Michael H. Terry

A dual closed-loop control system for mechanical ventilation.

Objective. Closed-loop mechanical ventilation has the potential to provide more effective ventilatory support to patients with less complexity than conventional ventilation. The purpose of this study was to investigate the effectiveness of an automatic technique for mechanical ventilation. Methods. Two closed-loop control systems for mechanical ventilation are combined in this study. In one of the control systems several physiological data are used to automatically adjust the frequency and tidal volume of breaths of a patient. This method, which is patented under US Patent number 4986268, uses the criterion of minimal respiratory work rate to provide the patient with a natural pattern of breathing. The inputs to the system include data representing CO2 and O2 levels of the patient as well as respiratory compliance and airway resistance. The I:E ratio is adjusted on the basis of the respiratory time constant to allow for effective emptying of the lungs in expiration and to avoid intrinsic positive end expiratory pressure (PEEP). This system is combined with another closed-loop control system for automatic adjustment of the inspired fraction of oxygen of the patient. This controller uses the feedback of arterial oxygen saturation of the patient and combines a rapid stepwise control procedure with a proportional-integral-derivative (PID) control algorithm to automatically adjust the oxygen concentration in the patients inspired gas. The dual closed-loop control system has been examined by using mechanical lung studies, computer simulations and animal experiments. Results. In the mechanical lung studies, the ventilation controller adjusted the breathing frequency and tidal volume in a clinically appropriate manner in response to changes in respiratory mechanics. The results of computer simulations and animal studies under induced disturbances showed that blood gases were returned to the normal physiologic range in less than 25 s by the control system. In the animal experiments under steady-state conditions, the maximum standard deviations of arterial oxygen saturation and the end-tidal partial pressure of CO2 were ± 1.76% and ± 1.78 mmHg, respectively. Conclusion. The controller maintained the arterial blood gases within normal limits under steady-state conditions and the transient response of the system was robust under various disturbances. The results of the study have showed that the proposed dual closed-loop technique has effectively controlled mechanical ventilation under different test conditions.

Helium-oxygen therapy for pediatric acute severe asthma requiring mechanical ventilation.

Objective To illustrate the use of helium-oxygen gas mixtures as therapy for pediatric patients with acute severe asthma requiring conventional mechanical ventilation. Design Retrospective review. Setting Tertiary care children’s teaching hospital. Patients All mechanically ventilated patients with severe asthma admitted to the pediatric intensive care unit from August 1994 to October 2000. Interventions Within 24 hrs of intubation or admission, patients were stabilized on volume ventilation, bronchodilator therapy, corticosteroids, and antibiotics when indicated. Hypercapnia was permitted while maintaining arterial blood gas pH ≥7.25. A helium-oxygen gas mixture then was begun with helium flow set at 5–7 L/min, and oxygen flow was titrated to maintain desired oxygen saturation. Only sedated, chemically paralyzed patients with adequate pre-helium-oxygen and post-helium-oxygen measurements were statistically analyzed. Measurements and Main Results Twenty-eight mechanically ventilated patients with severe asthma placed on helium-oxygen gas mixtures were identified who met study entry criteria. Mean patient age was 8.8 yrs (range, 1.1–14.6). Before helium-oxygen therapy began, mean peak inspiratory pressure was 40.5 ± 4.2 cm H2O, mean arterial blood gas pH was 7.26 ± 0.05, and mean CO2 partial pressure was 58.2 ± 8.5 torr. After patients were placed on helium-oxygen therapy, there was a significant decrease in mean peak inspiratory pressure to 35.3 ± 3.0 cm H2O. Mean pH increased significantly to 7.32 ± 0.06, and mean partial pressure CO2 decreased significantly to 50.5 ± 7.4 torr. Initial mean inspired helium was 57 ± 4% (range, 32–74). Mechanical ventilation days ranged from 1 to 23 days (mean, 5.0). Hospital stay ranged from 4 to 29 days (mean, 10.1), with an average pediatric intensive care unit stay of 6.9 days (range, 2–24). There were two incidences of pneumothorax. Conclusions In the pediatric patient with severe asthma requiring conventional mechanical ventilation, helium-oxygen administration appears to be a safe therapy and may assist in lowering peak inspiratory pressure and improving blood gas pH and partial pressure CO2.

Inhaled Nitrite Reverses Hemolysis-Induced Pulmonary Vasoconstriction in Newborn Lambs Without Blood Participation

Background— Nitrite can be converted to nitric oxide (NO) by a number of different biochemical pathways. In newborn lambs, an aerosol of inhaled nitrite has been found to reduce pulmonary blood pressure, possibly acting via conversion to NO by reaction with intraerythrocytic deoxyhemoglobin. If so, the vasodilating effects of nitrite would be attenuated by free hemoglobin in plasma that would rapidly scavenge NO. Methods and Results— Pulmonary vascular pressures and resistances to flow were measured in anesthetized newborn lambs. Plasma hemoglobin concentrations were then elevated, resulting in marked pulmonary hypertension. This effect was attenuated if infused hemoglobin was first oxidized to methemoglobin, which does not scavenge NO. These results further implicate NO as a tonic pulmonary vasodilator. Next, while free hemoglobin continued to be infused, the lambs were given inhaled NO gas (20 ppm), inhaled sodium nitrite aerosol (0.87 mol/L), or an intravascular nitrite infusion (3 mg/h bolus, 5 mg · kg−1 · h−1 infusion). Inhaled NO and inhaled nitrite aerosol both resulted in pulmonary vasodilation. Intravascular infusion of nitrite, however, did not. Increases in exhaled NO gas were observed in lambs while breathing the nitrite aerosol (≈20 ppb NO) but not during intravascular infusion of nitrite. Conclusions— We conclude that the pulmonary vasodilating effect of inhaled nitrite results from its conversion to NO in airway and parenchymal lung tissue and is not dependent on reactions with deoxyhemoglobin in the pulmonary circulation. Inhaled nitrite aerosol remains a promising candidate to reduce pulmonary hypertension in clinical application.

Closed-Loop Control of the Inspired Fraction of Oxygen in Mechanical Ventilation

Objective.Supplemental oxygen treatment of patients on mechanical ventilation is crucial in maintaining the patients’ oxygen levels in the normal range. The purpose of this study was to evaluate the effectiveness of a closed-loop controller for automatic adjustment of the fraction of inspired oxygen, FIO2. More specifically, the aim of the study was to assess the robustness of the controller in correcting hypoxemia as well as its effectiveness in prevention of hyperoxemia and oxygen toxicity. Methods.The microprocessor-based feedback control system combines a rapid control algorithm with a proportional-integral-derivative (PID) control procedure to automatically adjust FIO2. The system is designed to prevent hypoxemia by applying a stepwise control procedure in response to rapid declines in arterial oxygen saturation while fine-tuning FIO2 and avoiding hyperoxemia by resuming to the PID control procedure when appropriate. The system includes a sophisticated safeguard unit which is designed to communicate any oxygenation problems or measurement artifacts to the medical personnel while keeping FIO2 at a safe and sufficiently high level. The control system has been tested by using computer simulations as well as animal studies. Results.In response to different disturbances, the arterial oxygen saturation returned to the normal safe range within less than 20 seconds, thereby avoiding any untoward effects of hypoxemia. Under steady state conditions, the variations in arterial oxygen saturation were kept within ± 3% of the mean value. The controller corrected hypoxemia within seconds while preventing hyperoxemia, rejecting artifacts, and minimizing exposure to high concentrations of oxygen. Conclusion.The results of the study attest to the reliability of the proposed closed-loop control scheme for automatic adjustment of FIO2. Further evaluation of the controller will require testing the effectiveness of the system on different patient groups.

Effect of chronic perinatal hypoxia on the role of rho-kinase in pulmonary artery contraction in newborn lambs

Exposure to chronic hypoxia during gestation predisposes infants to neonatal pulmonary hypertension, but the underlying mechanisms remain unclear. Here, we test the hypothesis that moderate continuous hypoxia during gestation causes changes in the rho-kinase pathway that persist in the newborn period, altering vessel tone and responsiveness. Lambs kept at 3,801 m above sea level during gestation and the first 2 wk of life were compared with those with gestation at low altitude. In vitro studies of isolated pulmonary arterial rings found a more forceful contraction in response to KCl and 5-HT in high-altitude compared with low-altitude lambs. There was no difference between the effects of blockers of various pathways of extracellular Ca(2+) entry in low- and high-altitude arteries. In contrast, inhibition of rho-kinase resulted in significantly greater attenuation of 5-HT constriction in high-altitude compared with low-altitude arteries. High-altitude lambs had higher baseline pulmonary artery pressures and greater elevations in pulmonary artery pressure during 15 min of acute hypoxia compared with low-altitude lambs. Despite evidence for an increased role for rho-kinase in high-altitude arteries, in vivo studies found no significant difference between the effects of rho-kinase inhibition on hypoxic pulmonary vasoconstriction in intact high-altitude and low-altitude lambs. We conclude that chronic hypoxia in utero results in increased vasopressor response to both acute hypoxia and serotonin, but that rho-kinase is involved only in the increased response to serotonin.

Local and systemic vasodilatory effects of low molecular weight S-nitrosothiols.

S-nitrosothiols (SNOs) such as S-nitroso-L-cysteine (L-cysNO) are endogenous compounds with potent vasodilatory activity. During circulation in the blood, the NO moiety can be exchanged among various thiol-containing compounds by S-transnitrosylation, resulting in SNOs with differing capacities to enter the cell (membrane permeability). To determine whether the vasodilating potency of SNOs is dependent upon membrane permeability, membrane-permeable L-cysNO and impermeable S-nitroso-D-cysteine (D-cysNO) and S-nitroso-glutathione (GSNO) were infused into one femoral artery of anesthetized adult sheep while measuring bilateral femoral and systemic vascular conductances. L-cysNO induced vasodilation in the infused hind limb, whereas D-cysNO and GSNO did not. L-cysNO also increased intracellular NO in isolated arterial smooth muscle cells, whereas GSNO did not. The infused SNOs remained predominantly in a low molecular weight form during first-passage through the hind limb vasculature, but were converted into high molecular weight SNOs upon systemic recirculation. At systemic concentrations of ~0.6 μmol/L, all three SNOs reduced mean arterial blood pressure by ~50%, with pronounced vasodilation in the mesenteric bed. Pharmacokinetics of L-cysNO and GSNO were measured in vitro and in vivo and correlated with their hemodynamic effects, membrane permeability, and S-transnitrosylation. These results suggest local vasodilation by SNOs in the hind limb requires membrane permeation, whereas systemic vasodilation does not. The systemic hemodynamic effects of SNOs occur after equilibration of the NO moiety amongst the plasma thiols via S-transnitrosylation.

Pulmonary Distribution of Lucinactant and Poractant Alfa and Their Peridosing Hemodynamic Effects in a Preterm Lamb Model of Respiratory Distress Syndrome

Tracheal instillation of surfactant to premature newborns improves their survivability but may transiently obstruct airways resulting in undesirable acute effects on cerebral blood flow (CBF) and oxygenation. The acute peridosing hemodynamic effects of surfactant administration may be avoided by minimizing the volume of surfactant administered, but smaller surfactant volumes may also result in less even distribution of surfactant throughout the lung. These experiments were undertaken to compare responses to two surfactants with different dose volumes (porcine-derived poractant alfa, 2.5 mL/kg vs peptide-based synthetic lucinactant, 5.8 mL/kg) given to newly delivered lambs at 85% gestation. Both surfactants resulted in similar improvements in blood gas values, a doubling of dynamic compliance, increases in brain tissue oxygen tension, and stable blood pressure with no significant change in CBF. Distribution of surfactant throughout the lungs was more uniform with lucinactant than poractant alfa when assessed by labeled microspheres. We conclude that improvements in lung mechanics, gas exchange, and changes in CBF are comparable for a porcine-derived and peptide-containing synthetic surfactant, despite instilled volumes differing by 2-fold. Intrapulmonary distribution of surfactant is more uniform after a larger volume is instilled.

Role of blood and vascular smooth muscle in the vasoactivity of nitrite

Recent evidence from humans and rats indicates that nitrite is a vasodilator under hypoxic conditions by reacting with metal-containing proteins to produce nitric oxide (NO). We tested the hypothesis that near-physiological concentrations of nitrite would produce vasodilation in a hypoxia- and concentration-dependent manner in the hind limb of sheep. Anesthetized sheep were instrumented to measure arterial blood pressure and femoral blood flows continuously in both hind limbs. Nitrite was infused into one femoral artery to raise the nitrite concentration in the femoral vein by 10 to 15-fold while the sheep breathed 50%, 14% or 12% oxygen in inspired air. In contrast to reports in humans and rats, the nitrite infusion had no measurable effect on mean femoral blood flows or vascular conductances, regardless of inspired O2 levels. In vitro experiments showed no significant difference in the release of NO from nitrite in sheep and human red blood cells. Further experiments demonstrated nitrite is converted to NO in rat artery homogenates faster than sheep arteries, and that this source of NO production is attenuated in the presence of a heme oxidizer. Finally, western blots indicate that concentrations of the heme-containing protein cytoglobin, but not myoglobin, are markedly lower in sheep arteries compared with rats. Overall, the results demonstrate that nitrite is not a physiological vasodilator in sheep. This is likely due to a lack of conversion of nitrite to NO within the vascular smooth muscle, perhaps due to deficient amounts of the heme-containing protein cytoglobin.

Effect of inhaled nitric oxide on cerebrospinal fluid and blood nitrite concentrations in newborn lambs

Inhaled nitric oxide (iNO) has many extrapulmonary effects. As the half-life of nitric oxide (NO) in blood is orders of magnitude less than the circulation time from lungs to the brain, the mediator of systemic effects of iNO is unknown. We hypothesized that concentrations of nitrite, a circulating byproduct of NO with demonstrated NO bioactivity, would increase in blood and cerebrospinal fluid (CSF) during iNO therapy. iNO (80 ppm) was given to six newborn lambs and results compared with six control lambs. Blood and CSF nitrite concentrations increased 2-fold in response to iNO. cGMP increased in blood but not CSF suggesting brain guanylate cyclase activity was not increased. When sodium nitrite was infused i.v. blood and CSF nitrite levels increased within 10 min and reached similar levels of 14.6 ± 1.5 μM after 40 min. The reactivity of nitrite in Hb-free brain homogenates was investigated, with the findings that nitrite did not disappear nor did measurable amounts of s-nitroso, n-nitroso, or iron-nitrosyl-species appear. We conclude that although nitrite diffuses freely between blood and CSF, due to its lack of reactivity in the brain, nitrites putative role as the mediator of the systemic effects of iNO is limited to intravascular reactions.

comparison of poractant alfa and lyophilized lucinactant in a preterm lamb model of acute respiratory distress

Introduction:A lyophilized formulation of lucinactant has been developed to simplify preparation and dosing. Endotracheal administration of surfactant can be associated with potentially harmful transient hemodynamic changes including decreases in cerebral blood flow and delivery of O2 to the brain. Efficacy and peri-dosing effects of poractant alfa and a lyophilized form of lucinactant were compared in this study.Methods:Premature lambs (126–129 d gestation) were delivered by c-section, tracheostomized, ventilated, and instrumented with cerebral laser Doppler flowmetry and tissue PO2 probes. Pulmonary compliance and tidal volumes were monitored continuously and surfactant lung distribution was assessed. Lambs received either poractant alfa or lyophilized lucinactant and were monitored for 3 h after treatment.Results:Both groups showed significant improvements in arterial pCO2, pH, pulmonary compliance, and tidal volume (all P < 0.01), a similar intra-pulmonary distribution profile, and no significant changes in arterial blood pressure or cerebral blood flow. Administration of poractant alfa was associated with higher mean airway pressures from 75 min post-dosing and transiently decreased heart rate and increased brain tissue PO2 during the first 30 min after treatment.Discussion:In this newborn lamb model of respiratory distress, lyophilized lucinactant results in improved lung function as compared with poractant alfa.