NPS are described below. The methods and physiological values used in modelling the subjects of the investigations are also described below.
1. McGowan and Skinner (1995) (6) demonstrated the importance of using very high oxygen fractions to assure adequate denitrogenation. They measured end-tidal oxygen fractions (FEO2) in conscious, healthy men of average body weight breathing oxygen fractions varying from 100% to 68%. The methodology for denitrogenation with 100%, 92%, 84%, and 68% oxygen were reproduced with the NPS. Several physiological values required for replicating the study group were not measured. Therefore, the following "population normal" values were assumed in modelling the subject group: ventilatory minute volume 440 mL x 13.5, oxygen consumption 3.3 mL · kg-1 · min-1, FRC 40 mL/kg, alveolar dead space 10% of tidal volume, and venous admixture 1% of cardiac output.
2. Findley et al. (1983) (7) measured arterial oxygen saturation (SaO2) and calculated PaO2 and PaCO2 in seven conscious, healthy men who were apneic at various lung volumes after breathing air. The methodologies for apnea at FRC and at total lung capacity were reproduced. The subject group was modelled by using the same "population normal" values used in modelling McGowan and Skinner’s (6) subjects (see above). The methodology for apnea at residual volume was not reproduced because the size of residual volume is heavily dependent on the effort used in exhaling. The methodologies for apnea during concurrent panting, Valsalva or Mueller maneuvers were not replicated because the description of these maneuvers did not include sufficient detail of the pressures and durations to allow accurate modelling.
3. Sasse et al. (1996) (8) measured arterial pH, PaO2, and PaCO2 during voluntary apnea at FRC in conscious, healthy individuals after breathing air. Modelling of the subject group was with the same "population normal" data used in modelling McGowan and Skinner’s subjects.
4. Berthoud et al. (1991) (5) studied six morbidly obese and six matched nonobese patients undergoing anesthesia. Subjects were anesthetized after denitrogenation and were subsequently apneic until tracheal intubation. They then received one breath of 100% oxygen to confirm tracheal intubation. The time taken for desaturation of oxyhemoglobin to 90% during apnea was recorded. Berthoud et al. (5) also examined the time taken to resaturate oxyhemoglobin to 96% although they stated neither the ventilatory rate nor the tidal volume used to ventilate their subjects’ lungs. This part of the methodology was thus not recreated. FRC of the subjects was not measured in the study, so the NPS was set up with values for FRC of 40 mL/kg for the nonobese and 14 mL/kg for the morbidly obese (9) and FRC was assumed to decrease by 50% on induction of anesthesia (9). Oxygen consumption was assumed to be 3.3 mL · kg-1 · min-1 in both groups. The minute ventilation before the induction of anesthesia was modelled as 440 mL x 13.5 for the nonobese subjects and 500 mL x 16 for the obese group, maintaining an arterial CO2 tension of 5.5–6.0 kPa. The airway was modelled as obstructed after the induction of anesthesia up to the point of tracheal intubation and was modelled as subsequently unobstructed once a tracheal tube was in place.
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Results |
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The results are presented for each of the clinical methodologies recreated.
1. McGowan and Skinner (1995) (6): End-tidal oxygen fractions reached a maximam of 90%, 80%, 74%, and 60% at 3 min, and the modelled values reached 88.7%, 81.4%, 73.8%, and 58.8% for 100%, 92%, 84%, and 68% inspired oxygen, respectively (Figure 2). Values for FEO2 differed between the NPS and the study by no more than 2% at any point during denitrogenation.
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2. Findley et al. (1983) (7): Values for SaO2, PaO2 and PaCO2 at 30 s in the clinical study for apnea at FRC were 90.3%, 8.9 kPa, and 6.4 kPa, while values predicted by the NPS were 92.3%, 9.6 kPa, and 6.2 kPa (Figure 3). Clinical values for apnea at total lung capacity were 97.0%, 12.4 kPa, and 6.0 kPa, while NPS values were 97.5%, 14 kPa, and 6.7 kPa (Figure 4).
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3. Sasse et al. (1996) (8): In their study, mean PaO2 decreased from 14.6 kPa to 8.0 kPa over 35 s, while the NPS modelled values decreased from 14.0 kPa to 8.0 kPa. Over the same period, mean PaCO2 increased from 4.94 to 6.3 kPa, while NPS values increased from 5.1 to 6.0 kPa. Mean arterial pH values decreased from 7.43 to 7.37 while NPS values decreased from 7.42 to 7.37. Figure 5 shows these results graphically.
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4. Berthoud et al. (1991) (5): The mean time taken for SaO2 to decrease to 90% in the obese subjects was 196 s and was 595 s in the nonobese subjects. The time taken for desaturation to 90% in the obese model was 214 s and was 540 s in the nonobese model.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The NPS contains complex, original respiratory models. It has been validated in predicting shunt fraction without pulmonary artery catheterization (2) and in predicting patients’ responses to changes in mechanical ventilation (3,4). It was considered unnecessary and difficult to justify further volunteer studies for validation in view of the data previously published. The accuracy of the simulator’s predictions of the results of the clinical papers was good not only in steady state conditions, but also during the phases when variables were rapidly changing.
Results derived from the NPS represent the expected mean for the population, and exact agreement between a small study and the NPS would be surprising and coincidental. Deviation from the results may be caused by inexact matching of the modelled patient to the patient group. For example, Berthoud et al. (5) did not measure FRC, but a value for FRC was required for the NPS to replicate the study’s subjects. It was thus necessary to use values for FRC determined in a different study (9), introducing potential sources of error. Equally, it is possible that our attempts to model the subjects of these previous studies were inaccurate and resulted in inadvertent matching of our results to those of the clinical studies. However, this is highly unlikely, because modelling of the subjects was performed before the recreation of the methodologies and was thus blinded.
Other investigators have modelled the physiological effects of apnea, but made assumptions that cannot be supported. One of these assumptions was that there is only a slight change in lung volume during obstructive apnea and none at all when the respiratory quotient is unity (10). During apnea, only a small proportion of the CO2 produced adds to lung volume because of its high water solubility (11), while most of the oxygen consumed is extracted from the lungs. Thus, during obstructive apnea, lung volume decreases at almost the rate that oxygen is consumed, and at lung volumes below FRC, negative intrathoracic pressures are produced. Modelling of dynamic thoracic compliance is included in the NPS, and as lung volume and intrathoracic pressure decrease, PaO2 and PaCO2 are consequently reduced.
Successful modelling of the study subjects of clinical studies and blinded reproduction of the studies’ results provides assurance that the NPS can accurately model the dynamic physiological processes in denitrogenation and apnea. Based on this validation, it seems acceptable to extend the use of the NPS to studying denitrogenation and apnea and to examine physiological extremes (e.g., severe hypoxemia), which would be impossible to study in volunteers or patients.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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- Drummond GB, Park GR. Arterial oxygen saturation before intubation of the trachea. J Anaesth 1984;56:987–93.
- Hardman JG, Bedforth NM. Estimating venous admixture using a physiological simulator. Anaesth 1998;82:346–9.
- Bedforth NM, Hardman JG, Aitkenhead AR. Predicting the patient’s response to changes in mechanical ventilation: a comparison between physicians and a physiological simulator. Br J Anaesth 1998;80:161–2.
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Hardman JG, Bedforth NM, Ahmed AB, et al. A physiology simulator: validation of its respiratory components and its ability to predict the patient’s responses to changes in mechanical ventilation. Br J Anaesth 1998;81:327–32.
[Abstract/Free Full Text] - Berthoud MC, Peacock JE, Reilly CS. Effectiveness of preoxygenation in morbidly obese patients. Anaesth 1991;67:464–6.
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McGowan P, Skinner A. Preoxygenation: the importance of a good face mask seal. Br J Anaesth 1995;75: 777–8.
[Abstract/Free Full Text] -
Findley LJ, Ries AL, Tisi GM, Wagner PD. Hypoxaemia during apnea in normal subjects: mechanisms and impact of lung volume. J App Physiol 1983;55:1777–83.
[Abstract/Free Full Text] -
Sasse SA, Berry RB, Nguyen TK, et al. Arterial blood gas changes during breath-holding from functional residual capacity. Chest 1996;110:958–64.
[Abstract/Free Full Text] -
Damia G, Mascheroni D, Croci M, Tarenzi L. Perioperative changes in functional residual capacity in morbidly obese patients. Br J Anaesth 1988;60:574–8.
[Abstract/Free Full Text] -
Farmery AD, Roe PG. A model to describe the rate of oxyhaemoglobin desaturation during apnoea. Br J Anaesth 1996;76:284–91.
[Abstract/Free Full Text] - Thomas LJ. Algorithms for selected acid-base and blood gas calculations. Physiol 1972;33:154–8.
- Nunn JF. Applied respiratory physiology. 4th ed. London:Butterworths, 1993.
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