Evaluating current guidelines for cardiopulmonary resuscitation using an integrated computational model of the cardiopulmonary system.

OBJECTIVE: We aimed to use a high-fidelity computational model that captures key interactions between the cardiovascular and pulmonary systems to investigate whether current CPR protocols could potentially be improved. METHODS: We developed and validated the computational model against available human data. We used a global optimisation algorithm to find CPR protocol parameters that optimise the outputs associated with return of spontaneous circulation in a cohort of 10 virtual subjects. RESULTS: Compared with current protocols, myocardial tissue oxygen volume was more than 5 times higher, and cerebral tissue oxygen volume was nearly doubled, during optimised CPR. While the optimal maximal sternal displacement (5.5 cm) and compression ratio (51%) found using our model agreed with the current American Heart Association guidelines, the optimal chest compression rate was lower (67 compressions min-1). Similarly, the optimal ventilation strategy was more conservative than current guidelines, with an optimal minute ventilation of 1500 ml min-1 and inspired fraction of oxygen of 80%. The end compression force was the parameter with the largest impact on CO, followed by PEEP, the compression ratio and the CC rate. CONCLUSIONS: Our results indicate that current CPR protocols could potentially be improved. Excessive ventilation could be detrimental to organ oxygenation during CPR, due to the negative haemodynamic effect of increased pulmonary vascular resistance. Particular attention should be given to the chest compression force to achieve satisfactory CO. Future clinical trials aimed at developing improved CPR protocols should explicitly consider interactions between chest compression and ventilation parameters.

Comparison of apnoeic oxygen techniques in term pregnant subjects: a computational modelling study.

BACKGROUND: Hypoxaemia during general anaesthesia can cause harm. Apnoeic oxygenation extends safe apnoea time, reducing risk during airway management. We hypothesised that low-flow nasal oxygenation (LFNO) would extend safe apnoea time similarly to high-flow nasal oxygenation (HFNO), whilst allowing face-mask preoxygenation and rescue. METHODS: A high-fidelity, computational, physiological model was used to examine the progression of hypoxaemia during apnoea in virtual models of pregnant women in and out of labour, with BMI of 24-50 kg m-2. Subjects were preoxygenated with oxygen 100% to reach end-tidal oxygen fraction (FE'O2) of 60%, 70%, 80%, or 90%. When apnoea started, HFNO or LFNO was commenced. To simulate varying degrees of effectiveness of LFNO, periglottic oxygen fraction (FgO2) of 21%, 60%, or 100% was configured. HFNO provided FgO2 100% and oscillating positive pharyngeal pressure. RESULTS: Application of LFNO (FgO2 100%) after optimal preoxygenation (FE'O2 90%) resulted in similar or longer safe apnoea times than HFNO FE'O2 80% in all subjects in labour. For BMI of 24, the time to reach SaO2 90% with LFNO was 25.4 min (FE'O2 90%/FgO2 100%) vs 25.4 min with HFNO (FE'O2 80%). For BMI of 50, the time was 9.9 min with LFNO (FE'O2 90%/FgO2 100%) vs 4.3 min with HFNO (FE'O2 80%). A similar finding was seen in subjects with BMI ≥40 kg m-2 not in labour. CONCLUSIONS: There is likely to be clinical benefit to using LFNO, given that LFNO and HFNO extend safe apnoea time similarly, particularly when BMI ≥40 kg m-2. Additional benefits to LFNO include the facilitation of rescue face-mask ventilation and ability to monitor FE'O2 during preoxygenation.

Ventilation strategies for front of neck airway rescue: an in silico study.

BACKGROUND: During induction of general anaesthesia a 'cannot intubate, cannot oxygenate' (CICO) situation can arise, leading to severe hypoxaemia. Evidence is scarce to guide ventilation strategies for small-bore emergency front of neck airways that ensure effective oxygenation without risking lung damage and cardiovascular depression. METHODS: Fifty virtual subjects were configured using a high-fidelity computational model of the cardiovascular and pulmonary systems. Each subject breathed 100% oxygen for 3 min and then became apnoeic, with an obstructed upper airway. When arterial haemoglobin oxygen saturation reached 40%, front of neck airway access was simulated with various configurations. We examined the effect of several ventilation strategies on re-oxygenation, pulmonary pressures, cardiovascular function, and oxygen delivery. RESULTS: Re-oxygenation was achieved in all ventilation strategies. Smaller airway configurations led to dynamic hyperinflation for a wide range of ventilation strategies. This effect was absent in airways with larger internal diameter (≥3 mm). Intrapulmonary pressures increased quickly to supra-physiological values with the smallest airways, resulting in pronounced cardio-circulatory depression (cardiac output <3 L min-1 and mean arterial pressure <60 mm Hg), impeding oxygen delivery (<600 ml min-1). Limiting tidal volume (≤200 ml) and ventilatory frequency (≤8 bpm) for smaller diameter cannulas reduced dynamic hyperinflation and gas trapping, preventing cardiovascular depression. CONCLUSIONS: Dynamic hyperinflation can be demonstrated for a wide range of front of neck airway cannulae when the upper airway is obstructed. When using small-bore cannulae in a CICO situation, ventilation strategies should be chosen that prevent gas trapping to prevent severe adverse events including cardio-circulatory depression.

Effect of variable pre-oxygenation endpoints on safe apnoea time using high flow nasal oxygen for women in labour: a modelling investigation.

BACKGROUND: Studies of pulmonary denitrogenation (pre-oxygenation) in obstetric populations have shown high flow nasal oxygen therapy (HFNO) is inferior to facemask techniques. HFNO achieves median end-tidal oxygen fraction (FE'O2) of 0.87 after 3 min. As HFNO prolongs safe apnoea times through apnoeic oxygenation, we postulated that HFNO would still extend safe apnoeic times despite the lower FE'O2 after pre-oxygenation. METHODS: The Interdisciplinary Collaboration in Systems Medicine simulation suite, a highly integrated, high-fidelity model of the human respiratory and cardiovascular systems, was used to study the effect of varying FE'O2 (60%, 70%, 80%, and 90%) on the duration of safe apnoea times using HFNO and facemask techniques (with the airway open and obstructed). The study population consisted of validated models of pregnant women in active labour and not in labour with BMI of 24, 35, 40, 45, and 50 kg m-2. RESULTS: HFNO provided longer safe apnoeic times in all models, with all FE'O2 values. Labour and increased BMI reduced this effect, in particular a BMI of 50 kg m-2 reduced the improvement in apnoea time to 1.8-8.5 min (depending on the FE'O2), compared with an improvement of more than 60 min in the subject with BMI 24 kg m-2. CONCLUSIONS: Despite generating lower FE'O2, HFNO provides longer safe apnoea times in pregnant subjects in labour. Care should be taken when used in patients with BMI ≥50 kg m-2 as the extension of the safe apnoea time is limited.

In Silico Modeling of Coronavirus Disease 2019 Acute Respiratory Distress Syndrome: Pathophysiologic Insights and Potential Management Implications.

OBJECTIVES: Patients with coronavirus disease 2019 acute respiratory distress syndrome appear to present with at least two distinct phenotypes: severe hypoxemia with relatively well-preserved lung compliance and lung gas volumes (type 1) and a more conventional acute respiratory distress syndrome phenotype, displaying the typical characteristics of the "baby lung" (type 2). We aimed to test plausible hypotheses regarding the pathophysiologic mechanisms underlying coronavirus disease 2019 acute respiratory distress syndrome and to evaluate the resulting implications for ventilatory management. DESIGN: We adapted a high-fidelity computational simulator, previously validated in several studies of acute respiratory distress syndrome, to: 1) develop quantitative insights into the key pathophysiologic differences between the coronavirus disease 2019 acute respiratory distress syndrome and the conventional acute respiratory distress syndrome and 2) assess the impact of different positive end-expiratory pressure, Fio2, and tidal volume settings. SETTING: Interdisciplinary Collaboration in Systems Medicine Research Network. SUBJECTS: The simulator was calibrated to represent coronavirus disease 2019 acute respiratory distress syndrome patients with both normal and elevated body mass indices undergoing invasive mechanical ventilation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: An acute respiratory distress syndrome model implementing disruption of hypoxic pulmonary vasoconstriction and vasodilation leading to hyperperfusion of collapsed lung regions failed to replicate clinical data on type 1 coronavirus disease 2019 acute respiratory distress syndrome patients. Adding mechanisms to reflect disruption of alveolar gas-exchange due to the effects of pneumonitis and heightened vascular resistance due to the emergence of microthrombi produced levels of ventilation perfusion mismatch and hypoxemia consistent with data from type 1 coronavirus disease 2019 acute respiratory distress syndrome patients, while preserving close-to-normal lung compliance and gas volumes. Atypical responses to positive end-expiratory pressure increments between 5 and 15 cm H2O were observed for this type 1 coronavirus disease 2019 acute respiratory distress syndrome model across a range of measures: increasing positive end-expiratory pressure resulted in reduced lung compliance and no improvement in oxygenation, whereas mechanical power, driving pressure, and plateau pressure all increased. Fio2 settings based on acute respiratory distress syndrome network protocols at different positive end-expiratory pressure levels were insufficient to achieve adequate oxygenation. Incrementing tidal volumes from 5 to 10 mL/kg produced similar increases in multiple indicators of ventilator-induced lung injury in the type 1 coronavirus disease 2019 acute respiratory distress syndrome model to those seen in a conventional acute respiratory distress syndrome model. CONCLUSIONS: Our model suggests that use of standard positive end-expiratory pressure/Fio2 tables, higher positive end-expiratory pressure strategies, and higher tidal volumes may all be potentially deleterious in type 1 coronavirus disease 2019 acute respiratory distress syndrome patients, and that a highly personalized approach to treatment is advisable.

Effect of oxygen fraction on airway rescue: a computational modelling study.

BACKGROUND: During induction of general anaesthesia, patients frequently experience apnoea, which can lead to dangerous hypoxaemia. An obstructed upper airway can impede attempts to provide ventilation. Although unrelieved apnoea is rare, it continues to cause deaths. Clinical investigation of management strategies for such scenarios is effectively impossible because of ethical and practical considerations. METHODS: A population-representative cohort of 100 virtual (in silico) subjects was configured using a high-fidelity computational model of the pulmonary and cardiovascular systems. Each subject breathed 100% oxygen for 3 min and then became apnoeic, with an obstructed upper airway, during induction of general anaesthesia. Apnoea continued throughout the protocol. When arterial oxygen saturation (Sao2) reached 20%, 40%, or 60%, airway obstruction was relieved. We examined the effect of varying supraglottic oxygen fraction (Fo2) on the degree of passive re-oxygenation occurring without tidal ventilation. RESULTS: Relief of airway obstruction during apnoea produced a single, passive inhalation (caused by intrathoracic hypobaric pressure) in all cases. The degree of re-oxygenation after airway opening was markedly influenced by the supraglottic Fo2, with a supraglottic Fo2 of 100% providing significant and sustained re-oxygenation (post-rescue Pao2 42.3 [4.4] kPa, when the airway rescue occurred after desaturation to Sao2 60%). CONCLUSIONS: Supraglottic oxygen supplementation before relieving upper airway obstruction improves the effectiveness of simulated airway rescue. Management strategies should be implemented to assure a substantially increased pharyngeal Fo2 during difficult airway management.

High oxygen fraction during airway opening is key to effective airway rescue in obese subjects.

Apnea is common after induction of anesthesia and may produce dangerous hypoxemia, particularly in obese subjects. Optimal management of airway emergencies in obese, apneic subjects is complex and controversial, and clinical studies of rescue strategies are inherently difficult and ethically-challenging to perform. We investigated rescue strategies in various degrees of obesity, using a highly-integrated, computational model of the pulmonary and cardiovascular systems, configured against data from 8 virtual subjects (body mass index [BMI] 24-57 kg m-2). Each subject received pre-oxygenation with 100% oxygen for 3 min, and then apnea with an obstructed airway was simulated until SaO2 reached 40%. At that time, airway rescue was simulated, opening of the airway with the provision of various patterns of tidal ventilation with 100% oxygen. Rescue using tidal ventilation with 100% oxygen provided rapid re-oxygenation in all subjects, even with small tidal volumes in subjects with large BMI. Overall, subjects with larger BMI pre-oxygenated faster and, after airway obstruction, developed hypoxemia more quickly. Our results indicate that attempts to achieve substantial tidal volumes during airway rescues are probably not worthwhile (and may be counter-productive); rather, it is the assurance of a high-inspired oxygen fraction that will prevent critical hypoxemia.

Assessment of diaphragmatic thickness by ultrasonography in Duchenne muscular dystrophy (DMD) patients.

INTRODUCTION: In Duchenne muscular dystrophy (DMD) the assessment of diaphragmatic function is crucial because respiratory muscle weakness can cause respiratory failure. We aimed to noninvasively assess diaphragmatic function in DMD by measuring diaphragmatic thickness by ultrasonography, under the hypothesis that the progressive decrease of lung function is related to alterations of diaphragmatic thickness. METHODS: Forty-four DMD patients and thirteen healthy controls were enrolled and subdivided into three age groups. Diaphragmatic thickness was measured during quiet breathing, inspiratory capacity, maximal inspiratory pressure and expiratory pressure maneuvers. RESULTS: In DMD, absolute values of diaphragmatic thickness were significantly lower than in controls in the majority of the manoeuvers and diaphragmatic thickness significantly decreased with age at end-expiration, remaining constant at end-inspiration and during maximal inspiratory pressure maneuvers. Comparing to controls, absolute values of diaphragmatic thickness and diaphragmatic thickness variations were significantly lower (p<0.001), with the exception of quiet breathing and maximal expiratory pressure maneuvers in the youngest DMD. During maximal inspiratory pressure maneuver, variation of diaphragmatic thickness was not significantly different in the all groups, nevertheless maximal inspiratory pressure decreases with age. CONCLUSIONS: The diaphragm is prone to pseudo-hypertrophy in the youngest DMD, and to progressive atrophy in middle-age and oldest DMD. Diaphragm impairment could be expressed as a dissociation between muscle drive and muscle developed force. Ultrasonography could be used as a noninvasive method to assess progressive diaphragmatic weakness.

Investigating the effect of cardiac oscillations and deadspace gas mixing during apnea using computer simulation.

Gaseous mixing in the anatomical deadspace with stimulation of respiratory ventilation through cardiogenic oscillations is an important physiological mechanism at the onset of apnea, which has been credited with various beneficial effects, e.g. reduction of hypercapnia during the use of low flow ventilation techniques. In this paper, a novel method is proposed to investigate the effect of these mechanisms in silico. An existing computational model of cardio-pulmonary physiology is extended to include the apneic state, gas mixing within the anatomical deadspace, insufflation into the trachea and cardiogenic oscillations. The new model is validated against data published in an experimental animal (dog) study that reported an increase in arterial partial pressure of carbon dioxide (PaCO2) during apnea. Computational simulations confirm that the model outputs accurately reproduce the available experimental data. This new model can be used to investigate the physiological mechanisms underlying clearance of carbon dioxide during apnea, and hence to develop more effective ventilation strategies for apneic patients.

Models of PaO2 response to the continuous distending pressure maneuver during high frequency oscillatory ventilation in healthy and ARDS lung model pigs.

UNLABELLED: Purpose/Aim : High-frequency oscillatory ventilation (HFOV) is a method of ventilation that theoretically achieves the goals of lung protective ventilation in acute respiratory distress syndrome (ARDS) patients. It is characterized by a rapid delivery of small tidal volumes at high frequencies oscillating around a continuous distending pressure (CDP). Optimization of CDP is not an easy task and it is titrated empirically in the clinical practice. The aim of this study is to investigate whether the level of CDP consistently affects the shape of the partial pressure of oxygen (PaO2) response to stepwise changes in CDP during HFOV of healthy and ARDS-induced pigs. MATERIALS AND METHODS: We performed two stepwise maneuvers of CDP in 14 pigs: one before and one after the lung lavage, inducing ARDS. For each CDP step performed, we fitted a segment of PaO2 curve with a one-term power model. RESULTS: PaO2 course follows shapes modeled by root, linear, quadratic, and cubic functions for values of PaO2 ≤ 110 mmHg and PaO2 ≤ 200 mmHg, before and after the lung lavage, respectively. PaO2 course follows a shape modeled exclusively by a root function for values of PaO2 > 110 mmHg and PaO2 > 200 mmHg, before and after the lung lavage, respectively. It is not possible to describe a relationship between the shape of the PaO2 course and the values of CDP. CONCLUSIONS: The PaO2 curve may give information about the level of recruitment of alveoli, but cannot be used for optimization of CDP level during HFOV in healthy and ARDS lung model pigs.

Thoraco-abdominal asymmetry and asynchrony in congenital diaphragmatic hernia.

OBJECTIVE: Congenital diaphragmatic hernia (CDH) consists of an incomplete formation of the diaphragm and the subsequent herniation of abdominal bowels. Diaphragmatic defect can be repaired by primary closure or placing a patch. Respiratory follow up usually focuses on spirometric and clinical evaluation. The aim of the study was to assess thoraco-abdominal volumes in CDH patients and to verify whether the action of the diaphragm on the chest wall is altered leading to an asymmetric and asynchronous expansion of the different thoracoabdominal compartments. PATIENTS AND METHODS: Total and compartmental chest wall volumes and asynchronies were measured by Opto-Electronic Plethysmography in 14 CDH patients (7 M/7F, age 5 ± 2 years, 12 left side operated) and in 9 age matched healthy subjects during quiet spontaneous breathing in supine position. Patients were divided in two groups: five patients with suture (group S) and nine patients with diaphragmatic patch (group P). Pulmonary function was assessed by spirometry and spirometric parameters were expressed as Z-score. RESULTS: In group P abdominal contribution to tidal volume was lower than healthy controls and group S. Unlike controls, in both CDH groups the right side of pulmonary rib cage moved inward with a correspondent left side expansion during inspiration. In group S, thoraco-abdominal asynchronies were higher than in group P and controls, especially in the right side. Five patients belonging to group P had a spirometric obstructive pattern. CONCLUSIONS: In overall CDH patients a reduced action of the treated (left) hemi-diaphragm is evident. In patients treated by primary suture, a compensatory action of the right side allows to reach a normal total diaphragmatic displacement and a proper contribution of the whole diaphragm to tidal volume. In patients treated by diaphragmatic patch, instead, thoraco-abdominal asynchronies are prevented.

Alterations of thoraco-abdominal volumes and asynchronies in patients with spinal muscle atrophy type III.

Spinal muscular atrophy (SMA) is characterized by degeneration of motor neurons resulting in muscle weakness. For the mild type III form, a sub-classification into type IIIA and IIIB, based on age of motor impairment, was recently proposed. To investigate if SMA IIIA (more severe) and IIIB differ also in terms of respiratory function, thoracoabdominal kinematics was measured during quiet breathing, inspiration preceding cough and inspiratory capacity on 5 type IIIA and 9 type IIIB patients. Four patients with SMA II (more severe than types III) and 19 healthy controls were also studied. Rib cage motion was similar in SMA IIIB and controls. Conversely, in SMA IIIA and SMA II it was significantly reduced and sometime paradoxical during quiet breathing in supine position. Our results suggest that in SMA IIIA intercostal muscles are weakened and the diaphragm is preserved similarly to SMA II, while in SMA IIIB the action of all inspiratory muscles is maintained. Sub-classification of type III seems feasible also for respiratory function.

Concomitant ventilatory and circulatory functions of the diaphragm and abdominal muscles.

Expulsive maneuvers (EMs) caused by simultaneous contraction of diaphragm and abdominal muscles shift substantial quantities of blood from the splanchnic circulation to the extremities. This suggests that the diaphragm assisted by abdominal muscles might accomplish ventilation and circulation simultaneously by repeated EMs. We tested this hypothesis in normal subjects by measuring changes (Δ) in body volume (Vb) by whole body plethysmography simultaneously with changes in trunk volume (Vtr) by optoelectronic plethysmography, which measures the same parameters as whole body plethysmography plus the volume of blood shifts (Vbs) between trunk and extremities: Vbs = ΔVtr-ΔVb. We also measured abdominal pressure, pleural pressure, the arterial pressure wave, and cardiac output (Qc). EMs with abdominal pressure ~100 cmH(2)O for 1 s, followed by 2-s relaxations, repeated over 90 s, produced a "stroke volume" from the splanchnic bed of 0.35 ± 0.07 (SD) liter, an output of 6.84 ± 0.75 l/min compared with a resting Qc of 5.59 ± 1.14 l/min. Refilling during relaxation was complete, and the splanchnic bed did not progressively empty. Diastolic pressure increased by 25 mmHg during each EM. Between EMs, Qc increased to 7.09 ± 1.14 l/min due to increased stroke volume and heart rate. The circulatory function of the diaphragm assisted by simultaneous contractions of abdominal muscles with appropriate pressure and duration at 20 min(-1) can produce a circulatory output as great as resting Qc, as well as ventilation. These combined functions of the diaphragm have potential for cardiopulmonary resuscitation. The abdominal circulatory pump can act as an auxiliary heart.