Isoflurane Inhalation Enhances Increased Physiologic Deadspace Volume Associated with Positive Pressure Ventilation and Compromises Arterial

Oxygenation
Claudia Praetel,
MD*,

Michael J. Banner,

PhD*,

Terri Monk,

MD*,

and Andrea Gabrielli,

MD*

Departments of *Anesthesiology, Physiology, and Surgery, University of Florida College of Medicine, Gainesville, Florida

Abnormally increased physiologic deadspace volume (Vdphys), consisting of alveolar deadspace volume and airway deadspace volume, is one of several causative factors predisposing to compromised arterial blood gas exchange. We compared the effects of two methods of general anesthesia on Vdphys when combined with positive pressure ventilation (PPV): total IV anesthesia (TIVA) and inhaled anesthesia with isoflurane. Forty patients with no history of pulmonary pathology undergoing elective surgery in the supine position were studied. A crossover design was used, and all patients received both anesthetic methods sequentially in randomized order. PPV and TIVA significantly increased Vdphys compared with baseline (preoperative and breathing spontaneously) from 164 60 mL to 264 79 mL (P 0.05). Isoflurane inhalation combined with

PPV significantly enhanced this increase, resulting in a twofold increase in Vdphys to 315 80 mL (P 0.05). Also, alveolar deadspace volume increased by more than 200% with isoflurane. Furthermore, isoflurane inhalation (1.15% end-tidal concentration) resulted in impaired arterial oxygenation, as evidenced by a significant decrease in the Pao2/fractional inspired oxygen concentration ratio compared with baseline values from 387 35 to 310 70 (P 0.05). Although significant increases in Vdphys resulted with PPV combined with TIVA, these adverse changes were much less compared with isoflurane inhalation and PPV. These findings may apply to subjects with compromised pulmonary function (i.e., acute respiratory distress syndrome or severe inhalational burn injury). (Anesth Analg 2004;99:110713)

ncreased physiologic deadspace volume (Vdphys) predisposes to compromised arterial blood gas exchange, especially for patients with preexisting pulmonary disorders, i.e., inhalational burns, severe chronic obstructive pulmonary disease (COPD), or acute respiratory distress syndrome (ARDS). Incomplete alveolar gas mixing with areas of increased alveolar ventilation/ A/Q ) mismatching within terminal respiraperfusion (V tory unitsand the preferential spread of distribution of ventilation to areas of less perfusionincreases alveolar deadspace volume (Vdalv). This increase in Vdalv, in unison with airway deadspace volume (Vdaw), constitutes increased Vdphys (1). Another important cause for abnormalities in gas exchange and reduction in efficiency of ventilation during anesthesia is atelectasis of dependent lung regions, which causes an
Accepted for publication April 23, 2004. Address correspondence and reprint requests to Michael J. Banner, PhD, University of Florida College of Medicine, Department of Anesthesiology, PO Box 100254, Gainesville, FL 32610-0254. Address e-mail to MBanner@anest.ufl.edu. DOI: 10.1213/01.ANE.0000131727.52766.F7
2004 by the International Anesthesia Research Society 0003-2999/04

increase in right-to-left intrapulmonary shunting of blood (2). Nuckton et al. (3) identified increased Vdphys as an independent predictor for mortality in a group of 179 patients with ARDS. Hubble et al. (4) previously demonstrated the usefulness of the Vdphys/tidal volume ratio in predicting successful extubation in critically ill pediatric patients. This study was designed to compare the effects of positive pressure ventilation (PPV) and total IV anesthesia (TIVA) versus PPV and inhaled anesthesia on Vdphys during general anesthesia. PPV, particularly at high lung inflation pressures, maldistributes A/Q (i.e., inhaled air, predisposing to areas of high V increased Vdalv), low VA/Q (i.e., relative shunt), and impaired lung carbon dioxide (CO2) elimination rate (5,6). Several studies indicate that inhaled anesthetics have regional effects on pulmonary blood flow and A/Q (7,8) and on airway smooth muscle (9). One V study demonstrated that propofol (unlike potent inhaled anesthetics) does not inhibit, but rather potentiates, hypoxic pulmonary vasoconstriction in a dog
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model (10). Furthermore, in contrast to inhaled anesthesia, propofol does not consistently decrease Pao2 (11). We chose two popular modes of general anesthesia combined with PPV for comparisonTIVA with propofol/fentanyl infusions and inhaled anesthesia with isofluraneto test the hypothesis that TIVA would have a lesser effect on Vdphys.

Table 1. Patient Demographic Data (n 40) Variable Age (yr) Sex (male/female) ASA class I/II/III Weight (kg) Height (cm) BMI (kg/m2) Obesity (BMI 30 kg/m2) Active smoker (n) Smoking history (n) Types of surgery (n) Abdominal Anterior cervical spine Hepatic Peripheral vascular
Values are mean sd or number of patients. BMI body mass index.

Value 58 15 17/23 1/10/29 81 19 170 11 28 6 15 6 16 14 7 8 11

Methods
The IRB of the University of Florida approved the study protocol, and written, informed consent was obtained from all patients before surgery. Forty adults (23 women and 17 men; age, 58 15 yr; weight, 81 19 kg) were studied who were scheduled for elective surgery in the supine position with general anesthesia (Table 1). Exclusion criteria were thoracic surgery or neurosurgery, orthopedic surgery with tourniquet use (because release of microemboli would be a possible confounding variable), clinical evidence of COPD, interstitial lung disease, heavy smoking (60 packyears), valvular cardiac disease, or the anticipated intraoperative use of nitrates. The following two-step sequence protocol for general anesthesia was used. Patients were randomly assigned to initially receive either TIVA (propofol 150 g kg1 min1 and fentanyl 12 g kg1 min1) for 45 min followed by inhaled anesthesia (isoflurane at 1 minimum alveolar anesthetic concentration [MAC]/1.15 vol% end-tidal concentration and fentanyl 12 g kg1 min1) or vice versa. Vecuronium was used for maintaining muscle relaxation during both techniques. The fractional inspired oxygen concentration (Fio2) was kept constant at 0.40, and nitrous oxide (N2O) was not used during either technique. Data were collected during three phases: before surgery while patients breathed room air spontaneously, 45 min after induction, at tracheal intubation and PPV while receiving TIVA or inhaled anesthesia with isoflurane (as described above), and then 60 min after conversion to the other type of anesthesia. The switch from inhaled anesthesia to TIVA was facilitated by temporarily using higher fresh gas flows without changing the Fio2 and then allowing a minimum 60min equilibration period to achieve a negligible endtidal isoflurane concentration (0.1%). Arterial blood samples obtained before and during surgery were analyzed immediately. Arterial Pco2 and body weight (BW) were subsequently entered into a portable bedside respiratory monitor (CO2SMO; Novametrix/Respironics, Medical Systems, Wallingford, CT). The monitor was calibrated on a daily basis at the beginning of each testing sequence. A combined

pressure/flow/CO2 sensor from the monitor was attached to the patient. Respiratory variables were computed during steady-state breathing with a moving average over the last 8 breaths. The respiratory monitor uses the method originally described by Fowler (12) and validated by Arnold et al. (13) in 1996; it requires single breath measurements of exhaled CO2 and tidal volume. CO2 is measured by a mainstream infrared absorption technique with a solid-state sensor. Exhaled flow is integrated with time to calculate volume. Exhaled CO2 is plotted over volume per breath. This is volume-based and not traditional time-based capnography. The respiratory monitor provides a single-breath exhaled CO2 wave form that can be divided into 3 phases. Phase 1 represents CO2-free gas from the conducting airways, Phase 2 represents a mixture of gas from both airway deadspace and alveolar deadspace, and Phase 3 (alveolar plateau) represents gas from alveolar ventilation only. Vdphys, composed of Vdalv and Vdaw, is calculated by analysis of the exhaled CO2 wave form (Fig. 1). The steep portion of the curve (Phase 2) reflects a rapid transition from airway to alveolar gas. The extrapolated slope of the alveolar plateau (Phase 3) is used. A line is drawn perpendicular to the x axis, intercepting the slope and creating 2 equal triangular areas around the CO2 wave form of Phase 2 (areas p and q) and thus providing the midpoint of the transition from a Vdaw to alveolar gas (14) (Fig. 1). The patients Paco2, obtained separately from an arterial blood gas, is manually entered into the monitors computer to calculate the various Vd components. Before surgery, with the patients lying in a supine position and breathing spontaneously, the respiratory monitors combined pressure/flow/CO2 sensor was connected to a mouthpiece, and a nose clip was attached. After 5 min, an arterial blood gas was obtained from a radial artery catheter placed electively, and all

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Figure 1. Diagrammatic view of the respiratory monitor, showing the combined pressure/flow/ CO2 sensor between the endotracheal tube and the ventilator breathing circuit. The graph on the monitor is a plot of exhaled CO2 over tidal volume, i.e., volume-based capnography. After the patients Paco2, obtained from a blood gas analysis, is entered into the monitor, the various deadspace volume components are calculated. Note the areas corresponding to alveolar and airway deadspace volumes, the sum of which is physiologic or total deadspace volume (see text).

respiratory measurements were determined. Preoperative sedation was administered after these baseline data were obtained. Surgical procedures included anterior cervical spine, peripheral vascular, hepatic, and abdominal surgery in the supine position. In patients scheduled for epidural catheter placement for postoperative pain control, the infusion was started after conclusion of all measurements. General anesthesia was induced by following a standardized protocol (thiopental 35 mg/kg, fentanyl 23 g/kg, and vecuronium 0.15 mg/kg). After tracheal intubation, volume ventilation (Aestiva/5 or Ohmeda 7800; Datex-Ohmeda) was started: tidal volume of 8 mL/kg ideal BW, inhalation/exhalation time ratio of 1:2, and ventilator frequency of 8 10 breaths/min to provide a partial pressure of end-tidal CO2 between 30 and 35 mm Hg. The Fio2 was set at 0.40, and the pulse oximeter hemoglobin saturation was maintained 95%.

N2O was not used. Minute ventilation and mean airway pressure remained unchanged throughout the study period. A bispectral index (BIS) monitor, a twitch monitor, and invasive arterial blood pressure monitoring were used in addition to standard ASA monitors. Muscle relaxation was maintained at 90%95% motor blockade, and the train-of-four ratio was assessed before each measurement. For measurements other than preoperative measurements, the respiratory monitor sensor was positioned between the Y-piece of the ventilator breathing circuit and the endotracheal tube. Surgery was in progress during the study. Respiratory measurements were obtained only during hemodynamically stable intervals to ensure uniform conditions; i.e., a measurement was postponed if the time frame coincided with intraoperative hypotension or hypertension. Manipulation of the depth of anesthesia and/or a fluid bolus were used to restore hemodynamic variables if needed. Fentanyl, in

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Table 2. Hemodynamic, Respiratory, and Bispectral Index Characteristics in 40 Patients Before Surgery (Pre-op), During Positive Pressure Ventilation (PPV) in Combination with Total Intravenous Anesthesia (TIVA), or During Isoflurane (ISO) Inhalation Variable Heart rate (bpm) Mean arterial blood pressure (mm Hg) Bispectral index Core temperature (C) Breathing frequency (breaths/min) Exhaled tidal volume (mL) Minute ventilation (L/min) Peak inflation pressure (cm H2O) Lung CO2 elimination rate (mL/min) Pre-op 79 12 88 18 N/A N/A 13 4 523 217 6.1 2.4 N/A 161 70 PPV and TIVA 79 13 84 12 31 11 36.4 0.4 8 0.7 672 180 6.0 1.4 21 5.6 125 36 PPV and ISO 80 13 84 10 33 9 36.3 0.5 8 0.7 689 145 6.0 1.4 21.2 5.2 121 33

Values are mean sd. N/A not applicable. No statistical difference was found between the two types of anesthesia (PPV with TIVA versus PPV with ISO).

25-g increments, was administered in response to increases in heart rate and systolic arterial blood pressure. The study was stopped in cases of hemodynamic instability due to sudden intraoperative blood loss. A crossover experimental study design was used that combined the data for each condition regardless of the order of presentation in the particular patient. Measured values showed a normal distribution. Unless otherwise indicated, data are presented as mean sd. Effects of PPV and method of anesthesia on Vdphys and the Fio2/Pao2 ratio were analyzed by twofactor repeated-measures analysis of variance followed by a post hoc Scheffe test. The following a priori null hypotheses were tested: 1. The combination of PPV and TIVA has no effect on Vdphys or arterial oxygenation compared with spontaneous ventilation. 2. The combination of PPV and inhalation of isoflurane has no effect on Vdphys or arterial oxygenation compared with PPV with TIVA and spontaneous ventilation. A null hypothesis was rejected with an error of 0.05. Statistical analysis was performed with commercially available software (SPSS; SPSS Inc., Chicago, IL).

relation to awake, spontaneous ventilation, the effects of PPV and TIVA versus inhaled isoflurane are shown in Figures 2 and 3. PPV during TIVA significantly increased Vdphys compared with baseline (before surgery and while breathing spontaneously) (P 0.05). When PPV was combined with inhalation of isoflurane, this resulted in a significantly larger increase in Vdphys (P 0.05) regardless of the order in which the anesthetics were administered. Vdalv, usually very small in patients without pulmonary pathology, constituted the major component of the increase in Vdphys. Vdalv increased approximately 190% from baseline as a result of PPV and TIVA and by approximately 225% during PPV with isoflurane anesthesia compared with preoperative values. Mechanical ventilation and TIVA did not appreciably increase Vdaw. PPV and inhaled isoflurane did cause a significant increase in Vdaw compared with spontaneous ventilation (Fig. 3). Note that before surgery, during spontaneous ventilation, the total Vd or Vdphys was 164 mL on average. With the application of PPV and TIVA, the mean Vdphys increased to 264 mL, and with the addition of isoflurane, it increased further to 315 mL. Inhaled 1.15% isoflurane (1 MAC) was associated with a deterioration of the arterial oxygen partial pressure, as evidenced by a significant decrease in the Pao2/Fio2 ratio from 387 35 to 310 70 (P 0.05) (Fig. 2).

Results
Forty patients were enrolled and completed this crossover study (Table 1). Four patients were excluded because of inability to follow instructions during the preoperative respiratory assessment or because of intraoperative acute blood loss with volume resuscitation. There were no significant changes in depth of anesthesia, cardiovascular variables, core temperature, peak inflation pressure, minute ventilation, pulmonary mechanics, or lung CO2 elimination rate between the two methods of anesthesia (Table 2). In

Discussion
The aim of this study was to compare two routine methods of general anesthesia and their effects on Vdphys and pulmonary gas exchange. PPV combined with TIVA was used primarily to assess the effects of mechanical ventilation on Vdphys. PPV and isoflurane inhalation were used to assess the combined effects of mechanical ventilation and inhaled anesthesia on Vdphys.

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Figure 2. The effects of spontaneous ventilation, positive pressure ventilation (PPV) with total IV anesthesia (TIVA), and PPV combined with inhaled isoflurane on physiologic deadspace volume (Vdphys) and arterial oxygenation, as reflected by the Pao2/ fractional inspired oxygen concentration (Fio2) ratio, are shown. PPV and TIVA resulted in a significant increase in Vdphys. Significantly larger increases in Vdphys, along with a significant decrease in arterial oxygenation, resulted when PPV was combined with isoflurane, regardless of the order in which the anesthetics were administered. P 0.05 compared with *spontaneous ventilation and compared with PPV with TIVA. Data are mean sd. PREOP before surgery.

Figure 3. Physiologic deadspace volume (Vdphys) changes, consisting of alveolar (Vdalv) and airway deadspace volume (Vdaw) components, are shown during spontaneous ventilation, positive pressure ventilation (PPV) with total IV anesthesia (TIVA), and PPV combined with inhaled isoflurane. PPV and TIVA increased Vdalv significantly compared with spontaneous ventilation. Significantly greater increases in Vdalv resulted when PPV was combined with isoflurane, irrespective of the order in which the anesthetics were given. A significant increase in Vdaw resulted when PPV was combined with isoflurane. Ostensibly, increases in Vdphys were the result of increases in Vdalv. P 0.05 compared with *preoperative data and compared with PPV with TIVA. Data are mean sd.

Our primary findings were that PPV during TIVA increases Vdphys, but the combination of PPV and isoflurane inhalation caused significantly larger increases in Vdphys. Isoflurane anesthesia also resulted in a significant decrease of arterial oxygenation, as evidenced by a decreased Pao2/Fio2 ratio. A similar finding has been described in a prospective study of 466 patients undergoing cardiac surgery. The authors reported that patients anesthetized with isoflurane had a lower Pao2/Fio2 ratio at one and six hours after cardiopulmonary bypass compared with TIVA or IV midazolam and fentanyl combined with enflurane (15). We speculate that different physiologic mechanisms may account for the significant change in Vdphys observed with the two methods of anesthesia. During PPV with controlled mechanical ventilation in a supine paralyzed patient, as during general anesthesia, a disproportionate amount of the tidal volume is directed toward the anterior nondependent lung A/Q regions, thus predisposing to areas of increased V mismatching, i.e., increased Vdalv (5). Spontaneous ventilation, conversely, promotes more normal distri A/Q matching (6,16). Downs and Mitchell bution of V (16) showed that increases in Vdphys were related to the rate of mechanical ventilator cycling, regardless of

whether positive end-expiratory pressure was used. Another ventilator-related cause of ventilated and underperfused alveoli (i.e., Vdalv) is increased mean positive airway pressure. Increased alveolar pressure predisposes some alveoli to overly distend, collapsing local pulmonary capillaries and decreasing perfusion, A/Q (i.e., West; thus leading to areas of increased V Zone 2 converted to Zone 1) (17). The observed increase in Vdphys during TIVA and PPV may or may not be entirely attributable to PPV alone, because the effect of TIVA on Vdphys is unknown. A possible reason as to why Vdaw did not appreciably increase during PPV with TIVA (Fig. 3) may be the moderate tidal volumes used in our study (i.e., 8 mL/kg BW). Comparisons of the effects of TIVA versus isoflurane anesthesia on arterial oxygenation during onelung ventilation (OLV) have yielded controversial results. Recent studies demonstrated lower Pao2 with desflurane (18) and isoflurane anesthesia during OLV in pigs as compared with propofol anesthesia, whereas perfusion of the nonventilated lung and shunt fraction remained comparable (19). Propofol anesthesia was compared with inhaled anesthesia with sevoflurane and isoflurane during OLV in patients undergoing esophageal surgery and resulted in improved oxygenation and a lower shunt fraction (20). Possible confounding factors are differences in the depth of anesthesia or metabolic rate and the absence of randomization of experimental sequence (order bias). In another report, the effects of propofol and

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isoflurane anesthesia on oxygenation and shunt fraction during OLV were investigated, and lower Pao2 and threefold higher shunt fractions were reported during isoflurane anesthesia compared with anesthesia with propofol (21). However, other studies did not support these findings (22). The effects of isoflurane inhalation on pulmonary vascular regulation and bronchomotor tone may constitute a mechanism for the larger increase in Vdalv and Vdaw in our study population. Numerous control mechanisms responsible for alterations in pulmonary vascular tone have been elucidated for both animal and human lungs. The pulmonary vasculature is affected by complex neural, humoral, and local mechanisms and is evidently in a state of active vasodilation, according to recent work regarding the role of nitric oxide in pulmonary vascular resistance in humans (1,23). Isoflurane anesthesia caused systemic vasodilation but did not exert a vasodilator influence on the pulmonary circulation in the setting of increased pulmonary vascular resistance after left lung autotransplantation in dogs (24). Extensive work by Murray, Fujiwara, and Gambone in the 1990s (25,26) on the effects of general anesthesia on the pulmonary vascular pressure-flow relationship demonstrated that there are various mechanisms whereby inhaled anesthesia can alter pulmonary vasoregulation. Compared with the conscious state, none of the volatile anesthetics exerts a net effect on the canine pulmonary circulation, but the above-mentioned results support the concept that they act to reduce the magnitude of response to various endogenous vasodilator metabolites that mediate pulmonary vasorelaxation at clinically relevant concentrations. This would suggest that isoflurane inhalation may lead to changes in pulmonary vasomotor regulation that decrease local alveolar perfusion, pre A/Q ). cipitating an Vdalv-like effect (areas of high V Bronchodilation is a well known effect of inhaled anesthesia (27). We observed a significant, although slight, increase in Vdaw during PPV and isoflurane anesthesia compared with spontaneous breathing. Another possible contributing mechanism involves the pathways of pulmonary collateral ventilation, which represent nongravitational determinants of the distribution of ventilation. A study investigating the influence of halothane and isoflurane on pulmonary collateral ventilation in dogs reported a 50% reduction in the flow resistance to collateral ventilation at 1.4 A/Q MAC halothane and 0.8 MAC isoflurane (28). V mismatch caused by alterations in collateral ventilation may have a contributory role, but the simplest explanation for our findings may indeed be that the bronchodilation caused by isoflurane predisposes to increases in Vdaw. This study has several limitations. Vdalv is influenced by changes in cardiac output (pulmonary blood flow). Pulmonary artery catheters were not inserted,

and, thus, we did not obtain cardiac output measurements. There were no cases of intraoperative arrhythmias. Arterial systolic, diastolic, and mean blood pressures and heart rates were not significantly different during TIVA and inhaled anesthesia, suggesting cardiovascular stability. There was no evidence to suggest any significant decreases in cardiac output that would have predisposed to increases in Vdalv. In addition, we stopped our investigation in two patients after episodes of significant blood loss and arterial blood pressure changes with ensuing volume resuscitation, and we excluded their data. Also, changes in the depth of anesthesia and metabolic rate could act as possible confounding variables. In this study, recorded BIS values and hemodynamic characteristics did not reveal a significant difference in depth of anesthesia during TIVA and inhaled isoflurane. Further, we inferred a stable metabolic profile because of intraoperative stability in cardiovascular measurements, core temperature, and lung CO2 elimination rate. The awake measurements were undertaken during spontaneous breathing at a comparable minute volume (slightly smaller tidal volume and higher breathing frequency) to that used in the operating room. Ventilator settings were kept constant during the surgery. In summary, for patients with relatively normal pulmonary function, the transition from spontaneous ventilation to TIVA and PPV resulted in significant increases in Vdphys. Isoflurane inhalation and PPV caused significantly larger increases in Vdphys regardless of the sequential order in which the anesthetics were administered. As a result, arterial blood gas exchange was compromised as reflected by a significant decrease in the Pao2/Fio2 ratio. In patients without pulmonary impairment, this may be offset by an increase in minute ventilation. Our results could imply adverse sequelae for patients with severe preoperative A/Q pulmonary pathology associated with severe V mismatch and a considerable increase in Vd/tidal volume (inhalational burn injury, severe COPD, ARDS, and so on) requiring surgery and anesthesia. Because fewer untoward changes in pulmonary function were found with TIVA and PPV, this combination may be a more appropriate anesthetic choice for patients with A/Q relationships and preexisting grossly abnormal V increased Vdphys. Future studies directed at examination of the effects of inhaled and IV anesthesia on Vdphys and arterial blood gas exchange in patients with severely compromised pulmonary function would be needed to validate this possible implication, given the pathophysiological pulmonary differences in such patients.
The authors thank Nikolaus Gravenstein, MD, and Christoph Seubert, MD, for their valuable assistance and critical analysis of the data.

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