A systematic review of outcomes reported inpediatric perioperative research: A report from the Pediatric Perioperative Outcomes Group.

The Pediatric Perioperative Outcomes Group (PPOG) is an international collaborative of clinical investigators and clinicians within the subspecialty of pediatric anesthesiology and perioperative care which aims to use COMET (Core Outcomes Measures in Effectiveness Trials) methodology to develop core outcome setsfor infants, children and young people that are tailored to the priorities of the pediatric surgical population.Focusing on four age-dependent patient subpopulations determined a priori for core outcome set development: i) neonates and former preterm infants (up to 60 weeks postmenstrual age); ii) infants (>60 weeks postmenstrual age - <1 year); iii) toddlers and school age children (>1-<13 years); and iv) adolescents (>13-<18 years), we conducted a systematic review of outcomes reported in perioperative studies that include participants within age-dependent pediatric subpopulations. Our review of pediatric perioperative controlled trials published from 2008 to 2018 identified 724 articles reporting 3192 outcome measures. The proportion of published trials and the most frequently reported outcomes varied across pre-determined age groups. Outcomes related to patient comfort, particularly pain and analgesic requirement, were the most frequent domain for infants, children and adolescents. Clinical indicators, particularly cardiorespiratory or medication-related adverse events, were the most common outcomes for neonates and infants < 60 weeks and were the second most frequent domain at all other ages. Neonates and infants <60 weeks of age were significantly under-represented in perioperative trials. Patient-centered outcomes, heath care utilization, and bleeding/transfusion related outcomes were less often reported. In most studies, outcomes were measured in the immediate perioperative period, with the duration often restricted to the post-anesthesia care unit or the first 24 postoperative hours. The outcomes identified with this systematic review will be combined with patient centered outcomes identified through a subsequent stakeholder engagement study to arrive at a core outcome set for each age-specific group.

Brain BOLD MRI O2 and CO2 stress testing: implications for perioperative neurocognitive disorder following surgery.

BACKGROUND: Mechanical ventilation to alter and improve respiratory gases is a fundamental feature of critical care and intraoperative anesthesia management. The range of inspired O2 and expired CO2 during patient management can significantly deviate from values in the healthy awake state. It has long been appreciated that hyperoxia can have deleterious effects on organs, especially the lung and retina. Recent work shows intraoperative end-tidal (ET) CO2 management influences the incidence of perioperative neurocognitive disorder (POND). The interaction of O2 and CO2 on cerebral blood flow (CBF) and oxygenation with alterations common in the critical care and operating room environments has not been well studied. METHODS: We examine the effects of controlled alterations in both ET O2 and CO2 on cerebral blood flow (CBF) in awake adults using blood oxygenation level-dependent (BOLD) and pseudo-continuous arterial spin labeling (pCASL) MRI. Twelve healthy adults had BOLD and CBF responses measured to alterations in ET CO2 and O2 in various combinations commonly observed during anesthesia. RESULTS: Dynamic alterations in regional BOLD and CBF were seen in all subjects with expected and inverse brain voxel responses to both stimuli. These effects were incremental and rapid (within seconds). The most dramatic effects were seen with combined hyperoxia and hypocapnia. Inverse responses increased with age suggesting greater risk. CONCLUSIONS: Human CBF responds dramatically to alterations in ET gas tensions commonly seen during anesthesia and in critical care. Such alterations may contribute to delirium following surgery and under certain circumstances in the critical care environment. TRIAL REGISTRATION: ClincialTrials.gov NCT02126215 for some components of the study. First registered April 29, 2014.

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.

Clinical update regarding general anesthesia-associated neurotoxicity in infants and children.

PURPOSE OF REVIEW: The U.S. Federal Drug Administration (FDA) recently released a warning stating that 'repeated or lengthy use of general anesthetic and sedation drugs during surgeries or procedures in children younger than 3 years or in pregnant women during their third trimester may affect the development of children's brains' (www.fda.gov/ucm582356.htm). The goal of this article is to review the most recent clinical studies which provide evidence that these concerns may be overstated for the majority of healthy young children who require surgery and anesthesia. RECENT FINDINGS: Three large retrospective matched cohort studies published within the past year provide data on a total of 59 814 children exposed to general anesthesia before age 4 (including 30 021 <2 years and 9814 multiple exposure). All three studies independently conclude that neither exposure to anesthesia in children under 2 years of age nor multiple exposures are associated with adverse neurodevelopmental consequences in the patient populations studied. Biological, environmental, and social factors were found to be of far greater import. SUMMARY: These findings suggest that anesthetic neurotoxicity is not a major contributory pathway for adverse neurodevelopmental outcomes in the majority of healthy children who require surgery before 3 years of age. Future work should focus on the particular vulnerabilities of the fetus, premature infant, and children with developmental disabilities, major congenital, cardiac or neurological abnormalities not specifically addressed by these studies.

Neurodevelopmental Assessment in Kindergarten in Children Exposed to General Anesthesia before the Age of 4 Years: A Retrospective Matched Cohort Study.

BACKGROUND: Animal studies demonstrate general anesthetic (GA) toxicity in the developing brain. Clinical reports raise concern, but the risk of GA exposure to neurodevelopment in children remains uncertain. METHODS: The authors undertook a retrospective matched cohort study comparing children less than 4 yr of age exposed to GA to those with no GA exposure. The authors used the Early Development Instrument (EDI), a 104-component questionnaire, encompassing five developmental domains, completed in kindergarten as the outcome measure. Mixed-effect logistic regression models generated EDI estimates for single versus multiple GA exposure and compared both single and multiple exposures by the age of 0 to 2 or 2 to 4 yr. Known sociodemographic and physical confounders were incorporated as covariates in the models. RESULTS: A total of 18,056 children were studied: 3,850 exposed to a single GA and 620 exposed to two or more GA, who were matched to 13,586 nonexposed children. In children less than 2 yr of age, there was no independent association between single or multiple GA exposure and EDI results. Paradoxically, single exposure between 2 and 4 yr of age was associated with deficits, most significant for communication/general knowledge (estimate, -0.7; 95% CI, -0.93 to -0.47; P < 0.0001) and language/cognition (estimate, -0.34; 95% CI, -0.52 to -0.16; P < 0.0001) domains. Multiple GA exposure at the age of 2 to 4 yr did not confer greater risk than single GA exposure. CONCLUSIONS: These findings refute the assumption that the earlier the GA exposure in children, the greater the likelihood of long-term neurocognitive risk. The authors cannot confirm an association between multiple GA exposure and increased risk of neurocognitive impairment, increasing the probability of confounding to explain the results.

Brain magnetic resonance imaging CO2 stress testing in adolescent postconcussion syndrome.

OBJECT A neuroimaging assessment tool to visualize global and regional impairments in cerebral blood flow (CBF) and cerebrovascular responsiveness in individual patients with concussion remains elusive. Here the authors summarize the safety, feasibility, and results of brain CO2 stress testing in adolescents with postconcussion syndrome (PCS) and healthy controls. METHODS This study was approved by the Biomedical Research Ethics Board at the University of Manitoba. Fifteen adolescents with PCS and 17 healthy control subjects underwent anatomical MRI, pseudo-continuous arterial spin labeling MRI, and brain stress testing using controlled CO2 challenge and blood oxygen level-dependent (BOLD) MRI. Post hoc processing was performed using statistical parametric mapping to determine voxel-by-voxel regional resting CBF and cerebrovascular responsiveness of the brain to the CO2 stimulus (increase in BOLD signal) or the inverse (decrease in BOLD signal). Receiver operating characteristic (ROC) curves were generated to compare voxel counts categorized by control (0) or PCS (1). RESULTS Studies were well tolerated without any serious adverse events. Anatomical MRI was normal in all study participants. No differences in CO2 stimuli were seen between the 2 participant groups. No group differences in global mean CBF were detected between PCS patients and healthy controls. Patient-specific differences in mean regional CBF and CO2 BOLD responsiveness were observed in all PCS patients. The ROC curve analysis for brain regions manifesting a voxel response greater than and less than the control atlas (that is, abnormal voxel counts) produced an area under the curve of 0.87 (p < 0.0001) and 0.80 (p = 0.0003), respectively, consistent with a clinically useful predictive model. CONCLUSIONS Adolescent PCS is associated with patient-specific abnormalities in regional mean CBF and BOLD cerebrovascular responsiveness that occur in the setting of normal global resting CBF. Future prospective studies are warranted to examine the utility of brain MRI CO2 stress testing in the longitudinal assessment of acute sports-related concussion and PCS.

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.

Pulse pressure variability during hemorrhage and reinfusion in piglets: effects of age and tidal volume.

PURPOSE: The dynamic change in arterial pulse pressure during mechanical ventilation (PPV) predicts fluid responsiveness in adults but may not be applicable to pediatric patients. We compared PPV during hemorrhage and reinfusion in immature vs mature piglets at two clinically relevant tidal volumes (VT). METHODS: Following Institutional Animal Care Committee approval, we measured hemodynamics and PPV in two groups of piglets, 10-15 kg (immature, n = 9) and 25-30 kg (mature, n = 10), under stable intravenous anesthesia at VT = 8 and 10 mL·kg(-1). Measurements were taken at baseline, with blood withdrawal in 5 mL·kg(-1) steps up to 30 mL·kg(-1), and during stepwise reinfusion. For each age group and VT, we constructed receiver operating characteristic (ROC) curves to determine the threshold value that was predictive of fluid responsiveness. RESULTS: Pulse pressure variability was significantly lower in immature vs mature pigs and at VT 8 vs VT 10 at every measurement period. The difference in PPV induced by changing VT was less in immature animals. Significant areas under the ROC curve were obtained in immature pigs at both VTs but in mature animals at VT 10 alone. A PPV threshold was calculated to be 8.2% at VT 8 and 10.9% at VT 10 in immature animals vs 15.9% at VT 10 in mature animals, but sensitivity and specificity were only 0.7. CONCLUSION: Pulse pressure variability values are lower and less sensitive to VT in immature vs mature pigs. Adult PPV thresholds do not apply to pediatric patients, and a single PPV value representing fluid responsiveness should not be assumed.

Resolution of pulmonary edema with variable mechanical ventilation in a porcine model of acute lung injury.

OBJECTIVE: Resolution of the acute respiratory distress syndrome (ARDS) requires clearance of pulmonary edema. Biologically variable ventilation (BVV) strategies that improve gas exchange, lung mechanics, and inflammatory mediators in ARDS may be beneficial in this regard. We used quantitative computed tomography (CT), a single indicator thermodilution system (PiCCO®) to determine extravascular lung water (EVLW), and the change in edema protein concentration over time to compare edema clearance with BVV vs conventional mechanical ventilation (CMV) in a porcine ARDS model. METHODS: Sixteen pigs with oleic acid lung injury were randomized to four hours of ventilation with either CMV (n = 8) or BVV (n = 8) at identical low tidal volume and minute ventilation over time. Hemodynamic variables, gas exchange, lung mechanics, and PiCCO derived EVLW were determined hourly. Computed tomography images and edema fluid samples were obtained at baseline lung injury and after four hours of ventilation. Wet and dry lung weights were determined postmortem. RESULTS: At four hours with BVV, peak airway pressure was decreased significantly and lung compliance improved compared with CMV (P = 0.003; P < 0.001, respectively). Hemodynamic variables and gas exchange were not different between groups. Also at four hours, computed tomography revealed an increase in total gas volume (P = 0.001) and a decrease in total lung weight and global lung density (P = 0.005; P = 0.04 respectively) with BVV. These findings were associated with a significant increase in the gas volume of normally aerated lung regions (P < 0.001) and a decrease in the poorly and non-aerated lung regions (P = 0.001). No change in any CT parameter occurred with CMV. The lung weights derived from computed tomography correlated well with postmortem wet weights (R(2) = 0.79; P < 0.01). The decrease in PiCCO derived EVLW from injury to four hours did not differ significantly between BVV and CMV. Extravascular lung water showed no correlation with postmortem wet weights and significantly underestimated lung water. Average alveolar fluid clearance rates were positive (1.4%·hr(-1) (3%)) with BVV and negative with CMV (-2.0%·hr(-1) (4%)). CONCLUSIONS: In a comparison between BVV and CMV, computed tomography evidence suggests that BVV facilitates enhanced clearance and/or redistribution of edema fluid with improved recruitment of atelectatic and poorly aerated lung regions; no such evidence was seen with either single thermodilution measurement of EVLW or edema clearance rates. The results of computed tomography provide further evidence of the benefit of BVV over conventional ventilation in ARDS.

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 x 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 computer- generated white noise (n = 10). RESULTS: The physiologically-derived noise had a power law alpha-exponent of -0.27 and a Hölder exponent of -0.38, indicative of auto-correlated noise. The computer-generated noise had an alpha-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 algorithm-derived files with multifractal characteristics, thereby eliminating the requirement to use physiologically-derived signals, is discussed.

Biologically variable ventilation improves gas exchange and respiratory mechanics in a model of severe bronchospasm.

OBJECTIVE: Mechanical ventilation can be lifesaving for status asthmaticus, but how best to accomplish mechanical ventilation is unclear. Biologically variable ventilation (mechanical ventilation that emulates healthy variation) and conventional control mode ventilation (monotonously regular) were compared in an animal model of bronchospasm to determine which approach yields better gas exchange and respiratory mechanics. DESIGN: A randomized prospective trial of biologically variable ventilation vs. control mode ventilation in swine. SETTING: University research laboratory. SUBJECTS: Eighteen farm-raised pigs. INTERVENTIONS: Methacholine was administered as a nebulized aerosol to initiate bronchospasm, defined as doubling of peak inspiratory pressure and respiratory system resistance, and then randomized (n = 9 each group) to either continue control mode ventilation or switch to biologically variable ventilation at the same minute ventilation. Over the next 4 hrs, hemodynamics, blood gases, respiratory mechanics, and carbon dioxide expirograms were recorded hourly. At end-experiment, tracheobronchial lavage was undertaken to determine interleukin-6 and -10 concentrations. MEASUREMENTS AND MAIN RESULTS: Measurements of physiologic variables and inflammatory cytokines showed that biologically variable ventilation significantly improved gas exchange, with greater arterial oxygen tensions (p = .006; group x time interaction), lower arterial carbon dioxide tensions (p = .0003; group effect), lower peak inspiratory pressures (p = .0001; group x time), greater static compliance (p = .0001; group x time), greater dynamic compliance (p = .0001; group x time), and lower total respiratory system resistance (p = .028; group x time), compared with conventional ventilation. The appearance of inflammatory cytokines in bronchoalveolar lavage fluid (interleukin-6 and -10) was not affected by mode of ventilation. CONCLUSIONS: In this experimental model, biologically variable ventilation was superior to control mode ventilation in terms of gas exchange and respiratory mechanics during severe bronchospasm.

Biologically variable bypass reduces enzymuria after deep hypothermic circulatory arrest.

BACKGROUND: Renal injury is common after open-heart surgery. Cardiopulmonary bypass contributes to the problem. We compared conventional nonpulsatile perfusion (NP) to biologically variable perfusion (BVP), which uses a computer controller to restore physiological beat-to-beat variability to roller pump flow. We hypothesized BVP would decrease renal injury after deep hypothermic circulatory arrest. METHODS: Pigs were randomly assigned to either BVP (n = 9) or NP (n = 9), cooled, arrested at 18 degrees C (1 hour), reperfused, and rewarmed and maintained normothermic (3 hours). Additional pigs had NP for a similar time as above, but without circulatory arrest (n = 3), or were sham-treated without bypass (n = 3). Hemodynamics, acid-base status, temperature, and urine volumes were measured. Urinary enzyme markers of tubular injury were compared post-hoc for gamma glutamyl transpeptidase, alkaline phosphatase, and glutathione S-transferase and by urine proteomics using mass spectrometry. RESULTS: Urine output at 1 hour after arrest was 250 +/- 129 mL with BVP versus 114 +/- 66 mL with NP (p < 0.02). All three renal enzyme markers were higher with NP after arrest compared with BVP. In animals on bypass without arrest or those sham-treated, no elevations were seen in renal enzymes. Urine proteomics revealed abnormal proteins, persisting longer with NP. Biologically variable perfusion decreased cooling to 21.0 +/- 9.0 minutes versus 31.7 +/- 7.5 minutes (p < 0.002), and decreased rewarming to 22.1 +/- 3.9 minutes versus 31.2 +/- 5.1 minutes (p < 0.002). CONCLUSIONS: Biologically variable perfusion improved urine output, decreased enzymuria, and attenuated mass spectrometry urine protein signal with more rapid temperature changes. This strategy could potentially shorten bypass duration and may decrease renal tubular injury with deep hypothermic circulatory arrest.

Biologically variable ventilation improves oxygenation and respiratory mechanics during one-lung ventilation.

BACKGROUND: Hypoxemia is common during one-lung ventilation (OLV). Atelectasis contributes to the problem. Biologically variable ventilation (BVV), using microprocessors to reinstitute physiologic variability to respiratory rate and tidal volume, has been shown to be advantageous over conventional monotonous control mode ventilation (CMV) in improving oxygenation during the period of lung reinflation after OLV in an experimental model. Here, using a porcine model, the authors compared BVV with CMV during OLV to assess gas exchange and respiratory mechanics. METHODS: Eight pigs (25-30 kg) were studied in each of two groups. After induction of anesthesia-tidal volume 12 ml/kg with CMV and surgical intervention-tidal volume was reduced to 9 ml/kg. OLV was initiated with an endobronchial blocker, and the animals were randomly allocated to either continue CMV or switch to BVV for 90 min. After OLV, a recruitment maneuver was undertaken, and both lungs were ventilated for a further 60 min. At predetermined intervals, hemodynamics, respiratory gases (arterial, venous, and end-tidal samples) and mechanics (airway pressures, static and dynamic compliances) were measured. Derived indices (pulmonary vascular resistance, shunt fraction, and dead space ventilation) were calculated. RESULTS: By 15 min of OLV, arterial oxygen tension was greater in the BVV group (group x time interaction, P = 0.003), and shunt fraction was lower with BVV from 30 to 90 min (group effect, P = 0.0004). From 60 to 90 min, arterial carbon dioxide tension was lower with BVV (group x time interaction, P = 0.0001) and dead space ventilation was less from 60 to 90 min (group x time interaction, P = 0.0001). Static compliance was greater by 60 min of BVV and remained greater during return to ventilation of both lungs (group effect, P = 0.0001). CONCLUSIONS: In this model of OLV, BVV resulted in superior gas exchange and respiratory mechanics when compared with CMV. Improved static compliance persisted with restoration of two-lung ventilation.

Mathematical modelling to centre low tidal volumes following acute lung injury: a study with biologically variable ventilation.

BACKGROUND: With biologically variable ventilation [BVV--using a computer-controller to add breath-to-breath variability to respiratory frequency (f) and tidal volume (VT)] gas exchange and respiratory mechanics were compared using the ARDSNet low VT algorithm (Control) versus an approach using mathematical modelling to individually optimise VT at the point of maximal compliance change on the convex portion of the inspiratory pressure-volume (P-V) curve (Experimental). METHODS: Pigs (n = 22) received pentothal/midazolam anaesthesia, oleic acid lung injury, then inspiratory P-V curve fitting to the four-parameter logistic Venegas equation F(P) = a + b[1 + e-(P-c)/d]-1 where: a = volume at lower asymptote, b = the vital capacity or the total change in volume between the lower and upper asymptotes, c = pressure at the inflection point and d = index related to linear compliance. Both groups received BVV with gas exchange and respiratory mechanics measured hourly for 5 hrs. Postmortem bronchoalveolar fluid was analysed for interleukin-8 (IL-8). RESULTS: All P-V curves fit the Venegas equation (R2 > 0.995). Control VT averaged 7.4 +/- 0.4 mL/kg as compared to Experimental 9.5 +/- 1.6 mL/kg (range 6.6 - 10.8 mL/kg; p < 0.05). Variable VTs were within the convex portion of the P-V curve. In such circumstances, Jensen's inequality states "if F(P) is a convex function defined on an interval (r, s), and if P is a random variable taking values in (r, s), then the average or expected value (E) of F(P); E(F(P)) > F(E(P))." In both groups the inequality applied, since F(P) defines volume in the Venegas equation and (P) pressure and the range of VTs varied within the convex interval for individual P-V curves. Over 5 hrs, there were no significant differences between groups in minute ventilation, airway pressure, blood gases, haemodynamics, respiratory compliance or IL-8 concentrations. CONCLUSION: No difference between groups is a consequence of BVV occurring on the convex interval for individualised Venegas P-V curves in all experiments irrespective of group. Jensen's inequality provides theoretical proof of why a variable ventilatory approach is advantageous under these circumstances. When using BVV, with VT centred by Venegas P-V curve analysis at the point of maximal compliance change, some leeway in low VT settings beyond ARDSNet protocols may be possible in acute lung injury. This study also shows that in this model, the standard ARDSNet algorithm assures ventilation occurs on the convex portion of the P-V curve.

Fractal ventilation enhances respiratory sinus arrhythmia.

BACKGROUND: Programming 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. METHODS: Pigs 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. RESULTS: Mean 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. CONCLUSION: These 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.

Convexity, Jensen's inequality and benefits of noisy mechanical ventilation.

Mechanical ventilators breathe for you when you cannot or when your lungs are too sick to do their job. Most ventilators monotonously deliver the same-sized breaths, like clockwork; however, healthy people do not breathe this way. This has led to the development of a biologically variable ventilator--one that incorporates noise. There are indications that such a noisy ventilator may be beneficial for patients with very sick lungs. In this paper we use a probabilistic argument, based on Jensen's inequality, to identify the circumstances in which the addition of noise may be beneficial and, equally important, the circumstances in which it may not be beneficial. Using the local convexity of the relationship between airway pressure and tidal volume in the lung, we show that the addition of noise at low volume or low pressure results in higher mean volume (at the same mean pressure) or lower mean pressure (at the same mean volume). The consequence is enhanced gas exchange or less stress on the lungs, both clinically desirable. The argument has implications for other life support devices, such as cardiopulmonary bypass pumps. This paper illustrates the benefits of research that takes place at the interface between mathematics and medicine.

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

BACKGROUND: Biologically 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. METHODS: We 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. RESULTS: PaO2 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. CONCLUSIONS: In 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.

Improved arterial oxygenation with biologically variable or fractal ventilation using low tidal volumes in a porcine model of acute respiratory distress syndrome.

We compared biologically variable ventilation (V (bv); n = 9) with control mode ventilation (V (c); n = 8) at low tidal volume (VT)--initial 6 ml/kg--in a porcine model of acute respiratory distress syndrome (ARDS). Hemodynamics, respiratory gases, airway pressures, and VT data were measured. Static P-V curves were generated at 5 h. Interleukin (IL)-8 and IL-10 were measured in serum and tracheal aspirate. By 5 h, higher Pa(O(2)) (173 +/- 30 mm Hg versus 119 +/- 23 mm Hg; mean +/- SD; p < 0.0001 group x time interaction [G x T]), lower shunt fraction (6 +/- 1% versus 9 +/- 3%; p = 0.0026, G x T) at lower peak airway pressure (21 +/- 2 versus 24 +/- 1 cm H(2)O; p = 0.0342; G x T) occurred with V (bv). IL-8 concentrations in tracheal aspirate and wet:dry weight ratios were inversely related; p = 0.011. With V (c), IL-8 concentrations were 3.75-fold greater at wet:dry weight ratio of 10. IL-10 concentrations did not differ between groups. In both groups, ventilation was on the linear portion of the P-V curve. With V (bv), VT variability demonstrated an inverse power law indicating fractal behavior. In this model of ARDS, V (bv) improved Pa(O(2)) at lower peak airway pressure and IL-8 levels compared with V (c).