Jeanne D. Mrozek

Prolonged partial liquid ventilation using conventional and high-frequency ventilatory techniques: gas exchange and lung pathology in an animal model of respiratory distress syndrome.

OBJECTIVE To evaluate the effect of prolonged partial liquid ventilation with perflubron (partial liquid ventilation), using conventional and high-frequency ventilatory techniques, on gas exchange, hemodynamics, and lung pathology in an animal model of lung injury. DESIGN Prospective, randomized, controlled study. SETTING Animal laboratory of the Infant Pulmonary Research Center, Childrens Health Care-St. Paul. SUBJECTS Thirty-six newborn piglets. INTERVENTIONS We studied newborn piglets with lung injury induced by saline lavage. Animals were randomized into one of five treatment groups: a) conventional gas ventilation (n = 8); b) partial liquid ventilation with conventional ventilation (n = 7); c) partial liquid ventilation with high-frequency jet ventilation (n = 7); d) partial liquid ventilation with high-frequency oscillation (n = 7); and e) partial liquid ventilation with high-frequency flow interruption (n = 7). After induction of lung injury, all partial liquid ventilation animals received intratracheal perflubron to approximate functional residual capacity. After 30 mins of stabilization, animals randomized to high-frequency ventilation were changed to their respective high-frequency modes. Hemodynamics and blood gases were measured before and after lung injury, after perflubron administration, and then every 4 hrs for 20 hrs. Histopathologic evaluation was carried out using semiquantitative scoring and computer-assisted morphometric analysis on pulmonary tissue from animals surviving at least 16 hrs. MEASUREMENTS AND MAIN RESULTS All animals developed acidosis and hypoxemia after lung injury. Oxygenation significantly (p < .001) improved after perflubron administration in all partial liquid ventilation groups. After 4 hrs, oxygenation was similar in all ventilator groups. The partial liquid ventilation-jet ventilation group had the highest pH; intergroup differences were seen at 16 and 20 hrs (p < .05). The partial liquid ventilation-oscillation group required higher mean airway pressure; intergroup differences were significant at 4 and 8 hrs (p < .05). Aortic pressures, central venous pressures, and heart rates were not different at any time point. Survival rate was significantly lower in the partial liquid ventilation-flow interruption group (p < .05). All partial liquid ventilation-treated animals had less lung injury compared with gas-ventilated animals by both histologic and morphometric analysis (p < .05). The lower lobes of all partial liquid ventilation-treated animals demonstrated less damage than the upper lobes, although scores reached significance (p < .05) only in the partial liquid ventilation-conventional ventilation animals. CONCLUSIONS In this animal model, partial liquid ventilation using conventional or high-frequency ventilation provided rapid and sustained improvements in oxygenation without adverse hemodynamic consequences. Animals treated with partial liquid ventilation-flow interruption had a significantly decreased survival rate vs. animals treated with the other studied techniques. Histopathologic and morphometric analysis showed significantly less injury in the lower lobes of lungs from animals treated with partial liquid ventilation. High-frequency ventilation techniques did not further improve pathologic outcome.

Randomized Controlled Trial of Volume-Targeted Synchronized Ventilation and Conventional Intermittent Mandatory Ventilation Following Initial Exogenous Surfactant Therapy

We set out to evaluate the impact of volume‐targeted synchronized ventilation and conventional intermittent mandatory ventilation (IMV) on the early physiologic response to surfactant replacement therapy in neonates with respiratory distress syndrome (RDS). We hypothesized that volume‐targeted, patient‐triggered synchronized ventilation would stabilize minute ventilation at a lower respiratory rate than that seen during volume‐targeted IMV, and that synchronization would improve oxygenation and decrease variation in measured tidal volume (Vt). This was a prospective, randomized study of 30 hospitalized neonates with RDS. Infants were randomly assigned to volume‐targeted ventilation using IMV (n = 10), synchronized IMV (SIMV; n = 10), or assist/control ventilation (A/C; n = 10) after meeting eligibility requirements and before initial surfactant treatment. Following measurements of arterial blood gases and cardiovascular and respiratory parameters, infants received surfactant. Infants were studied for 6 hr following surfactant treatment.

High-frequency oscillation versus conventional ventilation following surfactant administration and partial liquid ventilation

Surfactant followed by partial liquid ventilation (PLV) with perfluorocarbon (PFC; LiquiVent®) improves oxygenation, lung compliance, and lung pathology in lung‐injured animals receiving conventional ventilation (CV). In this study, we hypothesize that high‐frequency oscillation (HFO) and CV will provide equivalent oxygenation in lung‐injured animals following surfactant repletion and PLV, once lung volume is optimized. After saline‐lavage lung injury during CV, newborn piglets were randomized to either HFO (n = 10) or CV (n = 9). HFO animals were stabilized over 15 min without optimization of lung volume; CV animals continued treatment with time‐cycled, pressure‐limited, volume‐targeted ventilation. All animals then received 100 mg/kg of surfactant (Survanta®). Thirty minutes later, all received intratracheal PFC to approximate functional residual capacity. Thirty minutes after PLV began, mean airway pressure (MAP) in both groups was increased to improve oxygenation. MAP was directly adjusted during HFO; PEEP and PIP were adjusted during IMV, maintaining a pressure sufficient to deliver 15 mL/kg tidal volume. Animals were treated for 4 h.

Effect of sepsis syndrome on neonatal protein and energy metabolism.

OBJECTIVE:It was our hypothesis that septic illness would alter both protein and energy metabolism in neonates, with elevations of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) serving as markers for these effects.STUDY DESIGN:A total of 31 infants with suspected sepsis were enrolled into four groups: septic, sick-nonseptic, healthy-nonseptic, and recovered septic infants. Degree of illness, oxygen consumption, nitrogen balance, urine 3-methylhistidine/creatinine (MeH/Cr), and TNF-α, IL-6, IL-1β, and C-reactive protein (CRP) were measured.RESULTS:Oxygen consumption increased, while nitrogen balance decreased and MeH/Cr increased with increasing degree of illness. Nitrogen balance improved on recovery from sepsis. IL-6 and CRP levels were elevated in septic infants compared with sick-nonseptic and healthy infants.CONCLUSION: Neonates experience a hypermetabolic response with increased nitrogen loss during septic illness, proportional to the degree of illness. Increased delivery of protein substrate may be nutritionally advantageous to the septic neonate.

Perfluorocarbon priming and surfactant: physiologic and pathologic effects.

OBJECTIVE To test the hypothesis that perfluorocarbon (PFC) priming before surfactant administration improves gas exchange and lung compliance, and also decreases lung injury, more than surfactant alone. DESIGN Prospective, randomized animal study. SETTING Animal research laboratory of Childrens Hospital of St. Paul. SUBJECTS Thirty-two newborn piglets, weighing 1.55 +/- 0.18 kg. INTERVENTIONS We studied four groups of eight animals randomized after anesthesia, paralysis, tracheostomy, and establishment of lung injury using saline washout to receive one of the following treatments: a) surfactant alone (n = 8); b) priming with the PFC perflubron alone (n = 8); c) priming with perflubron followed by surfactant (n = 8); and d) no treatment (control; n = 8). Perflubron priming was achieved by instilling perflubron via the endotracheal tube in an amount estimated to represent the functional residual capacity, ventilating the animal for 30 mins, and then removing perflubron by suctioning. After all treatments were given, animals were mechanically ventilated for 4 hrs. MEASUREMENTS AND MAIN RESULTS We evaluated oxygenation, airway pressures, respiratory system compliance, and hemodynamics at baseline, after induction of lung injury, and at 30-min intervals for 4 hrs. Histopathologic evaluation was carried out using a semiquantitative scoring system and by computer-assisted morphometric analysis. After all treatments, animals had decreased oxygenation indices (p < .001) and increased respiratory system compliance (p < .05). Animals in PFC groups had similar physiologic responses to treatments as animals treated with surfactant only; both the PFC-treated groups and the surfactant-treated animals required lower mean airway pressures throughout the experiment (p < .001) and had higher pH levels at 90 and 120 mins (p < .05) compared with the control group. Pathologic analysis demonstrated decreased lung injury in surfactant-treated animals compared with animals treated with PFC or the controls (p < .02). CONCLUSIONS Priming the lung with PFC neither improved the physiologic effects of exogenous surfactant nor improved lung pathology in this animal model.

Dynamics of spontaneous breathing during patient-triggered partial liquid ventilation

This study evaluates different ventilator strategies during gas (GV) and partial liquid ventilation (PLV) in spontaneously breathing animals. We hypothesized that during PLV, spontaneously breathing animals would self‐regulate respiratory parameters by increasing respiratory rate (RR) and minute ventilation (V′E) when compared to animals mechanically ventilated with gas, and further that full synchronization of each animals effort to the ventilator cycle would decrease RR at stable tidal volumes (VT). We studied 12 newborn piglets (1.54 ± 0.24 kg) undergoing GV and PLV in 3 different modes: intermittent mandatory ventilation (IMV), synchronized IMV (SIMV), and assist control ventilation (AC). Modes occurred sequentially in random order during GV first, with the same order then repeated during PLV. Animals initially received continuous positive airway pressure (CPAP) and returned to CPAP during PLV at the end of the experiment. Pressure‐limited, volume‐targeted ventilation was used with a tidal volume goal of 13 cc/kg. Rate was set at 10/min during IMV and SIMV, with a back‐up rate of 10/min during AC. RR, V′E, mechanical (VT) and spontaneous tidal volumes (sVT) were measured breath‐to‐breath using a computer‐assisted lung mechanics analyzer; mean values were determined over 30‐min periods. Data analysis used paired t‐tests with Bonferroni correction as needed (P < 0.05).

Neonatal Sepsis: Effect on Protein and Energy Metabolism † 1405

Protein catabolism and oxygen consumption are increased in septic adults in proportion to degree of illness. Inflammatory cytokines are thought to mediate proteolysis to maintain synthesis of acute phase proteins (e.g. C-reactive protein [CRP]) during sepsis. Septic neonates have immature immunologic responses characterized by elevated IL-6, but not tumor necrosis factor (TNF) levels. To study the impact of sepsis on cytokines and protein metabolism in neonates, we studied 25 newborns (36±3 wks EGA; 2910±840g) divided into three groups: Group 1 (septic, positive blood culture [BC]), Group 2 (sick, negative BC), Group 3 (healthy, rule out sepsis). Infants had oxygen consumption (VO2 [mL/kg/min]), 6 hour nitrogen balance (N Bal[g/kg/d]), urinary 3-methyl Histidine/Creatinine (3MH/Cr), serum TNF & IL-6 (pg/mL), CRP (mg/dL), and Score for Neonatal Acute Physiology (SNAP) measured at 12-36 hours after onset of illness. Data are mean±SD.Table

Dynamics of Spontaneous Breathing during Partial Liquid Ventilation. |[dagger]| 1466

We tested the hypothesis that partial liquid ventilation (PLV) with perflubron (LiquiVent®) in spontaneously breathing (SB) animals would increase respiratory rate (RR), minute ventilation (Ve), and work of breathing when compared to animals treated with gas ventilation (GV). We studied 8 newborn piglets after sedation with ketamine, intubation, and placement of catheters and an esophageal balloon. CPAP was initially used, then animals were randomized to sequentially receive different modes of ventilation during GV (Drager Babylog): IMV-SIMV-AC, or AC-SIMV-IMV. We then instilled perflubron to FRC and repeated the sequence during PLV. Animals returned to CPAP during PLV at the end of the experiment. Each treatment lasted 30 minutes. Ventilator rate during IMV and SIMV, and backup rate during AC, was 10/minute. RR, Ve, and pressure- time product (PTP=ΔPes·Ti, by flow) were measured for all spontaneous and triggered breaths. Standardized PTP•RR is an index of work of breathing. Blood gases were measured and OI calculated every 15 minutes. Reported values are means for the treatment periods. Data analysis used paired t-tests (p<0.05).Table

Exogenous Surfactant during Partial Liquid Ventilation: Lung Pathology.† 1550

Surfactant (surf, Survanta®) followed by partial liquid ventilation(PLV) with perflubron (LiquiVent®) improves lung mechanics and oxygenation more than S only, PLV only, or PLV followed by S (Peds Res 1996:39;343A). Histologic and morphometric analysis was performed on slides from the upper anterior and lower posterior lobes of 32 newborn piglets (1.7±0.8 kg) with saline lavage-induced lung injury (PaO2<60 torr, FiO2 1.0) after randomization into 4 groups and treatment for 2 hours with: 1) surf only (S; n=8); 2) PLV only (PLV; n=8); 3) PLV followed by surf (PLV-S; n=8 and 4) surf followed by PLV (S-PLV; n=8). Ventilators were adjusted to maintain tidal volume of 15 cc/kg; FiO2 was 1.0. Histologic variables (alveolar, interstitial inflammation; alveolar, interstitial hemorrhage; edema; atelectasis; necrosis) were scored on a 0-4 point scale (no injury = 0, injury in 25% of field = 1, injury in 50% of field = 2, injury in 75% of field = 3, and injury throughout field = 4). Morphometric analysis on trichrome-stained slides analyzed total cellular to air space, expressed as percent tissue area (% tissue area =[cellular area/total area] × 100). Kruskal-Wallis, Wilcoxin, and paired t-tests with Bonferroni correction (p<0.05) were used to assess differences. Table

Partial Liquid Ventilation Using High Frequency Oscillation: Effects of Changes in Frequency on Gas Exchange. † 1593

Partial Liquid Ventilation Using High Frequency Oscillation: Effects of Changes in Frequency on Gas Exchange. † 1593