Muscle proteolysis and weight loss in a neonatal rat model of sepsis syndrome.

Our hypothesis is that nitrogen loss in septic neonates is caused by increased muscle proteolysis. Sprague-Dawley rat pups (P7) were injected intraperitoneally with NaCl or 4 mg/kg/BW lipopolysaccharide (LPS) and then sacrificed at 2, 4, 24, and 48 hr. Sepsis syndrome was confirmed by elevated serum tumor necrosis factor (24.6 ng/mL +/- 18.4 [LPS] and < 1.0 ng/mL [controls]; p < .05). Proteolysis in gastrocnemius/soleus muscle was analyzed by quantitation of tissue tyrosine loss. The neonatal rats injected with LPS had significant media tyrosine release at 24 hr compared to the controls (0.39 +/- 0.14 versus 0.25 +/- 0.11 micromol tyrosine/g muscle; p < .05). At 48 hr, LPS-induced muscle tyrosine release ceased (0.24 +/- 0.04 [control] versus 0.23 +/- 0.03 micromol tyrosine/g muscle [LPS]). After 48 hr, gastrocnemius/soleus weight was less in the LPS-injected rats (50.5 +/- 4.8 to 31.2 +/- 4.0 g; p < .0001). Similar changes were not seen in the extensor digitorum longus, suggesting that some muscles were relatively preserved. Also, LPS resulted in significant weight loss. We conclude that selective muscle proteolysis contributes to nitrogen loss in neonatal sepsis. Although proteolysis abates by 48 hr, short-term injury results in significant muscle-mass deficit.

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-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1 beta (IL-1 beta) 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-alpha, IL-6, IL-1 beta, 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.

Variations in end-expiratory pressure during partial liquid ventilation: impact on gas exchange, lung compliance, and end-expiratory lung volume.

STUDY OBJECTIVES: To determine the effects of different levels of positive end-expiratory pressure (PEEP) during partial liquid ventilation (PLV) on gas exchange, lung compliance, and end-expiratory lung volume (EELV). DESIGN: Prospective animal study. SETTING: Animal physiology research laboratory. SUBJECTS: Nine piglets. INTERVENTIONS: Animals underwent saline solution lavage to produce lung injury. Perflubron was instilled via the endotracheal tube in a volume estimated to represent functional residual capacity. The initial PEEP setting was 4 cm H(2)O, and stepwise changes in PEEP were made. At 30-min intervals, the PEEP was increased to 8, then 12, then decreased back down to 8, then 4 cm H(2)O. MEASUREMENTS AND RESULTS: After 30 min at each level of PEEP, arterial blood gases, aortic and central venous pressures, heart rates, dynamic lung compliance, and changes in EELV were recorded. Paired t tests with Bonferroni correction were used to evaluate the data. There were no differences in heart rate or mean BP at the different PEEP levels. CO(2) elimination and oxygenation improved directly with the PEEP level and mean airway pressure (Paw). Compliance did not change with increasing PEEP, but did increase when PEEP was lowered. EELV changes correlated directly with the level of PEEP. CONCLUSIONS: As previously reported during gas ventilation, oxygenation and CO(2) elimination vary directly with PEEP and proximal Paw during PLV. EELV also varies directly with PEEP. Dynamic lung compliance, however, improved only when PEEP was lowered, suggesting an alteration in the distribution of perflubron due to changes in pressure-volume relationships.

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 (V(t)). 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. Infants assigned to each mode of ventilation had similar birth weight, gestational age, and Apgar scores at birth, and similar oxygenation indices at randomization. Three patients were eliminated from final data analysis because of exclusionary conditions unknown at randomization. Oxygenation improved significantly following surfactant therapy in all groups by 1 hr after surfactant treatment (P < 0.05). No further improvements occurred with time. Total respiratory rate was lowest (P < 0.05) and variation in tidal volume (V(t)) was least in the A/C group (P < 0. 05). Minute ventilation (V(')(E)), delivered airway pressures, respiratory system mechanics, and hemodynamic parameters were similar in all groups. We conclude that volume-targeted A/C ventilation resulted in more consistent tidal volumes at lower total respiratory rates than IMV or SIMV. Oxygenation and lung mechanics were not altered by synchronization, possibly due to the volume-targeting strategy. Of the modes studied, A/C, a fully-synchronized mode, may be the most efficient method of mechanical ventilator support in neonates receiving surfactant for treatment of RDS.

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 Children's 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.

Synchronized gas and partial liquid ventilation in lung-injured animals: improved gas exchange with decreased effort.

We hypothesized that partial liquid ventilation (PLV) with perflubron in spontaneously breathing lung-injured animals would increase respiratory workload compared to animals treated with gas ventilation (GV), and that a fully synchronized mode, assist-control ventilation (AC), would reduce the piglets' effort when compared to intermittent mandatory ventilation (IMV) or synchronized IMV (SIMV) during both GV and PLV. Newborn piglets with saline lavage-induced lung injury were randomized to sequential 30-min periods of IMV --> SIMV --> AC (n = 5), or AC --> SIMV --> IMV (n = 5) during GV followed by PLV. Pulmonary mechanics measurements and an esophageal patient effort index (PEI, defined as the product of the area below baseline of the esophageal pressure-time curve and respiratory rate [RR]) were determined to estimate the patient's nonmechanical work of breathing, using a computer-assisted lung mechanics analyzer. GV to PLV comparisons showed no change in PEI (IMV, 57.8 vs. 49.7; SIMV, 52.3 vs. 46.8; AC, 15.7 vs. 13.7 cm H2O x s/min); intermode comparisons showed significantly decreased PEI in AC vs. IMV and SIMV during GV, and in AC vs. SIMV (AC vs. IMV, P = 0.06) during PLV. AC consistently resulted in the highest minute ventilation, lowest total respiratory rate, most physiologic pH, and least tidal volume variability. These observations suggest that synchronization with AC during GV and PLV may have substantial physiologic benefits.

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 animal's effort to the ventilator cycle would decrease RR at stable tidal volumes (V(T)). 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 (V(T)) and spontaneous tidal volumes (sV(T)) 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). Blood gases were stable in all modes during GV and PLV. RR (min(-1)) and V'E (L x min(-1)/kg) increased in all modes from GV to PLV (RR: CPAP 71 vs. 128; IMV 69 vs. 112; SIMV 65 vs. 107; AC 33 vs. 47. V'E: CPAP 0.47 vs. 0.72; IMV 0.46 vs. 0.61; SIMV 0.45 vs. 0.61; AC 0.38 vs. 0.53; P < 0.05). Intermode comparisons during PLV showed a lower RR with AC (P < 0.02), and a higher V'E with CPAP (P < 0.05). V(T) and dynamic respiratory system compliance decreased from GV to PLV (V(T) P < 0.05; C(rs,dyn) P < 0.01); sV(T) remained unchanged. V(T) and sV(T) did not differ in intermode comparisons. We conclude that during PLV, spontaneously breathing piglets with normal lungs maintain physiologic blood gases by increasing V'E through increased RR. AC produced the most efficient respiratory pattern during PLV, with increased V'E achieved by a modest increase in RR.

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. The CV group showed improved oxygenation following surfactant administration (OI: 26.79 +/- 1.98 vs. 8.59 +/- 6.29, P < 0.0004), with little further improvement following PFC administration or adjustments in MAP. Oxygenation in HFO-treated animals did not improve following surfactant, but did improve following PFC (0I: 27.78 +/- 6.84 vs. 15.86 +/- 5.53, P < 0.005) and adjustments in MAP (OI: 15.86 +/- 5.53 vs. 8.96 +/- 2.18, P < 0.03). After MAP adjustments, there were no significant intergroup differences in oxygenation. Animals in the CV group required lower MAP than animals in the HFO group to maintain similar oxygenation. We conclude that surfactant repletion followed by PLV improves oxygenation during both CV and HFO. The initial response to administration of surfactant and PFC was different for the conventional and high-frequency oscillation groups, likely reflecting the ventilation strategy used; animals in the CV group responded most to surfactant, whereas animals in the HFO group responded most after PFC instillation. The ultimately similar oxygenation of the two groups once lung volume had been optimized suggests that HFO may be used effectively during administration of, and treatment with, surfactant and perfluorocarbon.

Exogenous surfactant and partial liquid ventilation: physiologic and pathologic effects.

We compared the effects of surfactant and partial liquid ventilation (PLV), and the impact of administration order, on oxygenation, respiratory system compliance (Crs), hemodynamics, and lung pathology in an animal lung injury model. We studied four groups: surfactant alone (S; n = 8); partial liquid ventilation alone (PLV-only; n = 8); surfactant followed by partial liquid ventilation (S-PLV; n = 8); and partial liquid ventilation-followed by surfactant (PLV-S; n = 8). Following treatments, all animals had improved oxygenation index (OI) and Crs. Animals in PLV groups showed continued improvement over 2 h (% change OI: PLV-S -83% versus S -47%, p < 0.05; % change Crs: S-PLV 73% versus S 13%, p < 0.05). We also saw administration-order effects: surfactant before PLV improved Crs (0.92 ml/cm H2O after surfactant versus 1.13 ml/cm H2O after PLV, p < 0.02) without changing OI, whereas surfactant after PLV did not change Crs and OI increased (5.01 after PLV versus 8.92 after surfactant, p < 0.03). Hemodynamics were not different between groups. Pathologic analysis demonstrated decreased lung injury in dependent lobes of all PLV-treated animals, and in all lobes of S-PLV animals, when compared with the lobes of the S animals (p < 0.05). We conclude that surfactant therapy in combination with PLV improved oxygenation, respiratory system mechanics, and lung pathology to a greater degree than surfactant therapy alone. Administration order affected initial physiologic response and ultimate pathology: surfactant given before PLV produced the greatest improvements in pathologic outcomes.

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, Children's 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.

Suspected betamethasone-induced leukemoid reaction in a premature infant.

The use of antenatal corticosteroids in threatened pregnancies of less than 34 weeks' duration is a valuable tool for assisting fetal lung maturation. Although this practice has existed for over 20 years, little is known about a rare extreme elevation of the newborn's white blood cell count, called a leukemoid reaction. A case of leukemoid reaction is discussed to assist the clinician with the current thought processes and diagnostic differential behind this benign condition.

Partial liquid ventilation: a comparison using conventional and high-frequency techniques in an animal model of acute respiratory failure.

OBJECTIVE: To test the hypothesis that high-frequency ventilation (HFV), when compared with conventional techniques, enhances respiratory gas exchange during partial liquid ventilation (PLV). DESIGN: A four-period crossover design. SETTING: Animal research laboratory of Children's Health Care-St. Paul. SUBJECTS: Thirty-two newborn piglets, weighing 1.40 +/- 0.39 kg. INTERVENTIONS: Animals were divided into four groups of eight animals: a) PLV with high-frequency jet ventilation; b) PLV with jet ventilation using a background intermittent mandatory ventilation (IMV) rate; c) PLV with high-frequency oscillation; or d) PLV with high-frequency flow interruption using a background IMV rate. After anesthesia, paralysis, and tracheotomy, a normal saline wash procedure produced lung injury. Perfluorocarbon was then instilled via the endotracheal tube in an amount estimated to represent functional residual capacity. Animals received randomly either PLV using conventional techniques or PLV using the selected HFV technique as initial treatment. Then, animals were crossed over to the alternative treatment at equal mean airway pressure, as measured at the endotracheal tube tip. This sequence was repeated for a total of four crossover periods, such that all animals were treated twice with PLV using conventional techniques and twice with PLV using HFV. MEASUREMENTS AND MAIN RESULTS: We measured airway pressures at the endotracheal tube tip, aortic and central venous blood pressures, arterial blood gases, and respiratory system mechanics at baseline, after induction of lung injury, and at specified intervals throughout the experiment. Measurements were made before and 15 mins after crossovers, then ventilators were adjusted to normalize gas exchange. Measurements were again made 30 mins later, at the end of the treatment period. All types of PLV provided adequate gas exchange. Only PLV using jet ventilation with IMV produced gas exchange equal to that seen during PLV using conventional techniques at equivalent mean airway pressure. By the end of the treatment periods, only PLV using high-frequency oscillation continued to require higher airway pressure than PLV using conventional techniques for equivalent gas exchange. CONCLUSIONS: Gas exchange was not enhanced during PLV-HFV. Application of HFV with PLV provides no clear acute physiologic advantages to PLV using more conventional techniques.

Lower respiratory rates without decreases in oxygen consumption during neonatal synchronized intermittent mandatory ventilation.

OBJECTIVE: We tested the hypothesis that synchronization to patient effort during intermittent mandatory ventilation (SIMV), when compared to conventional unsynchronized intermittent mandatory ventilation (IMV), will decrease energy expenditure, as reflected by decreased oxygen consumption (VO2). DESIGN: We used a four-period crossover design. Each patient was studied over four 30-min continuous time intervals. Patients were randomized to receive initially IMV or SIMV, then crossed over such that each patient was treated twice with each modality. Data were analyzed using an analysis of variance technique. SETTING: Patients were receiving treatment in the newborn intensive care unit of Children's Hospital, St. Paul. PATIENTS: We studied 17 patients, who ranged from 23 to 37 weeks gestation, were < or = 14 days old, and had study weights from 623 to 3015 g. All were mechanically ventilated for hyaline membrane disease. MEASUREMENTS AND RESULTS: We measured and compared VO2, carbon dioxide consumption (VCO2), minute ventilation (VE), total respiratory rate, heart rate, arterial blood pressure, and arterial oxygen saturation (SaO2) values during IMV and SIMV. Total respiratory rate fell significantly during SIMV (73 +/- 26 during IMV, 57 +/- 17 during SIMV, p < 0.01) in spite of no significant change in VO2 (0.6 +/- 0.16% fall in VO2 during SIMV) or VCO2 (4.2 +/- 0.19% increase in VCO2 during SIMV) values. Moreover, there were no significant differences in heart rate, blood pressure, VE, or SaO2 values with either form of therapy. CONCLUSIONS: Though total respiratory rate fell, these data do not support the hypothesis that SIMV significantly reduces respiratory rate by decreasing oxygen consumption and carbon dioxide production during infant mechanical ventilation. Rather, the marked fall in respiratory rate may be due to a more efficient respiratory pattern.

Mechanical ventilation of the newborn. An overview.

Mechanical ventilation of the newborn infant is an ever-changing area. Its evolution has been hampered and stimulated by problems of small size, inadequate technology, unexpected complications, and changing expectations. With synchronized ventilation, a new technique in the neonatal ICU, clinicians again are reassessing their assumptions. HFV, a "new" technique for 15 years, has found a niche in the treatment of infants failing CV. Its use as an initial therapy for RDS, advocated by some, remains controversial. Monitoring gas flow patterns, tidal and minute volumes, and lung mechanics has become a part of the CV, but complications still occur. The only thing certain is that change will continue.

Monosomy 9p24-->pter and trisomy 5q31-->qter: case report and review of two cases.

Partial deletion of the short arm of chromosome 9 (p24-->pter) and partial duplication of the long arm of chromosome 5 (q32-->qter) were observed in an abnormal boy who died at age 8 weeks of a complex cyanotic cardiac defect. He also had minor anomalies, sagittal craniosynostosis, triphalangeal thumbs, hypospadias, and a bifid scrotum. Two other infants with similar cytogenetic abnormalities were described previously. These patients had severe congenital heart defect, genitourinary anomalies, broad nasal bridge, low hairline, apparently low-set ears, short neck, and triphalangeal thumbs, in common with our patient. We suggest that combined monosomy 9p23,24-->pter and trisomy 5q31,32-->qter may constitute a clinically recognizable syndrome.