M. Ruth Graham

A comparison of biologically variable ventilation to recruitment manoeuvres in a porcine model of acute lung injury

BackgroundBiologically variable ventilation (return of physiological variability in rate and tidal volume using a computer-controller) was compared to control mode ventilation with and without a recruitment manoeuvre – 40 cm H2O for 40 sec performed hourly; in a porcine oleic acid acute lung injury model.MethodsWe compared gas exchange, respiratory mechanics, and measured bronchoalveolar fluid for inflammatory cytokines, cell counts and surfactant function. Lung injury was scored by light microscopy. Pigs received mechanical ventilation (FIO2 = 0.3; PEEP 5 cm H2O) in control mode until PaO2 decreased to 60 mm Hg with oleic acid infusion (PaO2/FIO2 <200 mm Hg). Additional PEEP to 10 cm H2O was added after injury. Animals were randomized to one of the 3 modes of ventilation and followed for 5 hr after injury.ResultsPaO2 and respiratory system compliance was significantly greater with biologically variable ventilation compared to the other 2 groups. Mean and mean peak airway pressures were also lower. There were no differences in cell counts in bronchoalveolar fluid by flow cytometry, or interleukin-8 and -10 levels between groups. Lung injury scoring revealed no difference between groups in the regions examined. No differences in surfactant function were seen between groups by capillary surfactometry.ConclusionsIn this porcine model of acute lung injury, various indices to measure injury or inflammation did not differ between the 3 approaches to ventilation. However, when using a low tidal volume strategy with moderate levels of PEEP, sustained improvements in arterial oxygen tension and respiratory system compliance were only seen with BVV when compared to CMV or CMV with a recruitment manoeuvre.

Quantitative computed tomography in porcine lung injury with variable versus conventional ventilation: Recruitment and surfactant replacement*

Objectives:Biologically variable ventilation improves lung function in acute respiratory distress models. If enhanced recruitment is responsible for these results, then biologically variable ventilation might promote distribution of exogenous surfactant to nonaerated areas. Our objectives were to confirm model predictions of enhanced recruitment with biologically variable ventilation using computed tomography and to determine whether surfactant replacement with biologically variable ventilation provides additional benefit in a porcine oleic acid injury model. Design:Prospective, randomized, controlled experimental animal investigation. Setting:University research laboratory. Subjects:Domestic pigs. Interventions:Standardized oleic acid lung injury in pigs randomized to conventional mechanical ventilation or biologically variable ventilation with or without green dye labeled surfactant replacement. Measurements and Main Results:Computed tomography-derived total and regional masses and volumes were determined at injury and after 4 hrs of ventilation at the same average low tidal volume and minute ventilation. Hemodynamics, gas exchange, and lung mechanics were determined hourly. Surfactant distribution was determined in postmortem cut lung sections. Biologically variable ventilation alone resulted in 7% recruitment of nonaerated regions (p < .03) and 15% recruitment of nonaerated and poorly aerated regions combined (p < .04). Total and normally aerated regional volumes increased significantly with biologically variable ventilation, biologically variable ventilation with surfactant replacement, and conventional mechanical ventilation with surfactant replacement, while poorly and nonaerated regions decreased after 4 hrs of ventilation with biologically variable ventilation alone (p < .01). Biologically variable ventilation showed the greatest improvement (p < .003, biologically variable ventilation vs. all other groups). Hyperaerated regional gas volume increased significantly with biologically variable ventilation, biologically variable ventilation with surfactant replacement, and conventional mechanical ventilation with surfactant replacement. Biologically variable ventilation was associated with restoration of respiratory compliance to preinjury levels and significantly greater improvements in gas exchange at lower peak airway pressures compared to all other groups. Paradoxically, gas exchange and lung mechanics were impaired to a greater extent initially with biologically variable ventilation with surfactant replacement. Peak airway pressure was greater in surfactant-treated animals with either ventilation mode. Surfactant was distributed to the more caudal/injured lung sections with biologically variable ventilation. Conclusions:Quantitative computed tomography analysis confirms lung recruitment with biologically variable ventilation in a porcine oleic acid injury model. Surfactant replacement with biologically variable ventilation provided no additional recruitment benefit and may in fact be harmful.

Fractal ventilation enhances respiratory sinus arrhythmia

BackgroundProgramming a mechanical ventilator with a biologically variable or fractal breathing pattern (an example of 1/f noise) improves gas exchange and respiratory mechanics. Here we show that fractal ventilation increases respiratory sinus arrhythmia (RSA) – a mechanism known to improve ventilation/perfusion matching.MethodsPigs were anaesthetised with propofol/ketamine, paralysed with doxacurium, and ventilated in either control mode (CV) or in fractal mode (FV) at baseline and then following infusion of oleic acid to result in lung injury.ResultsMean RSA and mean positive RSA were nearly double with FV, both at baseline and following oleic acid. At baseline, mean RSA = 18.6 msec with CV and 36.8 msec with FV (n = 10; p = 0.043); post oleic acid, mean RSA = 11.1 msec with CV and 21.8 msec with FV (n = 9, p = 0.028); at baseline, mean positive RSA = 20.8 msec with CV and 38.1 msec with FV (p = 0.047); post oleic acid, mean positive RSA = 13.2 msec with CV and 24.4 msec with FV (p = 0.026). Heart rate variability was also greater with FV. At baseline the coefficient of variation for heart rate was 2.2% during CV and 4.0% during FV. Following oleic acid the variation was 2.1 vs. 5.6% respectively.ConclusionThese findings suggest FV enhances physiological entrainment between respiratory, brain stem and cardiac nonlinear oscillators, further supporting the concept that RSA itself reflects cardiorespiratory interaction. In addition, these results provide another mechanism whereby FV may be superior to conventional CV.

Brain MRI CO2 Stress Testing: A Pilot Study in Patients with Concussion

Background There is a real need for quantifiable neuro-imaging biomarkers in concussion. Here we outline a brain BOLD-MRI CO2 stress test to assess the condition. Methods This study was approved by the REB at the University of Manitoba. A group of volunteers without prior concussion were compared to post-concussion syndrome (PCS) patients – both symptomatic and recovered asymptomatic. Five 3-minute periods of BOLD imaging at 3.0 T were studied – baseline 1 (BL1– at basal CO2 tension), hypocapnia (CO2 decreased ∼5 mmHg), BL2, hypercapnia (CO2 increased ∼10 mmHg) and BL3. Data were processed using statistical parametric mapping (SPM) for 1st level analysis to compare each subject’s response to the CO2 stress at the p = 0.001 level. A 2nd level analysis compared each PCS patient’s response to the mean response of the control subjects at the p = 0.05 level. Results We report on 5 control subjects, 8 symptomatic and 4 asymptomatic PCS patients. Both increased and decreased response to CO2 was seen in all PCS patients in the 2nd level analysis. The responses were quantified as reactive voxel counts: whole brain voxel counts (2.0±1.6%, p = 0.012 for symptomatic patients for CO2 response < controls and 3.0±5.1%, p = 0.139 for CO2 response > controls: 0.49±0.31%, p = 0.053 for asymptomatic patients for CO2 response < controls and 4.4±6.8%, p = 0.281 for CO2 response > controls). Conclusions Quantifiable alterations in regional cerebrovascular responsiveness are present in concussion patients during provocative CO2 challenge and BOLD MRI and not in healthy controls. Future longitudinal studies must aim to clarify the relationship between CO2 responsiveness and individual patient symptoms and outcomes.

Isoflurane and halothane impair both systolic and diastolic function in the newborn pig.

PurposeVolatile anaesthetics have considerable effects on diastolic relaxation in the adult myocardium. We hypothesized that isoflurane (I) and halothane (H) may have even greater effects on diastolic function in the newborn, as the newborn heart has increased passive stiffness and altered calcium handling relative to the adult. Using a newborn pig model, we compared I and H at three clinically relevant concentrations with respect to both systolic and diastolic function.MethodsSixteen newborn pigs were randomized for study at control (background fentanyl 100 μg · kg−1 · hr−1 and 0.5, 1.0 and 1.5 MAC of I (n = 8) or H (n = 8). Temperature, arterial blood gasex, and LVEDP were controlled. Left ventricular pressure (LVP) was monitored continuously and LV anteriorposterior dimension was determined by using sonomicrometry crystals. Systolic function was assessed by peak positive dP/dT (dP/dTmax) and the slope of the end-systolic pressure-dimension (ESP-D) relationship. Diastolic relaxation was given by peak negative dP/dT (−dP/dTmax) and the time constant for ventricular relaxation (τ). Left ventricular stiffness was calculated from the slope of the end-diastolic pressure-dimension (EDP-D) relationship.ResultsAt equal MAC concentrations, I and H were identical in effect for every variable studied. Systolic function was depressed at all anaesthetic concentrations. Control dP/dTmax (1:1815 ± 561 (SD) mmHg · sec−1, H:1841 ± 509) decreased to 832 ± 341 with 1.5 MAC I and 691 ± 127 with 1.5 MAC H (P < 0.05 vs control). ESP-D slope decreased from 62 ± 31 mmHg · mm−1 at control to 15 ± 11 with 1.5 MAC I and from 79 ± 16 to 37 ± 15 with 1.5 MAC H (P < 0.05 vs control). Diastolic function was affected only at higher MAC anaesthesia. Control τ increased from 18.0 ± 6 msec to 29.1 ± 7.5 with 1.5 MAC I and from 20.8 ± 5.9 to 30.0 ± 11.3 with 1.5 MAC H (P < 0.05). EDP-D slope was increased at both 1 and 1.5 MAC anaesthesia. EDP-D slope increased from 0.16 ± 0.24 mmHg · mm−1 at control to 0.58 ± 0.46 with 1 MAC I and from 0.16 ± 11 to 0.50 ± 0.35 with 1 MAC H. The −dP/dTmax decreased at every MAC level of anaesthesia.ConclusionThese combined systolic and diastolic effects help to explain the increased sensitivity of the newborn myocardium to volatile anaesthetics.RésuméObjectifLes anesthésiques volatils ont un effet considérable sur la relaxation diastolique du myocarde adulte. Nous avons émis une hypothèse selon laquelle l’isoflurane (I) et l’halothane (H) pourraient avoir une effet encore plus important sur la fonction diastolique du nouveau-né, parce que la rigidité cardiaque passive du nouveau-né est plus grande et que son utilisation du calcium diffère de celle de l’adulte.MéthodesSeize porcelets nouveau-nés ont été répartis aléatoirement pour étude de contrôle (fond de fentanyl 100 μg · kg−1 · h−1), et à 0,5 MAC, 0,1 MAC et 1,5 MAC de I (n = 8) ou de H (n = 8). La température, les gaz artériels et la pression ventriculaire télédiastolique gauche ont été contôlées. La pression du ventricule gauche (VC) a été monitorée en continu et la dimension antéro-postérieure du VC déterminée à l’aide de cristaux sonométriques. La fonction systolique a été évaluée avec le dP/dt maximal (dP/dtmax) et la courbe de la dimension télésystolique. La relaxation diastolique a été mesurée par le dP/dt maximal négatif (−dP/dtmax) et la constante de temps (τ). La rigidité ventriculaire gauche a été calculée à partir de la pente de la relation pression têlédiastolique-dimension.RésultatsA MAC égal, I et H ont été identiques pour toutes les variables étudiées. La fonction systolique était déprimée à toutes les concentrations. Le dP/dtmax de contrôle (1:1815 ±561 (ET) mm · Hg · sec−1, H: 1841 ± 509) a diminué à 832 ±341 avec 1,5 MAC 1 et à 691 ± 127 avec 1,5 MAC H (P < 0,05 vs contrôle). La pente de la relation pression télédiastoliquedimension a diminué de 62 ± 31 mmHg · mm−1 (contrôle) à 15 ± 11 avec 1,5 MAC I et de 79 ± 16 à 37 ± avec 1,5 MAC H (P < 0,05). La fonction diastolique n’était affectée que par l’anesthésie à des MAC plus élevés. Le contrôle τ a augmenté de 18,0 ± 6 msec à 29,1 ± 7,5 avec 1,5 MAC ± et de 20,8 ±5,9 à 30,0 ± 11,3 avec 1,5 MAC H (P < 0,05). La pente de la relation pression télédiastolique-dimension a augmenté sous anesthésie à 1 et à 1,5 MAC. Elle a augmenté de 0,16 ± 0,24 mmHg · mm−1 (contrôle) à 0,58 ± 0,46 avec 1 MAC I et de 0,16 ± 11 à 0,5 ± 0,35 avec 1 MAC H. Le −dP/dtmax a diminué sous anesthésie à chacun des niveaux de MAC.ConclusionCes effets systoliques et diastoliques combinés aident à comprendre la plus grande sensibilité du myocarde néonatal aux anesthésiques volatils.

Physiological noise versus white noise to drive a variable ventilator in a porcine model of lung injury.

Purpose: Variable ventilation is superior to control mode ventilation in a number of circumstances. The nature of the breathing file used to deliver the variable rate and tidal volume has not been formally examined.Methods: We compared two different noise files in a randomized prospective trial of variable ventilation. Pigs were anesthetized, intubated, and mechanically ventilated. Oleic acid was infused to introduce lung injury. The animals were ventilated at a tidal volume of 7 mL·kg−1, in variable mode, with either physiologically-derived noise (variability file − 1,587 breath intervals-obtained from a spontaneously breathing volunteer;n=10) or a variability file of identical length derived from computergenerated white noise (n=10).Results: The physiologically-derived noise had a power law α-exponent of −0.27 and a Hölder exponent of −0.38, indicative of auto-correlated noise. The computer-generated noise had an α-exponent of −0.52 and a Hölder exponent of −0.49, indicative of white noise. Both files showed multifractal characteristics. There were no differences between groups, at any time period, for PaO2, PaCO2, and static or dynamic respiratory system compliance. No differences were observed between groups for wet:dry lung weight ratios or for interleukin-8 in bronchoalveolar lavage fluid.Conclusion: This study demonstrates that the nature of the variability files, chosen to drive the variable ventilator, had no effect on indices of gas exchange or respiratory mechanics in this model. A considerable overlap of the multifractal files existed. The potential to drive a variable ventilator using algorithmderived files with multifractal characteristics, thereby eliminating the requirement to use physiologically-derived signals, is discussed.RésuméObjectif: La ventilation en mode variable est supérieure à la ventilation en mode contrôlée dans plusieurs situations. La nature du fichier de respiration utilisé pour engendrer la fréquence et le volume courant variable n’a pas été évaluée de façon formelle.Méthode: Nous avons comparé deux fichiers de bruit différents dans une étude prospective randomisée de la ventilation en mode variable. Les cochons ont été anesthésiés, intubés et ventilés mécaniquement. Ils ont reçu une perfusion d’acide oléique afin de provoquer une lésion pulmonaire. Les animaux ont été ventilés à un volume courant de 7 mL·kg−1, en mode variable, avec soit du bruit de provenance physiologique (fichier de variabilité — 1587 intervalles de respiration — obtenus d’un volontaire respirant spontanément ; n=10) ou un fichier de variabilité de longueur identique dérivé d’un bruit blanc généré par ordinateur (n=10).Résultats: Le bruit d’origine physiologique avait un exposant α de la loi de puissance de −0,27 et un exposant de Hölder de −0,38, ce qui indique un bruit auto-corrélé. Le bruit généré par ordinateur avait un exposant α de −0,52 et un exposant de Hölder de −0,49, ce qui indique un bruit blanc. Les deux fichiers ont montré des caractéristiques multifractales. Il n’y a pas eu de différence entre les groupes, à n’importe quelle période de temps, pour la PaO2, la PaCO2, et la conformité statique et dynamique du système respiratoire. Aucune différence n’a été observée entre les groupes en ce qui touche aux rapports de poids oedème pulmonaire/poumon sec ou pour l’interleukine 8 dans le liquide de lavage bronchoalvéolaire.Conclusion: Cette étude démontre que la nature des fichiers de variabilité sélectionnés pour entraîner le respirateur en mode variable n’a pas eu d’effet sur les indices d’échange gazeux ou de mécanique respiratoire dans ce modèle. Un chevauchement considérable est apparu dans les fichiers multifractals. La possibilité d’entraîner un respirateur en mode variable avec des fichiers dérivés d’algorithmes avec des caractéristiques multifractales, éliminant ainsi le besoin de recourir à des signaux d’origine physiologique, est discutée ici.

Benefits of an individualized perioperative plan for children with autism spectrum disorder

Perioperative care for children with autism spectrum disorder may be challenging. Previous investigators recommend development of an individualized perioperative management plan with caregiver involvement.

Postoperative Delirium, Learning, and Anesthetic Neurotoxicity: Some Perspectives and Directions

Evidence of anesthetic neurotoxicity is unequivocal when studied in animal models. These findings have translated poorly to the clinical domain when equated to postoperative delirium (POD) in adults and postoperative cognitive dysfunction (POCD) in either children or the elderly. In this perspective, we examine various reasons for the differences between animal modeling of neurotoxicity and the clinical situation of POD and POCD and make suggestions as to potential directions for ongoing research. We hypothesize that the animal anesthetic neurotoxicity models are limited, in part, due to failed scaling correction of physiological time. We posit that important insights into POCD in children and adults may be gleaned from studies in adults examining alterations in perioperative management designed to limit POD. In this way, POD may be more useful as the proxy for POCD rather than neuronal dropout or behavioral abnormalities that have been used in animal models but which may not be proxies for the human condition. We argue that it is time to move beyond animal models of neurotoxicity to directly examine these problems in well-conducted clinical trials with comprehensive preoperative neuropsychometric and psychiatric testing, high fidelity intraoperative monitoring of physiological parameters during the anesthetic course and postoperative assessment of subthreshold and full classification of POD. In this manner, we can “model ourselves” to better understand these important and poorly understood conditions.

Variable ventilation and Jensen's inequality: citation corrections

We would like to commend Huhle and co-authors [1] for their extensive review of variable ventilation featuring citations from our pioneering work. We would suggest a couple of corrections to the cited articles, however. The authors reference important work by Venegas and colleagues [2], including Figure 4 in their manuscript. This figure explains the convex and concave portions of the sigmoidal pressure-volume curve indicating where variable ventilation has beneficial and detrimental effects, respectively, as suggested by Jensen’s theorem. No mention of Jensen’s ‘theorem’ or ‘inequality’ is discussed in the paper by Venegas et al. This explanation is advanced in a paper by us and not cited (‘Convexity, Jensen’s inequality and benefits of noisy mechanical ventilation’ [3]). The data supplement in our paper gives a comprehensive mathematical explanation for conditions where non-linear systems can and cannot benefit from the addition of noise. Mechanical ventilation is but one example where noisy life support systems may provide benefit to patients.