Cardiopulmonary Effects of Hypercapnia during ControlledIntermittent Positive Pressure Ventilation in the Horse

Arun K. Khanna, Wayne N. McDonell, Doris H. Dyson, and Polly M. Taylor

ABSTRACT

The cardiopulmonary effects ofeucapnia (arterial CO2 tension[PaCO2] 40.4 ± 2.9 mm Hg, mean +SD), mild hypercapnia (PaCO2, 59.1 -+-3.5 mm Hg), moderate hypercapnia(PaCO2, 82.6 ± 4.9 mm Hg), andsevere hypercapnia (PaCO2, 110.3 +12.2 mm Hg) were studied in 8 horsesduring isoflurane anesthesia with vol-ume controlled intermittent positivepressure ventilation (IPPV) and neu-romuscular blockade. The sequenceof changes in PaCO2 was randomized.Mild hypercapnia produced

bradycardia resulting in a signifi-cant (P <0.05) decrease in cardiacindex (CI) and oxygen delivery(9O2), while hemoglobin concentra-tion (Hb), the hematocrit (Hct), sys-tolic blood pressure (SBP), meanblood pressure (MBP), systemicvascular resistance *(SVR), andvenous admixture (Q/QT) increasedsignificantly. Moderate hypercap-nia resulted in a significant rise inCI, stroke index (SI), SBP, MBP,mean pulmonary artery pressure(PAP), Hct, Hb, arterial oxygen con-tent (CaO2), mixed venous oxygencontent (CVO2), and DO2, with heartrate (HR) staying below eucapniclevels.

Severe hypercapnia resulted in amarked rise in HR, CI, SI, S*BP,PAP, Hct, Hb, CaO2, CvO2, and DO2.Systemic vascular resistance was sig-nificantly decreased, while MBP lev-els were not different from thoseduring moderate hypercapnia. Nocardiac arrhythmias were recordedwith any of the ranges of PaCO2.Norepinephrine levels increased

progressively with each increase inPaCO2, whereas plasma cortisol lev-els remained unchanged.

It was concluded that hypercap-nia in isoflurane-anesthetized horseselicits a biphasic cardiopulmonaryresponse, with mild hypercap.niaproducing a fall in CI and DO2despite an increase in MBP, whilemoderate and severe hypercapniaproduce an augmentation of the car-4iopulmonary performance andDO2.

RESUME

Les effets cardiopulmonaires del'eucapnie (pression partielle de CO2dans le sang arteriel [PaCO2] 40,4 ±2,9 mm Hg, moyenne ± ecart type),de l'hypercapnie legere (PaCO2 59,1± 3,5 mm Hg), de l'hypercapniemoderee (PaCO2 82,6 ± 4,9 mm Hg)et de l'hypercapnie severe (PaCO2110,3 ± 12,2 mm Hg) ont ete etudieschez huit chevaux pendant uneanesthesie a l'isoflurane associee aune ventilation intermittente a pres-sion positive et une inhibition neuro-musculaire squelettique. L'ordredes changements de la PaCO2 etaitaleatoire.L'hypercapnie legere produisait

une bradycardie provoquant unediminution significative (P <0,05)de l'index cardiaque (Cj) et de ladistribution d'oxygene (DO2), alorsque la concentration d'hemoglobine(Hb), l'hematocrite (Hct), la pres-sion arterielle systolique (SBP), lapression arte'rielle moyenne (MBP),la resistance vasculaire systemique(SVR) et la proportion de shunt(Qs/QT) augmentaient de facon

significative. L'hypercapnie mod-eree provoquait une augmentationsignificative de CI, de l'indexd'ejection (SI), de SBP, de MBP, dela pression arterielle pulmonairemoyenne (PAP), de Hct, de Hb, ducontenu arteriel en oxygene (CaO2),du contenu en oxygene dans le sangveineux mele (CVO2) et de la DO2.La frequence cardiaque (HR) restaiten dessous des valeurs obtenuespendant la phase d'eucapnie.L'hypercapnie severe resultait en

une augmentation marquee de HR,de CI, de SI, de SBP, de PAP, deIct, de Hb, de CaO2, de CIvO2 et deDO2. La resistance vasculaire syste-mique etait diminuee de facon signi-ficative alors que la valeur de laMBP etait similaire a celle obtenuependant l'hypercapnie moderee. Laconcentration d'epinephrine aug-mentait progressivement pourchaque augmentation de la PaCO2tandis que la concentration plasma-tique de cortisol restait inchangee.En conclusion, I'hypercapnie

chez des chevaux anesthesies 'al'isoflurane provoque une reponsecardiopulmonaire de type biphasi-que. L'hypercapnie lege.re entraineune baisse de CI et de DO2 malgreune augmentation de la MBP, alorsque l'hypercapnie severe provoqueune augmentation de la perfor-mance cardiopulmonaire et de laDO2.

(Traduitpar Docteur Philippe Pibarot)

INTRODUCTION

Horses are especially prone to thedevelopment of important cardiopul-monary alterations during general

Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, Ontario NIG 2W1 (Khanna, McDonell, Dyson) andAnimal Health Trust, P.O. Box 5, Newmarket, Suffolk, CB8 7DW, England (Taylor). Present address of Dr. A.K. Khanna: 9433 Palm Tree Drive,Windermere, Florida 34786, USA.Address correspondence to Dr. W.N. McDonell.

Reprints not available.

Funding for this project was provided by Anaquest, Burroughs Wellcome, and the Ontario Ministry of Agriculture, Food and Rural Affairs.

Submitted July 9, 1993.

Can J Vet Res 1995; 59: 213-221 213

anesthesia (1-4). General anesthesiais accompanied by decreased cardiacoutput (0) and arterial blood pressure,with an increased alveolar to arterialoxygen tension difference (PAO2-PaO2) leading to lower than expectedarterial oxygen tensions (PaO2) (1-3,5,6). A progressive and pronouncedincrease in arterial carbon dioxide ten-sion (PaCO2) is commonly observedduring general anesthesia in the horse(5-10). It has been recommended bysome authors that hypercapnia alwaysbe prevented through the use of inter-mittent positive pressure ventilation(IPPV) (1 1-13).A recent study compared sponta-

neous ventilation with assisted or con-trolled IPPV in the anesthetized horseand demonstrated significant deleteri-ous effects with IPPV, especiallywhen the controlled mode of IPPVwas used (8). Cardiac output, oxygentransport (DO2), and mixed venousoxygen content (CvO2) were lowerduring controlled IPPV when com-pared with spontaneous ventilation.Assisted IPPV produced less cardio-vascular depression compared withcontrolled IPPV, and PaCO2 washigher with assisted ventilation.The deleterious cardiovascular

effects of IPPV appear to be morepronounced in the horse than in otherspecies, but it is not clear whether thisis due to the negative influence ofIPPV per se through reduction invenous return, or to an altered hemo-dynamic state with the abolition of theelevated PaCO2 levels that accompanyspontaneous respiration in the anes-thetized horse (14).

In conscious and anesthetized sub-jects, moderate hypercapnia leads toan increase in Q and arterial bloodpressure through stimulation of thesympathetic nervous system (15-20).To date, only 1 controlled study hasbeen conducted on anesthetizedhorses to investigate the influence ofcarbon dioxide (CO2) on hemo-dynamic performance during IPPV(21). Improved hemodynamic perfor-mance was observed when halothane-anesthetized horses were exposed toincreased PaCO2 of 60-70 mm Hg andthen 75-85 mm Hg. Unfortunately,the sequence of exposure to CO2 wasnot randomized. During prolongedgeneral anesthesia with halothane orisoflurane, some improvement in car-diovascular performance occurs over

time; this improvement occurs irre-spective of the mode of ventilationand might bias the conclusions drawn(6,9,22). In addition, some of thehorses breathed spontaneously duringhypercapnia and the study did notexamine the effects of mild hypercap-nia (PaCO2, 55-65 mm Hg).The present study was undertaken to

define further the hemodynamiceffects of CO2 in anesthetized horsesusing isoflurane, controlled IPPV withneuromuscular blockade, and random-ized exposure to various PaCO2 levels.

MATERIALS AND METHODS

Eight mature horses (7 females,1 gelding) weighing between 415 and550 kg (495 ± 44.3 kg, mean ± SD)were used. Each horse was studiedonce. Based on previous health his-tory, clinical examination, arterialblood gas analysis, hematocrit, andtotal protein determination, the horseswere free of any cardiopulmonary dis-ease. The horses were maintained, andthe experiments were conducted, inaccordance with the guidelines of theCanadian Council on Animal Care.

ANESTHESIA

Food was withheld for 12 h prior toanesthesia, while water was availableuntil premedication was administered.After aseptic placement of a jugularcatheter (14 gauge, 13.3 cm; Angio-cath, Deseret Medical Inc, BectonDickinson and Company, Sandy,Utah) the horses were premedicatedwith 0.3 mg/kg xylazine (Anased,Lloyd Laboratories, Shenandoah,Iowa) given IV, and anesthesia wasinduced with IV administration of100 mg/kg guaifenesin (LangfordLaboratories, Guelph, Ontario) andketamine 2.0 mg/kg (Rogarsetic,Rogar/STB, Pointe Claire, Quebec).The guaifenesin was prepared as a10% solution in 5% dextrose in water.The horses were placed in left lat-

eral recumbency on a 25 cm thickfoam pad and an endotracheal tubewas introduced (26 or 30 mm internaldiameter, Bivona Inc., Grey, Indiana).Immediately following endotrachealintubation, IPPV was commenced witha commercial volume controlled largeanimal ventilator (Narkovet E LargeAnimal Control Center, North Ame-rican Drager, Telford, Pennsylvania).

A respiratory rate of 6 breaths/min,with an inspiratory to expiratory (I:E)ratio of 1:2.5 and a tidal volume (VT)of 12-15 mL/kg, was used.

Anesthesia was maintained withisoflurane (AErrane, Anaquest,Mississauga, Ontario) in oxygen (02)using a precision vaporizer (Isoflu-rane Vapour 19.1, North AmericanDrager). A high 02 floW (10 L/min)and a relatively high inspired isoflu-rane concentration (2.5-3.0%) wereutilized for initial transfer to theinhalant anesthetic. Subsequently, an02 flow of 5.0 L/min was used and theinspired isoflurane concentration wasadjusted to maintain an end-tidalisoflurane level of 1.6%, which isequivalent to 1.2 times the minimumalveolar concentration (MAC) (23).

Isoflurane concentration (inspira-tory and expiratory), inspired 02 con-centration (FI02), and end-tidal CO2tension (PETCO2), were monitoredusing an infrared airway gas analyzer(Datex 254 Airway Gas Monitor, Puri-tan Bennett Corporation, Wilmington,Massachusetts). The gas analyzer wascalibrated prior to each experiment for02, CO2, and isoflurane using room airand the manufacturer's calibration gasmixture. Further verification of thecalibration for isoflurane was carriedout with a precision gas mixture con-taining 2% isoflurane in nitrogen(Matheson Gas Products, Whitby,Ontario). Recalibration was carriedout periodically during each experi-ment. The sampling tube, provided bythe manufacturer, was threaded intothe trachea just beyond the tip of theendotracheal tube.

INSTRUMENTATION

An initial interval (55 to 90 min)was utilized as a stabilization periodand for instrumentation of the horses.Five litres of lactated Ringer's solu-tion (Travenol Canada Inc., Ontario)was infused through a catheter in theleft median vein (16 gauge, 5.1 cm;Deseret) over the 1st 30 to 45 min,following which the fluid was admin-istered at a rate of 2-3 mL/kg/h forthe duration of the experiment.The electrocardiogram and heart

rate (HR) were monitored continu-ously using a base apex lead systemand a 4-channel oscilloscope monitor-ing system (Physio Control VSMI,Physio Control Corporation, Redpond,Washington). A catheter (20 gauge,

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5.1 cm; Deseret) was placed in thefacial artery for collection of arterialblood samples and for measurement ofsystolic, diastolic, and mean bloodpressures (SBP, DBP, and MBP) usinga disposable pressure transducer(Spectramed DTX Pressure Trans-ducer System, Spectramed Inc., Criti-cal Care Division, Oxnard, California)connected to the 4-channel monitor.The system was calibrated against amercury manometer prior to, and dur-ing, each experiment. The sternalmidline was taken as the zero refer-ence point for all blood pressure mea-surements. Airway pressure was mea-sured with a needle in the proximalendotracheal tube connected to ananeroid manometer, which had beenpreviously calibrated against a mer-cury manometer.A 125 cm long, large-bore polyethy-

lene catheter (Intramedic,ID 1.57 mm, outer diameter [OD]2.08 mm, Clay Adams, Parsippany,New Jersey) was introduced through apreviously placed 10 gauge jugularcatheter (Angiocath, Deseret). The tipwas positioned in the right atrium formeasurement of central venous pres-sure (CVP) and to permit rapid injec-tion of cold 5% dextrose in water for Qdetermination by thermodilution.A thermodilution catheter (129 cm,7 gauge Swan Ganz; AmericanEdwards Laboratories, Santa Ana, Cal-ifornia) was placed in the right jugularvein using an introducing kit (ArrowInternational Inc., Reading, Pennsylva-nia) and advanced to the pulmonaryartery. Placement of the right atrial andpulmonary artery catheters was con-firmed by observation of characteristicpressure wave forms. Cardiac outputwas determined by thermodilution aspreviously reported (24,25), using acomputerized system (COM-2 CardiacOutput Computer, Baxter Health CareCorporation, Santa Ana, California).Chilled 5% dextrose in water (40 mL)was used as the thermal indicator. Inorder to standardize the respiratoryconditions during Q determination, theventilator was turned off at the time ofthis process. A minimum of 3 replicateQdeterminations were made at eachsampling interval. Cardiac output foreach sampling period was taken as themean of at least 2 determinations thatwere within 10% of each other.

In 4 animals, another large-borepolyethylene catheter (Clay Adams)

was placed in the pulmonary artery ina manner similar to the placement ofthe thermodilution catheter. Thiscatheter was used to obtain pulmonaryarterial blood samples for blood gasand acid base analysis.

Arterial and mixed venous (pul-monary artery) blood gas samples(5 mL each) were collected anaerobi-cally into heparinized glass syringescontaining a small washer. The sam-ples were stored in ice and analysiswas carried out within 20 min. Bloodgas and acid base analysis was carriedout on an automated system (ABL-3Acid Base Laboratory, Radiometer,Copenhagen, Denmark). This analyzerwas calibrated with reference liquidsamples (Qualicheck R, Radiometer)before and after each experiment, andwith gas calibration between experi-ments. Blood gas and acid base valueswere corrected to core body tempera-ture. Hemoglobin (Hb) levels weredetermined separately using thecyanohemoglobin method, while thehematocrit (Hct) and total proteindeterminations were carried out usinga microhematocrit centrifuge andrefractometer, respectively.

EXPERIMENTAL DESIGN

At the completion of the instrumen-tation and stabilization period, a load-ing dose of 0.1 mg/kg atracurium(Tracurium, Burroughs WellcomeInc., Kirkland, Quebec) was given IVto ensure that there were no sponta-neous ventilatory efforts during thesubsequent periods of exposure tohypercapnia. Supplemental atracu-rium doses of 0.05 mg/kg were givenat intervals of 20 to 25 min to main-tain diaphragmatic paralysis (26).

For each experiment, horses weremaintained at 4 different PaCO2 levelsusing a randomized schedule of treat-ment. Changes in PaCO2 levels werebrought about by adding 100% CO2 tothe inspiratory side of the anestheticsystem beyond the soda lime absorber.The 4 ranges of arterial CO2 tensionsused in this study were 35-45 mm Hg(eucapnia), 55-65 mm Hg (mildhypercapnia), 75-85 mm Hg (moder-ate hypercapnia), and >95 mm Hg(severe hypercapnia). Arterial bloodgas analysis was used to confirmwhether the PaCO2 was in the desiredrange. Once established, the desiredrange of PaCO2 was maintained for atleast 20 min and then 2 sets of obser-

vations at least 10 min apart wereobtained. The measurements includedHR, arterial blood pressure, CVP,mean pulmonary artery pressure(PAP), Q, airway pressures, PETCO2,F102, inspiratory and expiratoryisoflurane concentrations, and corebody temperature obtained from thethermodilution catheter in the pul-monary artery. Arterial and mixedvenous blood gas samples were col-lected anaerobically for blood gas andacid base analysis. A further venousblood sample (10 mL) was collectedinto heparinized tubes containing amixture of ethylene glycol-bis-tetraacetic acid and glutathione. Thesesamples were kept in ice and cen-trifuged to harvest plasma, which wasimmediately stored in liquid nitrogen.Catecholamine assays were carriedout by high performance liquid chro-matography (HPLC) using the methoddeveloped by Bioanalytical SystemsInc. (1985) for an Anachem HPLCsystem as described elsewhere (27).Plasma cortisol was measured byradioimmunoassay as described previ-ously (28).The derived cardiopulmonary val-

ues included were: cardiac index (CI)expressed as mL/kg/min; stroke index(SI) as mL/kg/beat (29); systemic vas-cular resistance (SVR) in dynes/sec/cm-5 (30); percent dead space (VJVT)(31); and PAO2-PaO2 difference.Alveolar oxygen tension was calcu-lated using a variation of the alveolarair equation (32):PAO2 = (PB-PH20) F102

-(PaCO2/R) -PEsowhere PB is barometric pressure,PH2O is the water vapor pressure, R isthe respiratory quotient at 0.85 (33),and PE1so is the partial pressure ofexpired halothane. Additional derivedvalues included the percent oxygensaturation based on PaO2, pH, andtemperature using an equation forequine blood (34); the oxygen contentof capillary arterial and mixed venousblood (29,35); DO2, oxygen uptake(V02) (29), and percentage shunt frac-tion (%QS/QT) (35).

STATISTICAL ANALYSIS

A paired Student's t-test was usedto test for differences in observationsbetween sampling periods 1 and 2 ateach PaCO2 level. One-way analysisof variance for repeat measures was

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Table I. Ventilation, body temperature, and anesthetic values during eucapnia and hypercapniawith constant volume intermittent positive pressure ventilation (IPPV) in isoflurane-anesthetized horses (mean + SD; n = 8)

PaCO,Variable 35-45 55-65 75-85 >95

Body temperature (°C) 34.7 ± I .2a 34.2 ± 0.7a 34.2 ± 1. Ia 34.3 ± 0.7aPIP airway (Cm H,O) 24.7 ± 6.2a 25.8 ± 6.3a 25.9 ± 6.3a 26.2 ± 6.1aPEP airway (Cm H,O) 3.2 ± 1.4a 3.2 ± 0.5a 3.3 ± 0.7a 3.4 ± 0.9aVT (L) 7.1 ± 0.7a 7.2 ± 0.5a 7.1 ± 0.7a 7.2 ± 0.5af (breaths/min) 7.0 ± I.Oa 6.0 ± 0.Oh 6.0 ± O.Ob 6.0 ± 0.0bET Iso (%) 1.6 ± 0.0a 1.6 ± 0.0a 1.6 ± O.la 1.6 ± O.la

j.b.c.d Significant differences between treatments are present when letters are different; P <0.05PIP: peak inspiratory pressure; PEP: peak expiratory pressure; VT: tidal volume; f: frequency;ET Iso: end-tidal isoflurane

Table II. Respiratory, arterial blood gas, and acid base values during eucapnia and hypercapniawith constant volume intermittent positive pressure ventilation (IPPV) in isoflurane-anesthetizedhorses (mean ± SD; n =8)

PaCO2Variable 35-45 55-65 75-85 >95

pHa 7.44 ± 0.04a 7.31 ± 0.03b 7.19 ± 0.03c 7.08 ± 0.04dPaCO, (mm Hg) 40.4 ± 2.9a 59.1 ± 3.5b 82.6 ± 4.5c 110.3 ± 12.2dPaO2(mm Hg) 284 ± 109a 170 ± 118a 162 ± 92a 203 ± 96a(HCO )a (mmol/L) 28.4 ± 2.5a 30.5 ± 1 .6b 31.9 ± 2.0c 32.5 ± 3.5dABEa (mmol/L) 3.4 ± 2.6a 2.9 ± 2.0a 1.1 ± 2.5b -2.0 ± 4.1cHb (gm/L) 85 ± 13a 89 ± 12b 106 ± 22c 123 ± 29dHct (%) 25 ± 5 28 ± 4b 34 ± 8c 40 ± 9dTP (gm-L) 48 ± 4a 48 ± 4a 50 ± 5a 53 ± 5aF102 (%) 98.1 ± 2.0a 97.6 ± 3.4b 94.0 ± 2.9c 87.7 ± 5dPETCO2 (mm Hg) 33.7 ± 4.6a 51.4 ± 6.1b 75.0 ± 6.1c 89.9 ± 0.4da-b-cd Significant differences between treatments are present when letters are different; P <0.05PaCO2: partial pressure of arterial carbon dioxide; PaO2: partial pressure of arterial oxygen;(HCO3 ): bicarbonate; ABEa: actual base excess; Hb: hemoglobin; Hct: hematocrit; TP: total pro-tein; FI02: inspired oxygen concentration; PETC02: end-tidal carbon dioxide partial pressure

Table III. Mixed venous blood gas and acid base values during eucapnia and hypercapnia withconstant volume intermittent positive pressure ventilation (IPPV) in isoflurane-anesthetizedhorses (mean ± SD; n =4)

PaCO2Variable 35-45 55-65 75-85 >95

pH- 7.41 ± 0.04a 7.29 ± 0.03b 7.19 ± 0.03c 7.09 ± 0.04dPvC02 (mm Hg) 47.2 ± 5.3a 62.7 ± 6.0b 86.7 ± 6.3c 115.9 ± 10.8dPv2 (mm Hg) 31.5 ± 1.4a 37.6 ± 5.1a 50.8 ± 14.4b 62.7 ± 15.2b(HCO3 )- (mmol/L) 30.8 ± 1.7a 30.6 ± 4.3b 33.6 ± 2.0a 34.9 ± 1.2aABE. (mmol/L) 4.9 ± 1.7a 2.9 ± 4.2b 2.6 ± 2.6b 0.3 ± 3.2cHb (gm/L) 83 ± 16a 86± 21a 101 ± 32b 115 ± 35cHct (%) 25 ± 7a 27 ± 6b 34 ± 10c 38 ± 12dah.c.d Significant differences between treatments are present when letters are different; P <0.05PvC02: mixed venous carbon dioxide partial pressure; Pv'02: mixed venous oxygen partial pressure;(HCO3 )-: bicarbonate; ABE-: actual base excess; Hb: hemoglobin; Hct: hematocrit

used for the effect of treatmentand was followed by Duncan's multi-ple range test. A confidence level of95% was selected and the dataobtained expressed as mean ± stan-dard deviation.

RESULTS

The instrumentation and stabiliza-tion period varied from 50 to 90 min(mean 68 min), while the total anes-thesia time varied from 6.5 to 7.5 h.

Seven of the 8 animals had uneventfulrecoveries. The 8th horse developedmoderately severe postanestheticmyopathy, requiring treatment withopioid analgesics and fluid therapy.Since this development should nothave influenced the earlier hemo-dynamic studies, data from this horsewere included in the analysis.

Significant differences were notfound for the various parametersbetween sampling periods 1 and 2, andthe data obtained at these 2 intervals

were pooled for subsequent analysis.It was not possible to obtain pul-monary artery blood samples from4 of the horses, so mixed venousblood data and oxygen uptake data arebased on 4, rather than 8, horses.

All horses were within PaCO2 lim-its established for this study foreucapnia, and for mild, moderate, andsevere hypercapnia at the time ofsample collection. Group mean PaCO2values of 40.4 ± 2.9 (SD), 59.1 ± 3.5,82.6 ± 4.5, and 110.3 ± 12.2 mm Hgwere achieved for the 4 treatments(Table I). Tidal volume, peak inspira-tory and expiratory airway pressure,end-tidal isoflurane concentration,core body temperature, PaO2, and TPwere not significantly different overthe 4 treatments (Tables I and II).When exposure to either moderate orsevere hypercapnia preceded theeucapnic treatment period, it wasoccasionally not possible to achieveeucapnia using a rate of 6 breaths/min.Eucapnia was achieved by increasingthe rate to 7 or 8 breaths/min ratherthan by altering VT or the peak inspi-ratory pressure, since we believe thatthis adaptation more closely main-tained the constant tidal volume IPPVcriteria established for the study.

Arterial blood gas and acid base val-ues are shown in Table II. As PaCO2levels increased from eucapnia tosevere hypercapnia, PHa declined sig-nificantly (P <0.05) and actual baseexcess (ABE) was significantly lessduring moderate and severe hypercap-nia. Both Hb and Hct increased witheach increase in PaCO2. Mixed venousblood gas and acid base values areshown in Table III. The most strikingchange was the significant increase inmixed venous oxygen tension (PVO2)with moderate and severe hypercapnia.Hemodynamic changes with hyper-

capnia are shown in Table IV, and therelationship between them is illus-trated in Fig. 1. Heart rate decreasedsignificantly with mild and moderatehypercapnia and it was significantlyhigher with severe hypercapnia,reaching 44 ± 8/min. Cardiac indexdecreased by 12% with mild hyper-capnia, but increased 20% and 86%during moderate and severe hypercap-nia, respectively. Stroke index did notchange between eucapnia and mildhypercapnia, while it increased pro-gressively during moderate and severehypercapnia. Systolic blood pressure

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increased by 13% when the PaCO2levels were in the mild hypercapniarange and showed further increases of41% and 64% during moderate andsevere hypercapnia, respectively.Diastolic blood pressure remainedunchanged from the eucapnic valueduring all levels of hypercapnia.Mean blood pressure increased signif-icantly as PaCO2 rose, plateauing atthe moderate and severe hypercapniclevels. Systemic vascular resistanceincreased with mild hypercapnia,returned to eucapnic levels with mod-erate hypercapnia, and decreased sig-nificantly with severe hypercapnia.Mean pulmonary artery pressure wasincreased significantly during moder-ate and severe hypercapnia, whilechanges in CVP were not significantamong treatments.

Additional indices of cardiopul-monary function are shown in Table V.Alveolar dead space and arterial oxy-gen saturation did not change signifi-cantly among treatments, whilePAO2 -PaO2 values were significantlylower during severe hypercapnia whencompared with eucapnia (280.8 +115.6 versus 365.3 ± 119.4 mm Hg),respectively. Arterial and mixedvenous oxygen content followed simi-lar trends; both parameters increasedsignificantly during moderate andsevere hypercapnia. There was a pro-gressive increase in %Q'QT with theincrease in PaCO2, which reached sig-nificance during mild and severehypercapnia. Oxygen deliverydecreased significantly during mildhypercapnia, while DO2 increased sig-nificantly with moderate and severehypercapnia. V02 was unchangedwith treatment.Plasma catecholamine and cortisol

concentrations are shown in Table V.Epinephrine concentrations werebelow the detection limit of the assay,but norepinephrine concentrationsincreased progressively with increas-ing hypercapnia. Cortisol concentra-tions did not change with hypercapnia.

DISCUSSION

The results of this study indicatethat hypercapnia elicits a biphasic car-diovascular response in horses duringisoflurane anesthesia and volume con-trolled IPPV. With mild hypercapnia(PaCO2, 59.05 ± 3.5 mm Hg), a 10%decrease in HR was accompanied by

Table IV. Hemodynamic and derived cardiovascular values during eucapnia and hypercapniawith constant volume intermittent positive pressure ventilation (IPPV) in isoflurane-anesthetized horses (mean + SD; n = 8)

PaCO2Variable 35-45 55-65 75-85 >95

HR (beats/min) 34 ± 4a 31 + 4b 32 ± 6c 44 ± 8dCI (mLfkg/min) 49 ± 16a 43 ± 7b 59 ± 13c 92 ± 27dSI (mLlkg/beat) 1.4 ± 0.3a 1.4 ± 0.3a 1.8 ± 0.4b 2.0 ± 0.5cMBP(mmHg) 70±23a 79±13b 91 ± 19c 92± 14cSBP (mm Hg) 88 ± 23a 1oo ± 19b 124 ± 25c 142 ± 17dDBP (mm Hg) 57 ± 18a 66 ± 14a 72 ± 14a 66 ± 12aSVR (dynes/sec/cm-5) 176 ± 77a 224 ± 65b 191 ± 62a 123 ± 50cCVP(mmHg) 19± 7a 21 + 8a 24+ 8a 28+ 12aPAP (mm Hg) 26 ± 4a 27 ± Sa 31 ± Sb 34 ± 4ca.b.c.d Significant differences between treatments are present when letters are different; P <0.05HR: heart rate; CI: cardiac index; SI: stroke index; MBP: mean blood pressure; SBP: systolic bloodpressure; DBP: diastolic blood pressure; SVR: systemic vascular resistance; CVP: central venouspressure; PAP: mean pulmonary artery pressure

Table V. Indices of cardiopulmonary function, norepinephrine, and cortisol levels duringeucapnia and hypercapnia with constant volume intermittent positive pressure ventilation(IPPV) in isoflurane-anesthetized horses (mean ± SD)

PaCO2Variable 35-45 55-65 75-85 >95

VJVT(%) n = 8 16.7 ± 9.0a 13.2 ± 7.6a 9.5 ± 6.6aPAO2-PaO2 (mm Hg) n = 8 365 ± 119a 448 ± 109a 401 ± 85a 281 ± 116bCaO2 (mL/L) n = 8 127 ± 17a 126 ± 15a 144 ± 24b 173 ± 39cCi02 (mL/L) n = 4 90 ± 18a 95± 21a 115 ± 38b 139 ± 46cQS/QT () n = 4 30.3 ± 9.4a 39.8 ± 21.2b 38.3 ± 19.7a.b 435 ± 11.6bDx02 (mL/kg/min) n = 8 6.2±1.9a 5.3 ±0.6b 8.4±2.2cb 15.3 +4.3cV02 (mL/kg/min) n = 4 1.4 ± 0.2a 1.3 ± 0.7a 1.5 ± 0.6a 1.6 ± 0.8aNorepinephrine (pg/mL) n = 8 67.3 ± 47.6a 95.4 ± 64.4a 238.9 ± 170a 485.6 ± 266.lbCortisol (ng/mL) n = 8 81.8 ± 29.4a 73.8 ± 23.9' 91.5 ± 27.8a 87.4 ± 26.0aa.b.c,d Significant differences between treatments are present when letters are different; P <0.05VD/VT: alveolar dead space; PAO2-PaO2: alveolar-arterial oxygen partial pressure difference;CaO2: arterial oxygen content; CvO2: mixed venous oxygen content; QS/QT: shunt fraction; DO2:oxygen delivery; V02: oxygen consumption

a significant reduction in CI of 12%.On the other hand, moderate (PaCO2,82.6 ± 4.5 mm Hg) and severe hyper-capnia (PaCO2, 110.3 ± 12.2 mm Hg)produced a marked degree of hemody-namic stimulation, although HRincreased only during severe hyper-capnia (Table IV, Fig. 1).

Elevation of PaCO2 and the associ-ated decrease in pH produce directmyocardial depression in isolatedmammalian heart muscle (36-38). Inintact humans and dogs, however,hypercapnia enhances cardiovascularperformance through an increasedsympathoadrenal response (15,39,40).Anesthesia blunts the hypercapniccardiovascular response to a variabledegree, depending on the agentinvolved and the time permitted forsympathoadrenal response to thePaCO2 elevation (16,17,19,41). ThePaCO2 in these earlier studies werecomparable to our mild hypercapnia.

The significant decrease in CI andHR during mild hypercapnia wasaccompanied by a rise in SVR, pro-ducing an increase in SBP and MBPof 14%. A similar increase in bloodpressure was seen in halothane-anesthetized, paralyzed horses at acomparable level of hypercapnia(mean PaCO2, 59.5 mm Hg) with nochange in HR, but cardiac output andSVR were not determined (42).

It was not possible to pinpoint thereason for the unexpected decrease inCI and HR with mild hypercapnia inour study. Horses have an inherenthigh degree of cardiac vagal tone andare prone to the development of brady-arrhythmias in response to increasingblood pressures. Light planes of anes-thesia with isoflurane (1.0-1.4 MAC)attenuate, but do not totally abolishthis baroreceptor response (43). Whenthe ot2-adrenergic agents xylazine anddetomidine are administered, the

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peripheral vasoconstriction and initialincrease in blood pressure producebradycardia by activation of aorticbaroreceptors and vagal stimulation(44). A similar initial bradycardicresponse is often seen clinically with13 -receptor stimulation using lowdoses of dobutamine, presumablyonce again in response to barorecep-tor-vagal activation as a result of risein blood pressure (45). Since nor-epinephrine concentration, SVR, andMBP increased with mild hypercap-nia, it seems likely that the bradycar-dia and fall in CI were produced bypredominance of the baroreceptor-vagal stimulation and perhaps a directCO2 myocardial depressant effectover the cardiac inotropic response tocatecholamine release. During halo-thane anesthesia, a significantincrease in circulating epinephrineand norepinephrine levels and indicesof ventricular contractility (positivedp/dt max) occurred when the horseswere subjected to a moderate degreeof hypercapnia (21).With moderate and severe hyper-

capnia (PaCO2, 86.61 ± 4.48 and110.32 ± 12.18 mm Hg, respectively),significant increases in cardiovascularperformance were observed. Moder-ate hypercapnia increased CI due toan enhanced SI, while HR was stillbelow the eucapnic levels. Systolicand mean blood pressures and PAPincreased significantly, while DBP,CVP, and SVR remained unchangedfrom the eucapnic state. This is a sig-nificant positive inotropic response tomoderate hypercapnia, as was alsoobserved during halothane anesthesia(21). With SVR not changing signifi-cantly, the increase in blood pressureand CI suggest that there is animprovement in whole body perfu-sion. The increases in C-vO2 and PvO2with moderate hypercapnia also indi-cate improved perfusion (46). A simi-lar, albeit greater, trend to enhance-ment of cardiovascular performancewas observed with hypercapnia of sim-ilar magnitude (mean PaCO2, 82 mmHg) in halothane-anesthetized horses(21). The halothane-anesthetizedhorses had a similar SI to ours (1.8 mL/kg/beat), but owing to a higher meanHR (40 versus 32.3 beats/min), thesehorses tended to have higher mean CI(70 versus 59 mL/kg/min).

Severe hypercapnia (PaCO2, 110.32± 12.18 mm Hg) was accompanied by

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EC MHC MOHC SHCFig. 1. Changes in cardiac index (CI), mean blood pressure (MBP), and systemic vascularresistance (SVR) (mean ± SD) associated with changes in PaCO2 in isoflurane-anesthetizedhorses (n = 8) with constant volume IPPV. EC: eucapnia (40.4 + 2.9 mm Hg SD); MHC: mildhypercapnia (59.1 ± 3.5 mm Hg); MDHC: moderate hypercapnia (82.6 ± 4.5 mm Hg); SHC:severe hypercapnia (110.3 t 12.2 mm Hg). Significant differences between treatments are pre-sent when letters (a,b,c,d) are different; P <0.05.

significant augmentation of CI due toan increase in SI and HR. At this levelof PaCO2, there was a significantdecrease in SVR, presumably as aresult of the direct peripheral vasodi-lation produced by CO2 (Fig. 1). Sys-tolic blood pressure increased signifi-cantly, while MBP and DBP were notdifferent from moderate hypercapnia.The increase in SBP probably resultedfrom increased SI and myocardialcontractility produced by catecho-

lamine stimulation (21). It has beenpreviously suggested that the cate-cholamine response in the horse mightbe maximal in the PaCO2 range of60-80 mm Hg (21), but our resultsclearly show that is not the case.

Hypercapnia produced a significantrise in Hct and Hb concentration, ashas been observed in spontaneouslybreathing isoflurane-anesthetizedhorses (9). These changes have beenattributed to splenic infusion of red

218

blood cells in response to the increasedsympathetic nervous system activityassociated with hypercapnia (9).

Alveolar to arterial 02 tension dif-ference was significantly decreasedduring severe hypercapnia, but notduring moderate or mild hypercapnia.This change could be attributed to theincrease in alveolar CO2 tension thatreplaces oxygen in the alveolus, thusdiminishing the measured PAO2-PaO2 difference. The degree ofvenous admixture (%QsOQT) actuallytended to increase as the degree ofhypercapnia increased, reaching sig-nificance during mild and severehypercapnia (Table V). The apparentdiscrepancy in PAO2, PaO2, and Q/QTvalues may be because the latter mea-surements could only be made on4 horses. Arterial oxygen saturationand PaO2 levels were unchanged byhypercapnia, although CaO2 increaseddue to the change in Hb concentration.The effects of hypercapnia on

whole body perfusion and 02 supplyare not clear-cut. There was an obvi-ous increase in DO2 with moderateand severe hypercapnia (Table V),which is a reflection of an increase inCI and Hct at these PaCO2 levels.Mixed venous P02 was significantlyelevated over eucapnic levels, whichwould strongly suggest that wholebody 02 requirements were being met.At the same time, an apparent meta-bolic acidosis occurred as reflected bythe fall in ABE (Table II). Interest-ingly, the same observation was madeby others during hypercapnia inhalothane-anesthetized horses (21),with an apparent reversal of themetabolic acidosis when the animalswere returned to the eucapnic state. Itmay well be that the change in ABEwith hypercapnia is not a true reflec-tion of metabolic acidosis, but ratheran erroneous result of using an acidbase nomogram devised for humans(47) on equine blood subjected tolarge pH and PCO2 changes. It is alsopossible that arteriovenous shunts areopening up due to endogenous cate-cholamine stimulation leading tosimultaneous inadequacy of 02 deliv-ery to at least some tissue beds, whilestill increasing Pv02. Further studiesare needed to clarify this aspect.The PaCO2 span established between

mild and moderate hypercapnia in thepresent study is reflective of the degreeof hypercapnia commonly seen during

clinical general anesthesia and duringcontrolled studies in spontaneouslyventilating horses (3,6-9,23,31,48,49).The previous study by Wagner et al(21) used a fairly high PaCO2 level forthe 1st degree of hypercapnia and, assuch, missed the apparent biphasicresponse seen in the present study. Forthe sake of completeness, it was consid-ered necessary to include severe hyper-capnia in the present protocol becausesuch a study is not available in the liter-ature. It was extremely difficult tomaintain a steady state of hypercapniaduring severe hypercapnia. This neces-sitated treating PaCO2 levels above95 mm Hg as severe hypercapnia.

Interestingly, we did not observeany arrhythmias at any level of hyper-capnia. Arrhythmias with hypercapniahave been reported in conscioushumans, but they were not consideredto be very significant (15). All otherstudies carried out in people, bothawake and anesthetized, do not reportany arrhythmias. Hypercapnic arrhyth-mic thresholds have been calculatedfor cyclopropane and halothane inpeople and they are 74 and 92 mm Hg,respectively (50); such a study has notbeen reported for isoflurane. In dogs,an increase in PCO2 up to 550 mm Hgdid not produce any arrhythmias witheither cyclopropane or halothane, thusa species difference does exist (50).No report of this nature is availablefor horses.

It is not clear if there is a differencein the degree of hemodynamic stimu-lation produced by hypercapnia dur-ing halothane and isoflurane anesthe-sia. Wagner et al (21) observed amuch greater effect of hypercapnia onMBP, CI, and SI (34%, 128%, and117% increase respectively) than weobserved during isoflurane anesthesia(28% in MBP, 21% CI, and 29% SI)at a similar level of hypercapnia(PaCO2 level of 82 mm Hg). Isoflu-rane depresses the myocardium lessthan halothane in horses (51), andeucapnic CI levels (49 mL/kg/min)were 63% higher in the present studythan the eucapnic CI values in thehalothane anesthetized horses (30 mL/kg/min). The apparently greaterdegree of hypercapnia-induced hemo-dynamic stimulation during halothaneanesthesia may simply be a reflectionof the starting point. In the halothaneanesthesia trial, the sequence of expo-sure to various hypercapnic levels

was not randomized, and the possibil-ity exists that time was a factor thatcontributed towards the enhancementof the cardiovascular performance(21). In humans, isoflurane does notblunt the cardiovascular effects ofhypercapnia other than to moderatethe blood pressure increase (52).

It was essential to ensure that thehorses did not breathe spontaneouslyduring the hypercapnic state, as spon-taneous inspiratory efforts in such sit-uations may alter the cardiovascularinfluence of IPPV. This was success-fully achieved by using the musclerelaxant atracurium as an adjunct toisoflurane anesthesia. Wagner et alreported spontaneous ventilatoryefforts by their halothane-anesthetizedhorses during hypercapnia, and thismay have contributed to the increasein CI they observed (21). The induc-tion regime and transfer to the inhalantanesthetic without surgical stimulationproduced fairly severe hypotension inthe early stages of anesthesia. Thisnecessitated volume loading with5.0 L of lactated Ringer's solution.The outcome of the trial should nothave been affected by this maneuverbecause of randomization, andbecause the initial volume loading wascompleted early on during stabiliza-tion and instrumentation.Although norepinephrine concen-

tration increased in parallel withhypercapnia, the catecholamine val-ues in this study were much lowerthan those reported in response tohypercapnia during halothane anes-thesia (21). As a result of technicalproblems, the assays were performedafter the plasma had been stored at-70°C for over 6 mo. This may haveresulted in some deterioration in thesamples. However, different anes-thetic agents may affect the response.One report where halothane-anesthetized ponies were subjected to40 min of hypercapnia (75 mm Hg)described no consistent increase incatecholamines in response to hyper-capnia (28). These animals hadreceived acepromazine and thiopen-tone, which might have affected theresponse. Although the absolute val-ues of norepinephrine in the presentstudy were not as high as thosereported by Wagner et al (21), thesame trend is evident, with a markedrise with increasing hypercapnia. Theobvious norepinephrine response, in

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contrast with the very low epine-phrine concentrations, may be a resultof sample deterioration, but couldindicate that the catecholamineresponse is primarily from the sympa-thetic nervous system, without amarked effect on the adrenal medulla.The changes in cortisol concentra-

tion are unremarkable; no significantchange with increasing hypercapniawas seen. Halothane anesthesia usu-ally causes a rise in plasma cortisol(53,54) that is partially dependent ontime. No increase is seen before about60 min anesthesia, but it thenincreases steadily. As a result of therandomization of the PaCO2 levels,the effect of time is obliterated. Nosamples were taken from consciousanimals, so the normal for each indi-vidual is unknown. A previous studyinvestigating the effect of hypercap-nia also reported little additionaleffect of hypercapnia over thatalready induced by halothane (28).Arterial blood pressure was generallywell maintained in the present study,and this may account for the relativelynormal cortisol values during anesthe-sia as adrenocortical activity appearsto increase during hypotension (55).

Subsequent to the commencementof the present study, it was reportedthat the particular infrared airwaymonitor we were using gave erro-neously high values for halothane inhorses and ruminants (56). Wedecided to check its efficiency in esti-mating isoflurane. In a simple trial,conducted in standing horses (n = 6)with and without fasting, tracheal andpharyngeal gas samples were ana-lyzed with the monitor for false posi-tive halothane and isoflurane read-ings. While the monitor consistentlyand seriously overestimated the levelof halothane present, presumablybecause of cross-reaction withmethane (57), the maximum overesti-mation of isoflurane was never morethan 0.1% except in 1 instance in anonfasted horse (0.2%). An error ofthat magnitude in measuring our end-tidal isoflurane levels would notlikely have affected results to anygreat degree.From the results of this study it can

be concluded that CO2 produces abiphasic cardiovascular response inisoflurane-anesthetized, mechanicallyventilated horses. It is beyond thescope of the study to determine the

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exact cause for the cardio-depressiveaction of mild hypercapnia. The dis-tinctly increased cardiovascular per-formance at moderate and severehypercapnia can be attributed to anincreased sympathoadrenal responseelicited by these levels of PaCO2. Thehemodynamic response increasedmarkedly when the PaCO2 waschanged from moderate to severehypercapnia. Thus it is likely that upto a PaCO2 of 110 mm Hg, the cate-cholamine response does not plateauas has been suggested elsewhere (21).

ACKNOWLEDGMENTS

The assistance of Anne Valliant forstatistical analysis and of MalcolmBloomfield for the HPLC analysis isgreatly appreciated.

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