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An implementation of apneustic anesthesia ventilation in the horse: comparison with conventional mechanical ventilation

Published:April 14, 2022DOI:https://doi.org/10.1016/j.vaa.2022.04.002

      Abstract

      Objective

      To compare the cardiopulmonary effects of apneustic anesthesia ventilation (AAV) and conventional mechanical ventilation (CMV) in dorsally recumbent anesthetized horses.

      Study design

      Randomized, crossover design.

      Animals

      A total of 10 healthy adult horses from a university-owned herd.

      Methods

      Following xylazine, midazolam and ketamine administration, horses were orotracheally intubated and positioned in dorsal recumbency. Anesthesia was maintained with isoflurane in oxygen [inspired oxygen fraction (FiO2) = 0.3 initially, with subsequent titration to maintain PaO2 ≥ 85 mmHg (11.3 kPa)]. Horses were instrumented and ventilated with AAV or CMV for 1 hour according to predefined criteria [10 mL kg–1 tidal volume (VT), PaCO2 of 40–45 mmHg (5.3–6.0 kPa) during CMV and <60 mmHg (8.0 kPa) during AAV]. Dobutamine was administered to maintain mean arterial pressure (MAP) >65 mmHg. Cardiopulmonary data were collected at baseline, 30 and 60 minutes. The effects of ventilation mode and time were analyzed using repeated-measures anova with significance defined as p < 0.05.

      Results

      Data from nine horses were analyzed. A significant effect of mode at one or more time points was found for respiratory rate, arterial and end-tidal CO2 tensions, arterial pH, mean airway pressure (Paw), respiratory system dynamic compliance index (CrsI), venous admixture (Q˙s/Q˙t), mean pulmonary artery pressure and systemic vascular resistance. No significant differences between modes were found for VT, FiO2, PaO2, arterial hemoglobin saturation, alveolar dead space, heart rate, MAP, cardiac index, stroke volume index, oxygen delivery index, oxygen extraction ratio and dobutamine administration.

      Conclusions and clinical relevance

      In dorsally recumbent anesthetized horses, both ventilation modes supported adequate oxygenation with minimal supplemental oxygen. Compared with CMV, AAV resulted in higher CrsI and lower Q˙s/Q˙t. Despite higher mean Paw with AAV, the cardiovascular effects of each mode were not different. Further trials of AAV in anesthetized horses are warranted.

      Keywords

      Introduction

      In horses, general anesthesia is associated with a variety of pathophysiologic abnormalities that promote respiratory gas exchange derangements (e.g. hypercapnia and/or hypoxemia), including decreased functional residual capacity (FRC) (
      • McDonell W.N.
      • Hall L.W.
      Functional residual capacity in conscious and anaesthetized horses.
      ;
      • McDonell W.N.
      • Hall L.W.
      • Jeffcott L.B.
      Radiographic evidence of impaired pulmonary function in laterally recumbent anaesthetised horses.
      ;
      • Sorenson P.R.
      • Robinson N.E.
      Postural effects on lung volumes and asynchronous ventilation in anesthetized horses.
      ), hypoventilation (
      • Steffey E.P.
      • Wheat J.D.
      • Meagher D.M.
      • et al.
      Body position and mode of ventilation influences arterial pH, oxygen, and carbon dioxide tensions in halothane-anesthetized horses.
      ,
      • Steffey E.P.
      • Kelly A.B.
      • Hodgson D.S.
      • et al.
      Effect of body posture on cardiopulmonary function in horses during five hours of constant-dose halothane anesthesia.
      ;
      • Hodgson D.S.
      • Steffey E.P.
      • Grandy J.L.
      • Woliner M.J.
      Effects of spontaneous, assisted, and controlled ventilatory modes in halothane-anesthetized geldings.
      ) and ventilation–perfusion mismatching (
      • Nyman G.
      • Hedenstierna G.
      Ventilation-perfusion relationships in the anaesthetised horse.
      ;
      • Nyman G.
      • Funkquist B.
      • Kvart C.
      • et al.
      Atelectasis causes gas exchange impairment in the anaesthetised horse.
      ). Traditionally, these abnormalities have been addressed using conventional mechanical ventilation (CMV) and elevated fraction of inspired oxygen (FiO2). Within this paradigm, additional strategies have been described, including positive end-expiratory pressure (PEEP) and alveolar recruitment maneuvers (ARMs) (
      • Ambrosio A.M.
      • Ida K.K.
      • Souto M.T.
      • et al.
      Effects of positive end-expiratory pressure titration on gas exchange, respiratory mechanics and hemodynamics in anesthetized horses.
      ;
      • Hopster K.
      • Ambrisko T.D.
      • Stahl J.
      • et al.
      Influence of xylazine on the function of the LiDCO sensor in isoflurane anaesthetized horses.
      ;
      • Araos J.D.
      • Lacitignola L.
      • Stripoli T.
      • et al.
      Effects of positive end-expiratory pressure alone or an open-lung approach on recruited lung volumes and respiratory mechanics of mechanically ventilated horses.
      ). The use of FiO2 <1 has also been investigated as a strategy to minimize absorption atelectasis, but results do not support a distinct advantage within the CMV framework (
      • Marntell S.
      • Nyman G.
      • Hedenstierna G.
      High inspired oxygen concentrations increase intrapulmonary shunt in anaesthetized horses.
      ;
      • Hubbell J.A.
      • Aarnes T.K.
      • Bednarski R.M.
      • et al.
      Effect of 50% and maximal inspired oxygen concentrations on respiratory variables in isoflurane-anesthetized horses.
      ;
      • Schauvliege S.
      • Savvas I.
      • Gasthuys F.
      The effect of the inspired oxygen fraction on arterial blood oxygenation in spontaneously breathing, isoflurane anaesthetized horses: a retrospective study.
      ). More recently, the use of continuous positive airway pressure (CPAP) in spontaneously breathing anesthetized horses improved ventilation–perfusion (V/Q) matching (
      • Mosing M.
      • Auer U.
      • MacFarlane P.
      • et al.
      Regional ventilation distribution and dead space in anaesthetized horses treated with and without continuous positive airway pressure: novel insights by electrical impedance tomography and volumetric capnography.
      ) and attenuated the magnitude of pulmonary venous admixture, but at the expense of significant hypercapnia (
      • Mosing M.
      • MacFarlane P.
      • Bardell D.
      • et al.
      Continuous positive airway pressure (CPAP) decreases pulmonary shunt in anaesthetized horses.
      ).
      Apneustic anesthesia ventilation (AAV) is a novel mode of mechanical ventilation, conceptually distinct from CMV (
      • Bratzke E.
      • Downs J.
      • Smith R.A.
      Intermittent CPAP: a new mode of ventilation during general anesthesia.
      ; Fig. 1). Specifically, AAV is characterized by a continuously applied, elevated baseline pressure (PHIGH) with transient, time-cycled intermittent release to a set lower pressure (PLOW) (Fig. 2). Implementation is such that the time of applied PHIGH (THIGH) is significantly longer than the time at PLOW (TLOW). Time at PHIGH promotes maintenance of lung volume and alveolar recruitment, whereas brief decreases in airway pressure (Paw) create tidal ventilation. AAV was designed to optimize lung function in the anesthetized human by elevating lung volume above FRC to prevent progressive formation of atelectasis and to minimize the occurrence of postoperative pulmonary complications. Because lung volume is rarely measured in the clinical setting, appropriate PHIGH and PLOW settings can be determined in a manner that optimizes respiratory system compliance. Importantly, TLOW is set to prevent expiratory flow stagnation during the release phase to prevent alveolar collapse. This contrasts with CMV, which is characterized by repetitive cycling from a baseline to an elevated airway pressure to achieve tidal ventilation, with the majority of respiratory cycle time occurring at the lower baseline pressure.
      Figure 1
      Figure 1Theoretical schematic illustration of dynamic pressure–volume curves (thin lines) for conventional mechanical ventilation (CMV) and apneustic anesthesia ventilation (AAV) superimposed on individual pressure–volume curves (bold lines) for the respiratory system. AAV was designed to preserve lung architecture and compliance in the anesthetized human by periodically releasing airway pressure from a high to low level while maintaining lung volume at or above functional residual capacity (FRC). By contrast, CMV ventilates the lung from below FRC leading to the development of atelectasis, shifting of the pressure–volume curve to the right, and lower compliance. In this scenario, higher pressures are required during CMV to achieve the same tidal volume. Reproduced with permission from Innovative Veterinary Medicine.
      Figure 2
      Figure 2(a) Schematic idealized illustrations and (b) examples of observed pressure, flow and volume versus time waveforms for conventional volume-controlled mechanical ventilation (CMV) and apneustic anesthesia ventilation (AAV). Grey background indicates periods of tidal ventilation corresponding to inspiratory time during CMV and the time (TLOW) at the low pressure setting (PLOW) during AAV. White background indicates expiratory time during CMV and the time (THIGH) of applied high pressure (PHIGH) during AAV. CMV intermittently raises pressure from ambient to peak inspiratory pressure with the majority of cycle time spent at ambient pressure. AAV intermittently releases pressure from PHIGH to PLOW to preserve lung volume. Importantly, the duration of each AAV release (TLOW) is limited to prevent expiratory flow stagnation (i.e. an expiratory flow of zero). In (a), the first AAV release illustrates proper limitation of release time whereas the second illustrates excessively long release time with flow stagnation (arrow). Reproduced with permission from Innovative Veterinary Medicine.
      The objectives of this study were: 1) to describe an implementation of AAV in anesthetized horses using a custom-built mechanical ventilator; and 2) to determine if this method of ventilating anesthetized horses would provide physiologic advantages compared with traditional CMV using low FiO2. Based on clinical experience and unpublished data, we hypothesized that 1) AAV would result in improved indices of pulmonary function [less venous admixture (Q˙s/Q˙t), lower required FiO2 and higher dynamic compliance] compared with CMV; and 2) no differences in cardiovascular performance would be observed between modes.

      Materials and methods

      Adult horses (eight female and two castrated males) from a university-owned herd, aged 16.2 ± 2.7 years and weighing 515 ± 40 kg (mean ± standard deviation), were anesthetized twice in random order. Breeds included seven American Quarter Horses, one Thoroughbred, one Paint and one Standardbred. All were determined to be healthy based on physical examination, complete blood count and biochemistry profile. Experiments were performed at the University of Missouri (MU; MO, USA) over two 1-week periods separated by 7 weeks. Randomization of ventilation mode order was via a binary random number generator (www.random.org; Ireland). The study protocol was approved by the MU Animal Care and Use Committee (protocol 9006) and the Department of the Navy, Bureau of Medicine and Surgery (protocol 1085). An a priori power analysis (G∗Power 3.1.9.2; University of Düsseldorf, Germany) (
      • Faul F.
      • Erdfelder E.
      • Lang A.G.
      • Buchner A.
      G∗Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences.
      ) for repeated-measures analysis of variance (anova) design with α=0.05, 1β=0.8, effect size of 0.5 and repeated-measures correlation of 0.5 suggested a sample size of 10.

      Anesthesia

      Prior to each treatment, horses were housed for 36–48 hours at the MU Veterinary Health Center. Food was withheld the evening prior to the study day with free access to water. Before anesthesia, a 14 gauge, 13.3 cm catheter (Angiocath; Becton Dickinson Infusion Therapy Systems Inc., UT, USA) was aseptically placed in the left jugular vein. Immediately before premedication, a 5 mL kg–1 intravenous (IV) bolus of lactated Ringer’s solution (Baxter Healthcare Corporation, IL, USA) was administered. Xylazine (1 mg kg–1; AnaSed; Akorn Inc., IL, USA) was administered IV 3–5 minutes before induction with ketamine (2.2 mg kg–1; Zetamine; VetOne, ID, USA) IV and midazolam (0.05 mg kg–1; Midazolam Injection USP; West-Ward Pharmaceutical Corp., NJ, USA) IV. Once recumbent, horses were orotracheally intubated with a 26 mm internal diameter cuffed silicone tube. Each horse was hoisted, positioned in dorsal recumbency on a padded table and connected to the circle breathing system of an anesthesia machine primed with 1.5% isoflurane (Isoflurane USP; Akorn Inc.) and 30% oxygen in medical air. Anesthetic delivery was adjusted to maintain 1.5% end-tidal isoflurane concentration (Fe′Iso) throughout each experiment. Lactated Ringer’s was administered at 5 mL kg–1 hour–1.

      Experimental protocol

      The modes of ventilation studied were CMV (defined as intermittent positive pressure ventilation in the absence of PEEP and ARMs) and AAV. CMV was applied using an unmodified large animal anesthesia machine with integrated descending bellows ventilator (Surgivet LDS3000 with DHV1000; Smiths Medical ASD Inc., OH, USA). AAV was applied using the same breathing system and bellows assembly but with a custom-built ventilator (DolVent; Innovative Veterinary Medicine, FL, USA) in place of the native drive mechanism. Each mode was implemented based on predefined criteria, CMV: 10 mL kg–1 tidal volume (VT) and an arterial carbon dioxide tension (PaCO2) within 40–45 mmHg (5.3–6.0 kPa), and AAV: 10 mL kg–1 VT and PaCO2 <60 mmHg (8.0 kPa). In CMV, these targets were realized by adjusting the inspiratory time and flow for VT, and respiratory rate (fR) for PaCO2. In AAV, ventilator settings proceeded as follows: 1) an initial fR of 8 breaths minute–1 was selected; 2) TLOW was set to the maximum value that prevented an expiratory flow of zero based on visual inspection of the flow waveform; 3) PHIGH was set to 25 cmH2O; 4) PLOW was adjusted up from zero to realize the target VT; 5) both PHIGH and PLOW were adjusted downward, while preserving their difference, to achieve the lowest values that maintained compliance at its maximum observed value; and 6) fR was adjusted to meet the PaCO2 target.
      Regardless of ventilation mode, arterial oxygen tension (PaO2) was maintained at ≥85 mmHg (11.3 kPa) and mean arterial blood pressure (MAP) was maintained at 65–80 mmHg. FiO2 was initially set at 0.30 using a medical air–oxygen blender (PM5300; Precision Medical Inc., PA, USA) and was increased in increments of 0.10 if PaO2 <85 mmHg (11.3 kPa) was observed on arterial blood analysis. Subsequently, FiO2 was not reduced. If MAP was <65 mmHg, dobutamine (Dobutamine Injection USP; Hospira Inc., IL, USA) infusion via a dedicated 20 gauge catheter in the right jugular vein was started at 0.5 μg kg–1 minute–1 (Medfusion 3500; Smiths Medical ASD Inc.) and adjusted up or down in 0.1 μg kg–1 minute–1 increments based on MAP response.
      Each experiment proceeded in three phases: instrumentation, data collection and recovery. Mechanical ventilation was initiated immediately after positioning in dorsal recumbency. During instrumentation, arterial blood analysis was performed every 15 minutes. Once PaO2, PaCO2 and MAP met their predefined physiologic targets, data were collected at three time points (T0, T30 and T60), each 30 minutes apart. Immediately after T60, monitoring devices were removed and the horse was weaned from mechanical ventilation and transferred to a padded stall for unassisted recovery. Xylazine (0.2 mg kg–1) IV was administered in recovery.

      Monitoring and data collection

      Once the horse was positioned, a Pitot tube-based (
      • Moens Y.P.
      • Gootjes P.
      • Ionita J.C.
      • et al.
      In vitro validation of a Pitot-based flow meter for the measurement of respiratory volume and flow in large animal anaesthesia.
      ) calibrated spirometer (DolVent EUI; Innovative Veterinary Medicine) was placed between the Y-piece of the breathing system and the tracheal tube for measurement of respiratory variables corrected for temperature and gas composition. Spirometer accuracy was checked at the beginning of each experimental day using a 7 L calibrated syringe (Model 4900; Hans Rudolph Inc., KS, USA) to ensure measured volumes were within ±100 mL of delivered volumes. Variables common to both modes included VT, fR, mean Paw and total dynamic compliance of the respiratory system (Crs). CMV specific variables included inspiratory-to-expiratory ratio, peak inspiratory pressure (PIP) and end-expiratory pressure (EEP). AAV-specific variables included PHIGH, PLOW, THIGH and TLOW. All respiratory variables were recorded directly from the spirometer except for airway gas concentrations and mean Paw in AAV mode, which was computed offline from raw pressure-time waveforms (Matlab Version R2018b; The MathWorks Inc., MA, USA). For CMV and AAV, Crs was computed as VT/(PIP – EEP) and VT/(PHIGHPLOW), respectively.
      A multiparameter monitor (Carescape B650; GE Healthcare, Finland) was used for monitoring base–apex electrocardiogram, pulse oximetry, side-stream airway gases [including FiO2, end-tidal carbon dioxide tension (Pe′CO2) and Fe′Iso], mean pulmonary artery pressure (MPAP), MAP and nasopharyngeal temperature. Airway gases were collected using polypropylene tubing with the tip level with the Murphy eye of the tracheal tube. Calibration of the airway gas module with manufacturer designated gas (755571-HEL; GE Healthcare) was performed at the beginning of each experimental day. An 8 Fr introducer (Prelude Sheath Introducer; Merit Medical Systems Inc., UT, USA) was placed in the right jugular vein and a 7 Fr, 110 cm balloon tipped catheter (111F7P; Edwards Lifesciences Corp., CA, USA) was positioned in the pulmonary artery using pressure waveform guidance and used for collection of mixed venous blood and determination of MPAP. A 20 gauge catheter was placed in the facial artery for determination of MAP and collection of arterial blood. For each experiment, new, disposable pressure transducers (Deltran II; Utah Medical Products Inc., UT, USA) were zeroed to atmospheric pressure and leveled to the point of the shoulder.
      Cardiac output (CO) was measured using lithium dilution (LiDCO Unity; Lidco Ltd, UK) with the lithium sensor connected to the arterial catheter. Sterile 1 m LiCl for injection was prepared by a pharmacist on the morning of each experimental day, and a standard dose of 2 mmol LiCl per determination was used. Lithium was injected peripherally via the left jugular vein catheter and all determinations were made per manufacturer recommendation.
      At each time point, cardiopulmonary data were recorded, systemic arterial and mixed venous blood samples were simultaneously collected (safePICO Aspirator; Radiometer Medical ApS, Denmark) for immediate analysis (ABL90 Flex; Radiometer Medical ApS) and CO was measured. Arterial blood analysis determined pHa, PaO2, PaCO2, hemoglobin saturation (SaO2) and hemoglobin concentration. Mixed venous blood analysis determined Pν¯O2 and Sν¯O2. Values were not corrected for body temperature. Dobutamine administration was quantified in two ways: 1) the instantaneous rate of administration at each time point (Dobutamine) and 2) the average rate of administration during the data collection period.

      Calculated data

      Data calculated using standard formulae (Appendix SA) included stroke volume (SV), alveolar dead space (VDalv/VTalv), systemic vascular resistance (SVR), Q˙s/Q˙t, oxygen delivery (DO2) and oxygen extraction ratio (O2ER). All calculations were performed at 37 °C. CO, SV, DO2, VT and Crs were indexed to body mass (denoted by an appended I).

      Statistical analysis

      Repeated-measures anova with two within subject factors (time point and ventilation mode) and one between subject factor (order) was used to model the data (SAS Version 9.4; SAS Institute, NC, USA). The covariance structure for the time point correlation was compound symmetry. After the full model – with main effects and interactions – was estimated, residual diagnostics were examined to verify the assumption of normality. Statistical significance was set at p < 0.05.
      Model interpretation began with examination of the significance of higher order interactions. For example, if time point and mode evidenced significant interaction, the effect of time was interpreted separately for each mode. The interaction between order (CMV first and AAV first), time point and mode was used to determine if order influenced time point measurements for each mode. When interactions were not significant, main effects were interpreted using the overall F-statistic and p-value, followed by post hoc mean comparisons and contrast estimation using Tukey’s simultaneous inference p-value adjustment. A paired t test was used to compare the average rate of dobutamine administration between modes.

      Results

      Data from one horse was incomplete during CMV because PaO2 failed to meet the criterion even at maximal FiO2. Data from this horse from both treatments were excluded. Data from the remaining nine horses were included in the analysis. Initial statistical analysis revealed that order was not a significant factor in the repeated measures model. Thus, order was excluded from the final analysis. Factors included in the final model were time point, ventilation mode and time point-by-mode interaction.
      The mean ± standard deviation experimental times were: time from induction to end instrumentation, 34 ± 3 and 31 ± 4 minutes; time from end instrumentation to T0, 37 ± 11 and 35 ± 16 minutes; time from T60 to start of recovery, 16 ± 6 and 13 ± 4 minutes for CMV and AAV, respectively. Descriptive statistics for variables unique to each ventilation mode are given in Table 1. Spontaneous ventilation was not observed in either mode at any point prior to weaning.
      Table 1Descriptive statistics of variables recorded during conventional mechanical ventilation (CMV) and apneustic anesthesia ventilation (AAV) in nine dorsally recumbent anesthetized horses at baseline (T0), 30 minutes (T30) and 60 minutes (T60). Data are presented as mean ± standard error of the mean. EEP, end-expiratory pressure; I:E, inspiratory-to-expiratory ratio; PHIGH, high pressure; PLOW, low pressure; PIP, peak inspiratory pressure; THIGH, time at PHIGH; TLOW, time at PLOW.
      Ventilation modeVariableTime point
      T0T30T60
      CMVPIP (cmH2O)19.0 ± 1.619.4 ± 1.819.9 ± 1.7
      I:E0.38 ± 0.020.40 ± 0.080.39 ± 0.07
      EEP (cmH2O)0.2 ± 0.10.2 ± 0.10.2 ± 0.1
      AAVPHIGH (cmH2O)16.6 ± 0.817.3 ± 1.118.0 ± 1.2
      PLOW (cmH2O)3.2 ± 0.13.1 ± 0.13.0 ± 0.0
      THIGH (seconds)7.0 ± 0.46.6 ± 0.46.5 ± 0.3
      TLOW (seconds)1.2 ± 0.01.3 ± 0.01.2 ± 0.0
      An effect of mode at one or more time points was found for fR, PaCO2, pHa, Pe′CO2, mean Paw, CrsI and Q˙s/Q˙t: fR was lower, and PaCO2 and Pe′CO2 were higher, in AAV than in CMV at each time point (p < 0.0001; Table 2). pHa was lower in AAV than in CMV at T0 (p = 0.0134), T30 (p = 0.0036) and T60 (p = 0.0065). Mean Paw was higher during AAV than in CMV at each time point (p < 0.0001). CrsI was higher during AAV than in CMV at T0 (p < 0.0001), T30 (p < 0.0001) and T60 (p = 0.0001). Q˙s/Q˙t was lower during AAV than in CMV at T0 (p = 0.0099) and T60 (p = 0.0065), but not at T30 (p = 0.0621). Within modes, both Pe′CO2 and VDalv/VTalv differed between time points. No significant differences between modes were found for nasopharyngeal temperature, VT, FiO2, PaO2 and SaO2.
      Table 2Measured and calculated respiratory variables and nasopharyngeal temperature in nine dorsally recumbent anesthetized horses ventilated with either apneustic anesthesia ventilation (AAV) or conventional mechanical ventilation (CMV) at baseline (T0), 30 minutes (T30) and 60 minutes (T60). All values are mean ± standard error of the mean. CrsI, respiratory system dynamic compliance index; fR, respiratory (CMV) or release (AAV) rate; FiO2, inspired fraction of oxygen; mean Paw, mean airway pressure; PaCO2, arterial carbon dioxide tension; PaO2, arterial oxygen tension; Pe′CO2, end-tidal carbon dioxide tension; pHa, arterial pH; Q˙s/Q˙t, venous admixture; SaO2, arterial hemoglobin saturation; T, nasopharyngeal temperature; VDalv/VTalv, alveolar dead space; VT, tidal volume.
      Different lowercase letters indicate significant differences between time points within a ventilation mode (p < 0.05). †Significantly different between modes at that time point (p < 0.05).
      VariableAAV modeCMV mode
      T0T30T60T0T30T60
      fR (breaths minute–1)8 ± 08 ± 08 ± 011 ± 111 ± 111 ± 1
      VT (mL kg–1)10.2 ± 0.110.1 ± 0.010.2 ± 0.110.1 ± 0.110.1 ± 0.110.1 ± 0.1
      FiO20.38 ± 0.030.40 ± 0.020.40 ± 0.020.42 ± 0.030.43 ± 0.040.47 ± 0.05
      PaO2 (mmHg)109 ± 4110 ± 4105 ± 5106 ± 5106 ± 7105 ± 7
      PaO2 (kPa)14.6 ± 0.514.7 ± 0.514.0 ± 0.614.1 ± 0.714.1 ± 0.914.0 ± 0.9
      SaO2 (%)95.6 ± 0.295.6 ± 0.295.4 ± 0.295.6 ± 0.295.5 ± 0.295.6 ± 0.3
      PaCO2 (mmHg)52.8 ± 1.354.5 ± 1.054.1 ± 1.544.9 ± 0.643.9 ± 0.843.3 ± 0.4
      PaCO2 (kPa)7.0 ± 0.27.3 ± 0.17.2 ± 0.26.0 ± 0.15.8 ± 0.15.8 ± 0.1
      pHa7.38 ± 0.017.37 ± 0.017.38 ± 0.027.43 ± 0.027.44 ± 0.027.44 ± 0.02
      Pe′CO2 (mmHg)46.3 ± 0.9†,a46.2 ± 0.8†,a43.9 ± 1.0†,b38.5 ± 0.9a36.1 ± 1.0b34.7 ± 0.8b
      Pe′CO2 (kPa)6.2 ± 0.1†,a6.2 ± 0.1†,a5.9 ± 0.1†,b5.1 ± 0.1a4.8 ± 0.1b4.6 ± 0.1b
      VDalv/VTalv0.12 ± 0.02a0.15 ± 0.02a0.18 ± 0.03b0.14 ± 0.02a0.18 ± 0.02b0.20 ± 0.02b
      Mean Paw (cmH2O)12.5 ± 0.612.5 ± 0.712.8 ± 0.74.9 ± 0.45.2 ± 0.55.3 ± 0.5
      CrsI (mL cmH2O−1 kg–1)0.79 ± 0.060.75 ± 0.060.72 ± 0.060.57 ± 0.050.57 ± 0.060.55 ± 0.05
      Q˙s/Q˙t0.23 ± 0.020.25 ± 0.020.21 ± 0.020.29 ± 0.020.29 ± 0.020.27 ± 0.03
      T (°C)35.9 ± 0.335.6 ± 0.335.2 ± 0.335.9 ± 0.135.6 ± 0.135.1 ± 0.1
      Different lowercase letters indicate significant differences between time points within a ventilation mode (p < 0.05). Significantly different between modes at that time point (p < 0.05).
      An effect of ventilation mode at one or more time points was found for MPAP and SVR (Table 3). Compared with CMV, MPAP was higher during AAV at T30 (p = 0.0179) and T60 (p = 0.0493), and SVR was higher at T60 (p = 0.0437). Within modes, MAP, CI, SVI, SVR, DO2I and Dobutamine differed between time points. No significant differences between modes were found for HR. Dobutamine administration (mean ± standard error) during T0–T60 was 0.52 ± 0.09 and 0.49 ± 0.10 μg kg–1 minute–1 for CMV and AAV, respectively (p = 0.74).
      Table 3Measured and calculated cardiovascular variables in nine dorsally recumbent anesthetized horses ventilated with either apneustic anesthesia ventilation (AAV) or conventional mechanical ventilation (CMV) at baseline (T0), 30 minutes (T30) and 60 minutes (T60). All values are mean ± standard error of the mean. CI, cardiac index; Dobutamine, instantaneous dobutamine infusion rate; DO2I, oxygen delivery index; HR, heart rate; MAP, mean arterial pressure; MPAP, mean pulmonary artery pressure; O2ER, oxygen extraction ratio; SVI, stroke volume index; SVR, systemic vascular resistance.
      Different lowercase letters indicate significant differences between time points within a ventilation mode (p < 0.05).†Significantly different between modes at that time point (p < 0.05).
      VariableAAV modeCMV mode
      T0T30T60T0T30T60
      HR (beats minute–1)47.1 ± 4.455.9 ± 4.944.0 ± 2.848.4 ± 4.249.9 ± 1.847.1 ± 2.6
      MAP (mmHg)67.1 ± 1.0a74.0 ± 1.5b73.6 ± 2.5b68.3 ± 1.3a76.2 ± 1.1b76.1 ± 1.7b
      MPAP (mmHg)18.3 ± 1.318.2 ± 1.116.1 ± 0.716.6 ± 1.5a15.1 ± 1.4a,b13.6 ± 1.0b
      CI (mL minute–1 kg–1)64 ± 4a67 ± 6a46 ± 4b75 ± 5a70 ± 6a55 ± 4b
      SVI (mL beat–1 kg–1)1.4 ± 0.1a1.2 ± 0.1b1.0 ± 0.1b1.6 ± 0.1a1.4 ± 0.1b1.2 ± 0.1c
      SVR (dyne second cm–5)172 ± 16a192 ± 24a274 ± 28†,b144 ± 9a179 ± 20a,b224 ± 19b
      DO2I (mL minute–1 kg–1)11.6 ± 0.8a12.2 ± 1.3a8.0 ± 0.9b13.6 ± 1.0a13.2 ± 1.5a9.6 ± 0.8b
      O2ER0.20 ± 0.01a0.20 ± 0.02a0.26 ± 0.03b0.17 ± 0.010.18 ± 0.020.22 ± 0.03
      Dobutamine (μg kg–1 minute–1)0.76 ± 0.13a0.50 ± 0.11b0.26 ± 0.10b0.79 ± 0.14a0.50 ± 0.10b0.28 ± 0.06b
      Different lowercase letters indicate significant differences between time points within a ventilation mode (p < 0.05).Significantly different between modes at that time point (p < 0.05).

      Discussion

      This study describes an implementation of AAV and found that this mode resulted in lower Q˙s/Q˙t, higher CrsI and higher mean Paw when compared with CMV. No differences between modes were found for VDalv/VTalv and the FiO2 required to maintain PaO2 >85 mmHg (11.3 kPa). Indices of cardiovascular function including HR, MAP, CI, SV, DO2I, O2ER and dobutamine administration were not different between modes. Variables that exhibited time dependence included Pe′CO2, VDalv/VTalv and all cardiovascular variables except HR. Although many of these differences were not considered clinically significant, CI and DO2I decreased at T60 and O2ER increased. This was likely secondary to reduced dobutamine administration needed to maintain MAP in the target range. Reduced CI may also explain increased VDalv/VTalv at T60.
      Each treatment started at FiO2 = 0.3 and, according to the design, required FiO2 > 0.5 only in one animal during CMV. Low FiO2 provides a more stringent testbed of the ability of each mode to maintain PaO2 because the masking effect of high FiO2 on low V/Q lung regions is removed. Low FiO2 also minimizes the confounding influence of absorption atelectasis and the conversion of low V/Q lung regions to shunt (
      • Joyce C.J.
      • Williams A.B.
      Kinetics of absorption atelectasis during anesthesia: a mathematical model.
      ;
      • Duggan M.
      • Kavanagh B.P.
      Pulmonary atelectasis: a pathogenic perioperative entity.
      ). However, our hypothesis that CMV would require higher FiO2 than AAV was not supported by the data. This could be secondary to our implementation strategy: FiO2 was only increased (never decreased), the increment was always 0.10, and ARMs were not attempted in either mode.
      Some observed differences between modes are explained by the implementation strategies with mild hypercapnia targeted during AAV and normocapnia targeted during CMV. Intentional hypercapnia during AAV contrasts with so-called permissive hypercapnia sometimes used with CMV. Although not originally described as a component of AAV (
      • Bratzke E.
      • Downs J.
      • Smith R.A.
      Intermittent CPAP: a new mode of ventilation during general anesthesia.
      ), hypercapnia is considered essential and allows a reduced release rate, with longer times at PHIGH, to support and promote alveolar recruitment and stability (Downs, personal communication). By contrast, CMV is traditionally used and described in the literature as a method to maintain normocapnia in anesthetized horses (
      • Steffey E.P.
      • Wheat J.D.
      • Meagher D.M.
      • et al.
      Body position and mode of ventilation influences arterial pH, oxygen, and carbon dioxide tensions in halothane-anesthetized horses.
      ,
      • Steffey E.P.
      • Mama K.R.
      • Galey F.D.
      • et al.
      Effects of sevoflurane dose and mode of ventilation on cardiopulmonary function and blood biochemical variables in horses.
      ;
      • Hodgson D.S.
      • Steffey E.P.
      • Grandy J.L.
      • Woliner M.J.
      Effects of spontaneous, assisted, and controlled ventilatory modes in halothane-anesthetized geldings.
      ;
      • Edner A.
      • Nyman G.
      • Essén-Gustavsson B.
      The effects of spontaneous and mechanical ventilation on central cardiovascular function and peripheral perfusion during isoflurane anaesthesia in horses.
      ). These implementations predictably resulted in significant differences between modes for fR and pHa (lower for AAV) as well as PaCO2 and Pe′CO2 (higher for AAV).
      Beyond PaCO2 management, the AAV paradigm is a significant departure from CMV. Tidal ventilation is created by transient pressure release during AAV, rather than raising pressure from baseline. As originally described in humans, AAV was designed to always maintain lung volume above FRC. By contrast, CMV (in the absence of PEEP) results in cycling of lung volume from below to above FRC. Although CMV can reliably correct hypercapnia in the anesthetized horse, efficacy in treating hypoxemia and reducing venous admixture is inconsistent (
      • Day T.K.
      • Gaynor J.S.
      • Muir III, W.W.
      • et al.
      Blood gas values during intermittent positive pressure ventilation and spontaneous ventilation in 160 anesthetized horses positioned in lateral or dorsal recumbency.
      ), and supplemental strategies including PEEP and ARMs are sometimes utilized. Whereas PaO2 was not different between modes, the present study found that a conservative, static AAV implementation, devoid of dynamic attempts to optimize pulmonary function, reduced Q˙s/Q˙t and improved CrsI compared with CMV without PEEP or ARMs. Applied clinically, the AAV parameters would be adjusted continuously in pursuit of optimal pulmonary function at the lowest possible PHIGH unconstrained by a fixed VT requirement, as described in this study.
      When combined with the cardiovascular depressant effects of inhaled anesthetics, elevated Paw may increase the incidence of hypotension and reduced DO2 that may compromise tissue function and integrity (
      • Wilson D.V.
      • Soma L.R.
      Cardiopulmonary effects of positive end-expiratory pressure in anesthetized, mechanically ventilated ponies.
      ;
      • Ambrosio A.M.
      • Ida K.K.
      • Souto M.T.
      • et al.
      Effects of positive end-expiratory pressure titration on gas exchange, respiratory mechanics and hemodynamics in anesthetized horses.
      ). Mean Paw is an important determinant of the cardiovascular impact of positive pressure ventilation (
      • Marini J.J.
      • Ravenscraft S.A.
      Mean airway pressure: physiologic determinants and clinical importance—Part 2: Clinical implications.
      ). During AAV, PHIGH is the primary determinant of mean Paw because the respiratory cycle is dominated by the time of applied PHIGH. Despite higher mean Paw of roughly 7.5 cmH2O during AAV in this study, no differences in cardiovascular function between modes were identified. However, this result may have been influenced by the CO2 implementation strategies with PaCO2 approximately 10 mmHg (1.3 kPa) higher during AAV than CMV (
      • Kalchofner K.S.
      • Picek S.
      • Ringer S.K.
      • et al.
      A study of cardiovascular function under controlled and spontaneous ventilation in isoflurane-medetomidine anaesthetized horses.
      ). Hypercapnia is associated with some physiologic advantages including higher concentrations of circulating catecholamines that may support cardiovascular function (
      • Wagner A.E.
      • Bednarski R.M.
      • Muir III, W.W.
      Hemodynamic effects of carbon dioxide during intermittent positive-pressure ventilation in horses.
      ;
      • Khanna A.K.
      • McDonell W.N.
      • Dyson D.H.
      • Taylor P.M.
      Cardiopulmonary effects of hypercapnia during controlled intermittent positive pressure ventilation in the horse.
      ). Furthermore, hypercapnia is an essential component of the AAV strategy as described above.
      One challenge in the original, theoretical description of AAV in the human relates to maintaining the lung at or above FRC. Lung volumes were not measured in the present study, preventing confirmation that this goal was met. Indeed, the measured Q˙s/Q˙t values strongly suggest the lung was below FRC during AAV, as implemented. In this regard, maintaining FRC is more an ideal than a methodology by which to judge success of a particular implementation. However, this goal may be achievable by use of elevated PHIGH and PLOW. As an indirect indicator of positioning on the pressure–volume curve, compliance is a practical, measurable surrogate because lung volume is an important determinant of lung compliance (
      • Lumb A.B.
      ).
      Implementation of AAV in the anesthetized animal involves setting four ventilator parameters: PHIGH, PLOW, fR, and TLOW. Combined, fR and TLOW define THIGH whereas TLOW crucially determines whether expiratory flow stagnation occurs during release, which is prevented by having a means to monitor flow. Flow stagnation promotes alveolar collapse and development of low V/Q lung regions. Although premature release phase termination provides less time for bulk gas movement and a lower expired VT, which will promote CO2 retention, AAV has been shown to be more efficient at CO2 removal than CMV in anesthetized humans (
      • Bratzke E.
      • Downs J.
      • Smith R.A.
      Intermittent CPAP: a new mode of ventilation during general anesthesia.
      ;
      • Downs J.B.
      • Robinson L.A.
      • Steighner M.L.
      • et al.
      Open lung ventilation optimizes pulmonary function during lung surgery.
      ). Release phase strategies, defined by PLOW and TLOW settings, alternative to that used here, warrant further study.
      The AAV pressure parameters, PHIGH and PLOW, their difference, and Crs together determine VT by influencing the pressure–volume curve position of the horse’s respiratory system. In this study, we only attempted to manipulate compliance during initial ventilation with AAV, prior to data collection. After this period, no additional manipulations (such as via a recruitment-type maneuver by increasing and then decreasing PHIGH and PLOW) were made. In practice, changes to AAV settings over time combined with recruitment techniques may be superior for maintaining and optimizing lung function. Based on the results of the present study, it may be more appropriate in the anesthetized horse to utilize multiple variables to determine optimal PHIGH and PLOW such as indices of gas exchange, oxygenation, compliance and cardiovascular function. Optimal pressure settings in the clinical environment are expected to be both horse and procedure dependent.
      Compared with CMV, AAV resulted in similar VDalv/VTalv (i.e. wasted ventilation from excessive alveolar pressure) but significantly lower Q˙s/Q˙t at two time points. Interpretation of the former finding is challenging because our VDalv/VTalv calculation was in proportion to total alveolar ventilation, which was not measured. In addition, observed differences in Q˙s/Q˙t between modes may have influenced VDalv/VTalv which, in the horse, may be more appropriately considered a global index of V/Q mismatching (
      • Mosing M.
      • Böhm S.H.
      • Rasis A.
      • et al.
      Physiologic factors influencing the arterial-to-end-tidal CO2 difference and the alveolar dead space fraction in spontaneously breathing anesthetised horses.
      ). However, the latter result points to an advantage of AAV over CMV and is consistent with the finding that 8 cmH2O CPAP reduced Q˙s/Q˙t in dorsally recumbent anesthetized horses breathing FiO2 = 0.5 compared with physiologic airway pressure (
      • Mosing M.
      • MacFarlane P.
      • Bardell D.
      • et al.
      Continuous positive airway pressure (CPAP) decreases pulmonary shunt in anaesthetized horses.
      ). That work also reported an average fR of 5–7 breaths minute–1 and an increase in Q˙s/Q˙t over time, particularly over the first hour of data collection in the CPAP group. Comparing with the
      • Mosing M.
      • MacFarlane P.
      • Bardell D.
      • et al.
      Continuous positive airway pressure (CPAP) decreases pulmonary shunt in anaesthetized horses.
      results, although a mode effect on Q˙s/Q˙t was observed in the present study, an effect of time on Q˙s/Q˙t was not observed. These findings of a lack of spontaneous ventilation and no effect of time on Q˙s/Q˙t may be secondary to higher mean Paw in the present study. There is evidence that spontaneous breathing improves V/Q distributions during mechanical ventilation in experimentally induced acute lung injury in dogs (
      • Putensen C.
      • Räsänen J.
      • López F.A.
      • Downs J.B.
      Effect of interfacing between spontaneous breathing and mechanical cycles on the ventilation-perfusion distribution in canine lung injury.
      ). Although spontaneous breaths were not observed during data collection, the AAV mode described herein supports spontaneous respiration: PHIGH is simply CPAP that is intermittently removed. Optimization of AAV in the anesthetized horse may involve a compromise between higher PHIGH and spontaneous respiration that is deserving of further study.
      Besides issues stemming from experimental design choices, such as differences in PaCO2 criteria, a data collection period shorter than many equine general anesthesia events and variable dobutamine administration secondary to a defined MAP target range, the use of lithium dilution to determine CO is potentially limiting. Some drugs commonly used in equine anesthesia, such as xylazine and ketamine, can bias CO determinations by this method because of concentration-dependent voltage sensor interference (
      • Ambrisko T.D.
      • Kabes R.
      • Moens Y.
      Influence of drugs on the response characteristics of the LiDCO sensor: an in vitro study.
      ;
      • Ambrisko T.D.
      • Moens Y.
      Voltage changes in the lithium dilution cardiac output sensor after exposure to blood from horses given xylazine.
      ;
      • Hopster K.
      • Ambrisko T.D.
      • Stahl J.
      • et al.
      Influence of xylazine on the function of the LiDCO sensor in isoflurane anaesthetized horses.
      ). All animals in the present study were anesthetized with the same drugs at the same doses. Furthermore, drugs known to interfere with CO determinations were only administered for premedication and induction, a minimum of 60 minutes before data collection, and no supplemental doses of xylazine or ketamine were administered. For these reasons, and because instrumentation times were similar between modes, any CO measurement interference would be of similar magnitude between modes and does not degrade the usefulness of these data for mode comparisons.

      Conclusions

      Both AAV and CMV, as implemented, ventilated anesthetized dorsally recumbent horses and supported adequate V/Q matching and oxygenation with minimal supplemental inspired oxygen. Despite the higher mean Paw utilized during AAV, no differences in the cardiovascular effects of AAV and CMV were identified. Further trials of AAV in anesthetized horses are warranted and should focus on determining implementation strategies that maximize the benefits of this novel mode of ventilation while minimizing any detrimental effects.

      Authors’ contributions

      AB, JD and JB: conceived the experiment, study design, conducted the experiment, data analysis, manuscript preparation. DH: study design, conducted the experiment, data analysis, manuscript preparation. CLeB: conducted the experiment, data analysis, manuscript preparation. LT: statistical analysis, data analysis, manuscript preparation. All authors read and approved the final version of the manuscript.

      Conflict of interest statement

      JB is the owner of Innovative Veterinary Medicine (IVM), which is the manufacturer of the DolVent system. JD was an employee of IVM during performance of this research and is the inventor of both airway pressure release ventilation (APRV; US patent 4,773,411) and apneustic anesthesia ventilation (AAV; US patent 6,123,072).

      Acknowledgements

      This work was supported by the Office of Naval Research (Contract Number N68335-16-C-0020: Anesthesia Ventilator for Atlantic Bottlenose Dolphins and California Sea Lions). The authors thank Mark Baird and Veronica Cendejas of the National Marine Mammal Foundation for technical assistance.

      Supporting Information

      The following is the Supplementary data to this article:

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