Praetel_2004_Anesth._Analg

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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 andairway deadspace volume, is one of several causative

factors predisposing to compromised arterial blood gasexchange. We compared the effects of two methods ofgeneral anesthesia on Vdphys whencombinedwith pos-itive pressure ventilation (PPV): total IV anesthesia(TIVA) and inhaled anesthesia with isoflurane. Fortypatients with no history of pulmonary pathology un-dergoing elective surgery in the supine position werestudied. A crossover design was used, and all patientsreceived both anesthetic methods sequentially in ran-domized order. PPV and TIVA significantly increasedVdphys compared with baseline (preoperative andbreathing spontaneously) from 164 60 mL to 264 79 mL (P 0.05). Isoflurane inhalation combined with

PPV significantly enhanced this increase, resulting in atwofold increase in Vdphysto 315 80 mL (P 0.05).Also, alveolar deadspace volume increased by more

than 200% with isoflurane. Furthermore, isoflurane in-halation (1.15% end-tidal concentration) resulted in im-paired arterial oxygenation, as evidenced by a signifi-cant decrease in the Pao2/fractional inspired oxygenconcentration ratio compared with baseline valuesfrom 387 35 to 310 70 (P 0.05). Although signifi-cant increases in Vdphysresulted with PPV combinedwith TIVA, these adverse changes were much less com-pared with isoflurane inhalation and PPV. These find-ings may apply to subjects with compromised pulmo-nary function (i.e., acute respiratory distress syndromeor severe inhalational burn injury).

(Anesth Analg 2004;99:110713)

Increased physiologic deadspace volume (Vdphys)predisposes to compromised arterial blood gas ex-change, especially for patients with preexisting pul-

monary disorders, i.e., inhalational burns, severe chronicobstructive pulmonary disease (COPD), or acute respi-ratory distress syndrome (ARDS). Incomplete alveolargas mixing with areas of increased alveolar ventilation/perfusion (VA/Q) mismatching within terminal respira-tory unitsand the preferential spread of distribution ofventilation to areas of less perfusionincreases alveolardeadspace volume (Vd

alv

). This increase in Vdalv

, inunison with airway deadspace volume (Vdaw), consti-tutes increased Vdphys(1). Another important causefor abnormalities in gas exchange and reduction inefficiency of ventilation during anesthesia is atelec-tasis of dependent lung regions, which causes an

increase in right-to-left intrapulmonary shunting ofblood (2).

Nuckton et al. (3) identified increased Vdphysas anindependent predictor for mortality in a group of 179patients with ARDS. Hubble et al. (4) previously dem-onstrated the usefulness of the Vdphys/tidal volumeratio in predicting successful extubation in critically illpediatric patients.

This study was designed to compare the effects ofpositive pressure ventilation (PPV) and total IV an-esthesia (TIVA) versus PPV and inhaled anesthesia

on Vdphys during general anesthesia. PPV, particu-larly at high lung inflation pressures, maldistributesinhaled air, predisposing to areas of high VA/Q (i.e.,increased Vdalv), low VA/Q (i.e., relative shunt), andimpaired lung carbon dioxide (CO2) eliminationrate (5,6).

Several studies indicate that inhaled anestheticshave regional effects on pulmonary blood flow andVA/Q (7,8) and on airway smooth muscle (9). Onestudy demonstrated that propofol (unlike potent in-haled anesthetics) does not inhibit, but rather poten-tiates, hypoxic pulmonary vasoconstriction in a dog

Accepted for publication April 23, 2004.Address correspondence and reprint requests to Michael J. Ban-

ner, PhD, University of Florida College of Medicine, Department ofAnesthesiology, PO Box 100254, Gainesville, FL 32610-0254. Ad-dress e-mail to [email protected].

DOI: 10.1213/01.ANE.0000131727.52766.F7

2004 by the International Anesthesia Research Society0003-2999/04 Anesth Analg 2004;99:110713 1107


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model (10). Furthermore, in contrast to inhaled anes-thesia, propofol does not consistently decrease Pao2(11).

We chose two popular modes of general anesthesiacombined with PPV for comparisonTIVA with

propofol/fentanyl infusions and inhaled anesthesiawith isofluraneto test the hypothesis that TIVAwould have a lesser effect on Vdphys.

MethodsThe IRB of the University of Florida approved thestudy protocol, and written, informed consent wasobtained 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 orneurosurgery, orthopedic surgery with tourniquet use(because release of microemboli would be a possibleconfounding variable), clinical evidence of COPD, in-terstitial lung disease, heavy smoking (60 pack-years), valvular cardiac disease, or the anticipated in-traoperative use of nitrates.

The following two-step sequence protocol for gen-eral anesthesia was used. Patients were randomly as-signed to initially receive either TIVA (propofol 150gkg1 min1 and fentanyl 12 gkg1 min1)for 45 min followed by inhaled anesthesia (isofluraneat 1 minimum alveolar anesthetic concentration[MAC]/1.15 vol% end-tidal concentration and fenta-nyl 12 gkg1 min1) or vice versa. Vecuroniumwas used for maintaining muscle relaxation during

both techniques. The fractional inspired oxygen con-centration (Fio2) was kept constant at 0.40, and nitrousoxide (N2O) was not used during either technique.Data were collected during three phases: before sur-gery while patients breathed room air spontaneously,45 min after induction, at tracheal intubation and PPVwhile receiving TIVA or inhaled anesthesia withisoflurane (as described above), and then 60 min after

conversion to the other type of anesthesia. The switchfrom inhaled anesthesia to TIVA was facilitated bytemporarily using higher fresh gas flows withoutchanging the Fio2 and then allowing a minimum 60-min equilibration period to achieve a negligible end-tidal isoflurane concentration (0.1%).

Arterial blood samples obtained before and duringsurgery were analyzed immediately. Arterial Pco2and body weight (BW) were subsequently entered intoa portable bedside respiratory monitor (CO2SMO;Novametrix/Respironics, Medical Systems, Walling-ford, 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 at-tached to the patient. Respiratory variables were com-puted during steady-state breathing with a movingaverage over the last 8 breaths.

The respiratory monitor uses the method originallydescribed by Fowler (12) and validated by Arnold etal. (13) in 1996; it requires single breath measurementsof exhaled CO2and tidal volume. CO2is measured bya mainstream infrared absorption technique with asolid-state sensor. Exhaled flow is integrated withtime to calculate volume. Exhaled CO2is plotted overvolume per breath. This is volume-based and not tra-

ditional time-based capnography. The respiratorymonitor provides a single-breath exhaled CO2 waveform that can be divided into 3 phases. Phase 1 rep-resents CO2-free gas from the conducting airways,Phase 2 represents a mixture of gas from both airwaydeadspace and alveolar deadspace, and Phase 3 (alve-olar plateau) represents gas from alveolar ventilationonly. Vdphys, composed of Vdalv and Vdaw, is calcu-lated by analysis of the exhaled CO2 wave form (Fig.1). The steep portion of the curve (Phase 2) reflects arapid transition from airway to alveolar gas. The ex-trapolated slope of the alveolar plateau (Phase 3) isused. A line is drawn perpendicular to the x axis,intercepting the slope and creating 2 equal triangularareas around the CO2wave form of Phase 2 (areaspandq) and thus providing the midpoint of the tran-sition from a Vdaw to alveolar gas (14) (Fig. 1). Thepatients Paco2, obtained separately from an arterial

blood gas, is manually entered into the monitors com-puter to calculate the various Vdcomponents.

Before surgery, with the patients lying in a supineposition and breathing spontaneously, the respiratorymonitors combined pressure/flow/CO2 sensor wasconnected to a mouthpiece, and a nose clip was at-tached. After 5 min, an arterial blood gas was obtained

from a radial artery catheter placed electively, and all

Table 1. Patient Demographic Data (n 40)

Variable Value

Age (yr) 58 15Sex (male/female) 17/23ASA class I/II/III 1/10/29

Weight (kg) 81 19Height (cm) 170 11BMI (kg/m2) 28 6Obesity (BMI 30 kg/m2) 15Active smoker (n) 6Smoking history (n) 16Types of surgery (n)

Abdominal 14Anterior cervical spine 7Hepatic 8Peripheral vascular 11

Values are mean sd or number of patients.BMI body mass index.

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respiratory measurements were determined. Preoper-ative sedation was administered after these baselinedata were obtained.

Surgical procedures included anterior cervical spine,peripheral vascular, hepatic, and abdominal surgery inthe supine position. In patients scheduled for epiduralcatheter placement for postoperative pain control, theinfusion was started after conclusion of all measure-ments. General anesthesia was induced by following astandardized protocol (thiopental 35 mg/kg, fentanyl23 g/kg, and vecuronium 0.15 mg/kg). After trachealintubation, volume ventilation (Aestiva/5 or Ohmeda7800; Datex-Ohmeda) was started: tidal volume of8 mL/kg ideal BW, inhalation/exhalation time ratio of1:2, and ventilator frequency of 810 breaths/min toprovide a partial pressure of end-tidal CO2between 30and 35 mm Hg. The Fio2was set at 0.40, and the pulse

oximeter hemoglobin saturation was maintained 95%.

N2O was not used. Minute ventilation and mean airwaypressure remained unchanged throughout the study pe-riod. A bispectral index (BIS) monitor, a twitch monitor,and invasive arterial blood pressure monitoring wereused in addition to standard ASA monitors. Musclerelaxation was maintained at 90%95% motor blockade,and the train-of-four ratio was assessed before each mea-surement. For measurements other than preoperativemeasurements, the respiratory monitor sensor was posi-tioned between the Y-piece of the ventilator breathingcircuit and the endotracheal tube. Surgery was inprogress during the study. Respiratory measurementswere obtained only during hemodynamically stable in-tervals to ensure uniform conditions; i.e., a measurementwas postponed if the time frame coincided with intra-operative hypotension or hypertension. Manipulation ofthe depth of anesthesia and/or a fluid bolus were used

to restore hemodynamic variables if needed. Fentanyl, in

Figure 1. Diagrammatic view of the respiratorymonitor, showing the combined pressure/flow/CO2sensor between the endotracheal tube and theventilator breathing circuit. The graph on the mon-itor is a plot of exhaled CO2over tidal volume, i.e.,

volume-based capnography. After the patientsPaco2, obtained from a blood gas analysis, is en-tered into the monitor, the various deadspace vol-ume components are calculated. Note the areascorresponding to alveolar and airway deadspacevolumes, the sum of which is physiologic or totaldeadspace volume (see text).

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25-

g increments, was administered in response to in-creases in heart rate and systolic arterial blood pressure.The study was stopped in cases of hemodynamic insta-

bility due to sudden intraoperative blood loss.A crossover experimental study design was used

that combined the data for each condition regardlessof the order of presentation in the particular patient.Measured values showed a normal distribution. Un-less otherwise indicated, data are presented as mean sd. Effects of PPV and method of anesthesia onVdphysand the Fio2/Pao2ratio were analyzed by two-factor repeated-measures analysis of variance fol-lowed by apost hocScheffetest. The followinga priori

null hypotheses were tested:1. The combination of PPV and TIVA has no effect

on Vdphysor arterial oxygenation compared withspontaneous ventilation.

2. The combination of PPV and inhalation of isoflu-rane has no effect on Vdphys or arterial oxygen-ation compared with PPV with TIVA and spon-taneous ventilation.

A null hypothesis was rejected with an error of0.05. Statistical analysis was performed withcommercially available software (SPSS; SPSS Inc.,Chicago, IL).

ResultsForty patients were enrolled and completed this cross-over study (Table 1). Four patients were excluded

because of inability to follow instructions during thepreoperative respiratory assessment or because of in-traoperative acute blood loss with volume resuscita-tion. There were no significant changes in depth ofanesthesia, cardiovascular variables, core tempera-ture, peak inflation pressure, minute ventilation, pul-monary mechanics, or lung CO2 elimination rate be-

tween the two methods of anesthesia (Table 2). In

relation to awake, spontaneous ventilation, the effectsof PPV and TIVA versus inhaled isoflurane are shownin Figures 2 and 3. PPV during TIVA significantlyincreased Vdphyscompared with baseline (before sur-gery and while breathing spontaneously) (P 0.05).When PPV was combined with inhalation of isoflu-rane, this resulted in a significantly larger increase inVdphys(P 0.05) regardless of the order in which theanesthetics were administered. Vdalv, usually verysmall in patients without pulmonary pathology,constituted the major component of the increase inVdphys. Vdalv increased approximately 190% from

baseline as a result of PPV and TIVA and by approx-

imately 225% during PPV with isoflurane anesthesiacompared with preoperative values. Mechanical ven-tilation and TIVA did not appreciably increase Vdaw.PPV and inhaled isoflurane did cause a significantincrease in Vdawcompared with spontaneous ventila-tion (Fig. 3). Note that before surgery, during sponta-neous ventilation, the total Vdor Vdphyswas 164 mLon average. With the application of PPV and TIVA, themean Vdphysincreased to 264 mL, and with the addi-tion of isoflurane, it increased further to 315 mL. In-haled 1.15% isoflurane (1 MAC) was associated with adeterioration of the arterial oxygen partial pressure, asevidenced by a significant decrease in the Pao2/Fio2ratio from 387 35 to 310 70 (P 0.05) (Fig. 2).

DiscussionThe aim of this study was to compare two routinemethods of general anesthesia and their effects onVdphys and pulmonary gas exchange. PPV combinedwith TIVA was used primarily to assess the effects ofmechanical ventilation on Vdphys. PPV and isofluraneinhalation were used to assess the combined effects ofmechanical ventilation and inhaled anesthesia on

Vdphys.

Table 2. Hemodynamic, Respiratory, and Bispectral Index Characteristics in 40 Patients Before Surgery (Pre-op), DuringPositive Pressure Ventilation (PPV) in Combination with Total Intravenous Anesthesia (TIVA), or During Isoflurane (ISO)Inhalation

Variable Pre-opPPV and

TIVAPPV and

ISO

Heart rate (bpm) 79 12 79 13 80 13Mean arterial blood pressure (mm Hg) 88 18 84 12 84 10Bispectral index N/A 31 11 33 9Core temperature (C) N/A 36.4 0.4 36.3 0.5Breathing frequency (breaths/min) 13 4 8 0.7 8 0.7Exhaled tidal volume (mL) 523 217 672 180 689 145Minute ventilation (L/min) 6.1 2.4 6.0 1.4 6.0 1.4Peak inflation pressure (cm H2O) N/A 21 5.6 21.2 5.2Lung CO2 elimination rate (mL/min) 161 70 125 36 121 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).



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Our primary findings were that PPV during TIVAincreases Vdphys, but the combination of PPV andisoflurane inhalation caused significantly larger in-creases in Vdphys. Isoflurane anesthesia also resultedin a significant decrease of arterial oxygenation, asevidenced by a decreased Pao2/Fio2 ratio. A similarfinding has been described in a prospective study of466 patients undergoing cardiac surgery. The authorsreported that patients anesthetized with isofluranehad a lower Pao2/Fio2ratio at one and six hours aftercardiopulmonary bypass compared with TIVA or IVmidazolam and fentanyl combined with enflurane(15). We speculate that different physiologic mecha-nisms may account for the significant change in Vdphysobserved with the two methods of anesthesia.

During PPV with controlled mechanical ventilationin a supine paralyzed patient, as during general anes-thesia, a disproportionate amount of the tidal volumeis directed toward the anterior nondependent lungregions, thus predisposing to areas of increased VA/Qmismatching, i.e., increased Vdalv (5). Spontaneousventilation, conversely, promotes more normal distri-

bution of VA/Q matching (6,16). Downs and Mitchell(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 un-derperfused alveoli (i.e., Vdalv) is increased mean pos-itive airway pressure. Increased alveolar pressure pre-

disposes some alveoli to overly distend, collapsinglocal pulmonary capillaries and decreasing perfusion,thus leading to areas of increased VA/Q (i.e., West;Zone 2 converted to Zone 1) (17). The observed in-crease in Vdphys during TIVA and PPV may or maynot be entirely attributable to PPV alone, because theeffect of TIVA on Vdphysis unknown. A possible rea-son as to why Vdawdid not appreciably increase dur-ing PPV with TIVA (Fig. 3) may be the moderate tidalvolumes used in our study (i.e., 8 mL/kg BW).

Comparisons of the effects of TIVA versus isoflu-rane anesthesia on arterial oxygenation during one-lung ventilation (OLV) have yielded controversial re-sults. Recent studies demonstrated lower Pao2 withdesflurane (18) and isoflurane anesthesia during OLVin pigs as compared with propofol anesthesia,whereas perfusion of the nonventilated lung andshunt fraction remained comparable (19). Propofol an-esthesia was compared with inhaled anesthesia withsevoflurane and isoflurane during OLV in patientsundergoing esophageal surgery and resulted in im-proved oxygenation and a lower shunt fraction (20).Possible confounding factors are differences in thedepth of anesthesia or metabolic rate and the absenceof randomization of experimental sequence (order

bias). In another report, the effects of propofol and

Figure 2. The effects of spontaneous ventilation, positive pressureventilation (PPV) with total IV anesthesia (TIVA), and PPV com-

bined 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. Signifi-cantly larger increases in Vdphys, along with a significant decrease inarterial oxygenation, resulted when PPV was combined with isoflu-rane, regardless of the order in which the anesthetics were admin-istered.P 0.05 compared with *spontaneous ventilation and com-pared with PPV with TIVA. Data are mean sd. PREOP beforesurgery.

Figure 3.Physiologic deadspace volume (Vdphys) changes, consist-ing of alveolar (Vdalv) and airway deadspace volume (Vdaw) com-ponents, are shown during spontaneous ventilation, positive pres-sure ventilation (PPV) with total IV anesthesia (TIVA), and PPVcombined with inhaled isoflurane. PPV and TIVA increased Vdalvsignificantly compared with spontaneous ventilation. Significantlygreater increases in Vdalv resulted when PPV was combined withisoflurane, irrespective of the order in which the anesthetics weregiven. A significant increase in Vdawresulted when PPV was com-

bined with isoflurane. Ostensibly, increases in Vdphys were theresult of increases in Vdalv. P 0.05 compared with *preoperativedata and compared with PPV with TIVA. Data are mean sd.



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isoflurane anesthesia on oxygenation and shunt frac-tion during OLV were investigated, and lower Pao2and threefold higher shunt fractions were reportedduring isoflurane anesthesia compared with anesthe-sia with propofol (21). However, other studies did not

support these findings (22).The effects of isoflurane inhalation on pulmonaryvascular regulation and bronchomotor tone may con-stitute a mechanism for the larger increase in Vdalvand Vdawin our study population. Numerous controlmechanisms responsible for alterations in pulmonaryvascular tone have been elucidated for both animaland human lungs. The pulmonary vasculature is af-fected by complex neural, humoral, and local mecha-nisms and is evidently in a state of active vasodilation,according to recent work regarding the role of nitricoxide in pulmonary vascular resistance in humans(1,23). Isoflurane anesthesia caused systemic vasodila-

tion but did not exert a vasodilator influence on thepulmonary circulation in the setting of increased pul-monary vascular resistance after left lung autotrans-plantation in dogs (24). Extensive work by Murray,Fujiwara, and Gambone in the 1990s (25,26) on theeffects of general anesthesia on the pulmonary vascu-lar pressure-flow relationship demonstrated that thereare various mechanisms whereby inhaled anesthesiacan alter pulmonary vasoregulation. Compared withthe conscious state, none of the volatile anestheticsexerts a net effect on the canine pulmonary circulation,

but the above-mentioned results support the conceptthat they act to reduce the magnitude of response to

various endogenous vasodilator metabolites that me-diate pulmonary vasorelaxation at clinically relevantconcentrations. This would suggest that isoflurane in-halation may lead to changes in pulmonary vasomotorregulation that decrease local alveolar perfusion, pre-cipitating an Vdalv-like effect (areas of high VA/Q).

Bronchodilation is a well known effect of inhaledanesthesia (27). We observed a significant, althoughslight, increase in Vdaw during PPV and isofluraneanesthesia compared with spontaneous breathing.

Another possible contributing mechanism involvesthe pathways of pulmonary collateral ventilation,which represent nongravitational determinants of thedistribution of ventilation. A study investigating theinfluence of halothane and isoflurane on pulmonarycollateral ventilation in dogs reported a 50% reductionin the flow resistance to collateral ventilation at 1.4MAC halothane and 0.8 MAC isoflurane (28). VA/Qmismatch caused by alterations in collateral ventila-tion may have a contributory role, but the simplestexplanation for our findings may indeed be that the

bronchodilation caused by isoflurane predisposes toincreases in Vdaw.

This study has several limitations. Vdalv is influ-enced by changes in cardiac output (pulmonary blood

flow). Pulmonary artery catheters were not inserted,

and, thus, we did not obtain cardiac output meas-urements. There were no cases of intraoperative ar-rhythmias. Arterial systolic, diastolic, and mean bloodpressures and heart rates were not significantly differ-ent during TIVA and inhaled anesthesia, suggesting

cardiovascular stability. There was no evidence tosuggest any significant decreases in cardiac outputthat would have predisposed to increases in Vdalv. Inaddition, we stopped our investigation in two patientsafter episodes of significant blood loss and arterial

blood pressure changes with ensuing volume resusci-tation, and we excluded their data. Also, changes inthe depth of anesthesia and metabolic rate could act aspossible confounding variables. In this study, re-corded BIS values and hemodynamic characteristicsdid not reveal a significant difference in depth ofanesthesia during TIVA and inhaled isoflurane. Fur-ther, we inferred a stable metabolic profile because of

intraoperative stability in cardiovascular measurements,core temperature, and lung CO2elimination rate.

The awake measurements were undertaken duringspontaneous breathing at a comparable minute volume(slightly smaller tidal volume and higher breathing fre-quency) to that used in the operating room. Ventilatorsettings were kept constant during the surgery.

In summary, for patients with relatively normalpulmonary function, the transition from spontaneousventilation to TIVA and PPV resulted in significantincreases in Vdphys. Isoflurane inhalation and PPVcaused significantly larger increases in Vdphysregard-less of the sequential order in which the anesthetics

were administered. As a result, arterial blood gas ex-change was compromised as reflected by a significantdecrease in the Pao2/Fio2 ratio. In patients withoutpulmonary impairment, this may be offset by an in-crease in minute ventilation. Our results could implyadverse sequelae for patients with severe preoperativepulmonary pathology associated with severe VA/Qmismatch and a considerable increase in Vd/tidal vol-ume (inhalational burn injury, severe COPD, ARDS,and so on) requiring surgery and anesthesia. Becausefewer untoward changes in pulmonary function werefound with TIVA and PPV, this combination may be amore appropriate anesthetic choice for patients withgrossly abnormal VA/Q relationships and preexistingincreased Vdphys. Future studies directed at examina-tion of the effects of inhaled and IV anesthesia onVdphys and arterial blood gas exchange in patientswith severely compromised pulmonary functionwould be needed to validate this possible implication,given the pathophysiological pulmonary differencesin such patients.

The authors thank Nikolaus Gravenstein, MD, and ChristophSeubert, MD, for their valuable assistance and critical analysis of thedata.



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Praetel_2004_Anesth._Analg