Partial liquid ventilation]

Partial liquid ventilation (PLV) is a relatively new therapeutic approach to acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS). The idea of combining the intrapulmonary application of an oxygen-carrying substance and positive pressure ventilation was introduced by Fuhrman in 1991 and originally called perfluorocarbon-associated gas exchange (PAGE). Nowadays, the technique is mostly known as partial liquid ventilation (PLV). The efficacy of PVL treatment has been demonstrated in numerous animal studies in different models of lung injury. The results of those studies led to multicenter phase I-II studies in patients of all age groups in the United States and Canada. Recently, the first randomized, controlled study in 90 adult patients suffering from ALI and ARDS was completed and first results have been published. Comparison of overall mortality and number of ventilator-free days (VFD's) in a 28-day period showed no differences between PLV and conventionally treated patients. A post-hoc stratification by age (< 55 years) demonstrated a tendency to lower mortality (PLV 25.6%; CMV 36.8%) and a significant increase of VFD (PLV 8.95 days; CMV 4.11 days; p = 0.03) in PLV when compared to conventionally treated patients. Perfluorocarbons (PFCs) are chemically stable and inert. They are mostly eliminated via exhalation (> 99%). The unique physicochemical properties of PFCs permit access to atelectatic, non-ventilated lung areas, enhance gas exchange and decrease inflammation. The dense PFCs prevent the endexpiratory collapse of alveoli and reestablish functional residual capacity (FRC). Comparable to positive endexpiratory pressure (PEEP), these effects have been described as "liquid or fluid PEEP". These properties offer a new approach to the underlying pathophysiology of ALI and ARDS. In addition, the combination with other therapeutic approaches to ALI and ARDS like high-frequency oscillations (HFO), inhaled nitric oxide (NO) therapy, and surfactant replacement can be considered and is already the subject of recent publications. However, combination therapy is still experimental and further investigation is necessary to evaluate efficacy and potential risks. Many questions still exist which need to be answered by experimental as well as human pilot studies. Based on these studies, the results of ongoing human trials can be assessed properly and new multicenter trials can be planned effectively.     

Is liquid ventilation a reasonable alternative?

Liquid breathing has been in medical literature for nearly 80 years and has been proposed as a means of improving gas exchange in critically ill infants since the 1970s. Extensive laboratory experience with perfluorochemical liquid ventilation has lead to clinical trials in infants, children, and adults. This article discusses the process and physiologic response to liquid breathing in neonates, and reviews some of the factors that need clarification prior to approval as a routine clinical therapy.     

Neutrophil accumulation is reduced during partial liquid ventilation

OBJECTIVE: This study evaluates the ability of perflubron to inhibit pulmonary neutrophil accumulation during partial liquid ventilation (PLV) in the setting of acute lung injury. DESIGN: Randomized, controlled, nonblinded study. SETTING: Research laboratory at a university. SUBJECTS: Male, Sprague-Dawley rats (n = 120, 506 +/- 42 g). INTERVENTIONS: Animals were divided into eight groups (n = 15 in each group, of which n = 12 for myeloperoxidase content and n = 3 for histologic neutrophil counting): a) GV-CVF group, animals received gas ventilation (GV) with the induction of lung injury using cobra venom factor (CVF); b) PLV-CVF group, animals received partial liquid ventilation before the induction of lung injury; c) PEEP-CVF group, animals received positive end-expiratory pressure (PEEP) before the administration of cobra venom factor; d) CVF-PLV group, animals received partial liquid ventilation after cobra venom factor; e) CVF-PEEP group, animals received PEEP after cobra venom factor; f) PLV only group, animals received partial liquid ventilation only; g) GV only group, animals received gas ventilation only; and h) NVSBA group, nonventilated spontaneous breathing animals. MEASUREMENTS AND MAIN RESULTS: After the experimental period, total lung myeloperoxidase content was significantly decreased in the PLV-CVF (0.29 +/- 0.08, p = .02) and PEEP-CVF (0.34 +/- 0.04, p = .01) groups when compared with the GV-CVF group (0.62 +/- 0.07). When compared with the GV-CVF group, a trend toward a reduction in myeloperoxidase was observed in the CVF-PLV (0.42 +/- 0.05, p = .07) and the CVF-PEEP (0.39 +/- 0.06, p = .07) groups. When compared with the cobra venom factor only group (GV-CVF 47 +/- 2 neutrophils/high-power field), reductions in neutrophil count were observed in all groups (neutrophils/high-power field): PLV-CVF (20 +/- 2, p = .009); PEEP-CVF (24 +/- 1, p = .01); CVF-PLV (30 +/- 2, p = .03); and CVF-PEEP (37 +/- 1, p = .04). CONCLUSION: These data suggest that both partial liquid ventilation and PEEP result in a reduction in neutrophil accumulation in the setting of acute lung injury.     

Partial liquid ventilation protects lung during resuscitation from shock

Preliminary animal experience with partial liquid ventilation (PLV) suggests that this therapy may diminish neutrophil invasion and capillary leak during acute lung injury. We sought to confirm these findings in a model of shock-induced lung injury. Sixty anesthetized rats were studied. After hemorrhage to an arterial pressure of 25 mmHg for 45 min, animals were resuscitated with blood and saline and treated with gas ventilation alone or with 5 ml/kg of intratracheally administered perflubron. Myeloperoxidase activity was used to measure lung neutrophil content. A permeability index (the bronchoalveolar-to-blood ratio of 125I-labeled albumin activity) quantified alveolar leak. Injury caused an increase in myeloperoxidase that was reversed by PLV (injury = 0.837 +/- 0.452, PLV = 0.257 +/- 0.165; P < 0.01). Capillary permeability also increased with hemorrhage, with a strong trend toward improvement in the PLV group (permeability indexes: injury = 0.094 +/- 0.102, PLV = 0.045 +/- 0.045; 95% confidence interval for injury--PLV: -0.024, 0.1219). We conclude that PLV is associated with a decrease in pulmonary neutrophil accumulation and a trend toward decreased capillary leak after hemorrhagic shock.     

Pulmonary pathology of patients treated with partial liquid ventilation

Adsorption and size exclusion in starch and cross-linked dextran were phenomena discovered in Uppsala in the 1950s [Porath (1979), Biochem. Soc. Trans. 7, 1197; Porath (1981), Current Content 19, 21; Porath (1981), J. Chromatogr. 218, 241; Janson (1987), Chromatographia 23, 361; Laurent (1993), J. Chromatogr. 633, 1]. These discoveries were the background to the development of a variety of affinity chromatographic methods. At present attempts are being made to combine size exclusion chromatography (SEC) with adsorption into a single operation that we call adsorptive SEC (AdSEC).     

Non-conventional respiratory support modalities applicable in the older child. High frequency ventilation and liquid ventilation

HFV, LV, and several other novel therapies offer promise to adults and children that the mortality associated with respiratory failure may be affected. Although there are several forms of HFV, HFOV is presently gaining favor in the treatment of severe respiratory failure and has generally supplanted HFJV in pediatric critical care. HFOV has the advantage of having an active expiratory phase, which helps to minimize air trapping and better modulate mean lung volume. Ventilators with sufficient power to perform HFOV in adults are currently under investigation, although there is a growing experience in using current ventilators in larger patients. To date, however, demonstration of lowered mortality with HFOV is lacking although intermediate outcome indicators are improved. PLV also offers promise in the treatment of ARF through its drastic ability to improve oxygenation, ventilation, and compliance in many lung injury models. Human trials are presently underway, but the optimal delivery of this novel therapy still necessitates extensive investigation. TLV is likely even more removed from general clinical application given the necessity of developing a new generation of ventilators for the delivery of liquid tidal volumes. How these and other modalities may piece together to improve the condition of our patients who have respiratory failure remains to be seen, but certainly, present and future investigation will be intriguing for years to come.     

Continuous low-flow tracheal gas insufflation during partial liquid ventilation in rabbits

BACKGROUND: Both partial liquid ventilation (PLV) and tracheal gas insufflation are novel techniques for mechanical ventilation. In this study we examined whether PLV superimposed by continuous low-flow tracheal gas insufflation (TGI) offers any advantage to the blood gases and lung mechanics in normal-lung rabbits compared to the use of PLV only. METHODS: Eighteen anesthetized, paralyzed and mechanically ventilated rabbits were used. After obtaining a baseline PaCO2 value between 29 and 39 mmHg (3.9 and 5.2 kPa), the animals were assigned to three equal groups according to the ventilation they received--A group: PLV superimposed by TGI; B group: PLV only; and C group: continuous mandatory ventilation (CMV) superimposed by TGI. Serial arterial blood gases, pH and lung mechanics were measured. RESULTS: The animals in each group were hemodynamically stable. In the case of the A group, PaO2 continuously increased, and PaCO2 stabilized around 40.8 +/- 5.5 mmHg (5.4 +/- 0.7 kPa, mean +/- SD, NS). In the B group, the tendency for PaO2 to increase was not as definite; PaCO2 continuously increased from 35.2 +/- 2.3 mmHg (4.7 +/- 0.3 kPa) to 56.3 +/- 12.7 mmHg (7.5 +/- 1.7 kPa, P < 0.05) at the end of the experiment. In the C group, PaO2 and PaCO2 were stable during the observation period. The superimposition of TGI on PLV did not decrease the airway pressures compared to PLV alone. CONCLUSION: In summary, continuous low-flow TGI superimposed on PLV can decrease and stabilize the PaCO2 elevation caused by the initiation of PLV.     

Perfluorochemical liquid ventilation: from the animal laboratory to the intensive care unit

Perfluorochemical or perfluorocarbon liquids have an enormous gas-carrying capacity. During tidal liquid ventilation the respiratory medium of both functional residual capacity and tidal volume is replaced by neat perfluorocarbon liquid. Tidal liquid ventilation is characterized by convective and diffusive limitations, but offers the advantage of preserved functional residual capacity, high compliance and improved ventilation-perfusion matching. During partial liquid ventilation only the functional residual capacity is replaced by perfluorocarbon liquid. Both tidal and partial liquid ventilation improve gas exchange and lung mechanics in hyaline membrane disease, adult respiratory distress models and meconium aspiration. Compared to gas ventilation, there is less histologic evidence of barotrauma after liquid ventilation. Cardio-pulmonary interaction, inherent to the high density of liquid, and long term safety need further study. However, extrapolating from animal data, and taking into account promising human pilot studies, liquid ventilation has the desired properties to occupy an important place in the therapy of restrictive lung disease in man.     

High-frequency partial liquid ventilation in respiratory distress syndrome: hemodynamics and gas exchange

Partial liquid ventilation using conventional ventilatory schemes improves lung function in animal models of respiratory failure. We examined the feasibility of high-frequency partial liquid ventilation in the preterm lamb with respiratory distress syndrome and evaluated its effect on pulmonary and systemic hemodynamics. Seventeen lambs were studied in three groups: high-frequency gas ventilation (Gas group), high-frequency partial liquid ventilation (Liquid group), and high-frequency partial liquid ventilation with hypoxia-hypercarbia (Liquid-Hypoxia group). High-frequency partial liquid ventilation increased oxygenation compared with high-frequency gas ventilation over 5 h (arterial oxygen tension 253 +/- 21.3 vs. 17 +/- 1.8 Torr; P < 0.001). Pulmonary vascular resistance decreased 78% (P < 0.001), pulmonary blood flow increased fivefold (P < 0.001), and aortic pressure was maintained (P < 0.01) in the Liquid group, in contrast to progressive hypoxemia, hypercarbia, and shock in the Gas group. Central venous pressure did not change. The Liquid-Hypoxia group was similar to the Gas group. We conclude that high-frequency partial liquid ventilation improves gas exchange and stabilizes pulmonary and systemic hemodynamics compared with high-frequency gas ventilation. The stabilization appears to be due in large part to improvement in gas exchange.     

Partial liquid ventilation decreases the inflammatory response in the alveolar environment of trauma patients

BACKGROUND: Perflubron is a perfluorocarbon with unique physical characteristics. It has twice the density of water, allows free diffusion of O2 and CO2, is easily dispersed, and is insoluble. Thus, it can act as "liquid positive end-expiratory pressure" to recruit collapsed alveoli and improve oxygenation. Results of laboratory studies suggest that perflubron exerts an anti-inflammatory effect on alveolar cells. Limited clinical data in neonates and adults with severe acute respiratory distress syndrome are promising. We present a single institution's experience with partial liquid ventilation (PLV) in trauma patients compared with conventional mechanical ventilation (CMV) with particular attention to the alveolar inflammatory response. METHODS: Ventilated patients with bilateral lung injury and PaO2/FIO2 < 300 were eligible in this prospective multicenter trial. Perflubron was administered by means of the endotracheal tube to fill up to functional residual capacity (approximately 30 mL/kg), followed by supplemental doses up to 96 hours. At this institution, bronchoscopy with bronchoalveolar lavage was performed serially for white blood cell count, protein, interleukin (IL)-1, IL-6, IL-8, and IL-10, and analyzed as early (< 48 hours) and late (48-96 hours). Clinical response was defined as a sustained 10% increase in PaO2/FIO2 at 48 hours. RESULTS: 16 patients were enrolled: 12 PLV patients and 4 CMV patients. There were no differences between groups relative to sex, Injury Severity Score, or initial PaO2/FIO2. There were no major outcome differences between groups in this pilot study relative to pneumonia (50% PLV and 75% CMV), deaths (one death in each group caused by multiple organ failure), or for oxygenation after 5 days. Eight PLV patients were responders (PLV-R) compared with four patients who did not (PLV-NR). The main differences between these subgroups was time from injury to study (1.8 days for PLV-R vs. 5.8 for PLV-NR, p < 0.02) and age (30 years for PLV-R vs. 42 years for PLV-NR, p < 0.04). Both white blood cell count and protein were higher in CMV, suggesting a greater inflammatory response. Neutrophils were significantly higher in CMV, despite equal IL-8 levels in both PLV and CMV. The inflammatory cytokines IL-1 and IL-6 were greater in CMV, and the anti-inflammatory IL-10 was lower in PLV. CONCLUSION: Early institution of partial liquid ventilation is effective at reducing the alveolar inflammatory response. Perflubron exhibits an anti-inflammatory effect in the alveolar environment with reduction of proinflammatory IL-1 and IL-6 (possibly removing a stimulus for IL-10), white blood cell count, and protein capillary leak. PLV also reduces alveolar neutrophils independent of IL-8. Further characterization of this altered inflammatory response is necessary.     

Surfactant replacement increases compliance in premature lamb lungs during partial liquid ventilation in situ

Treatments available to improve compliance in surfactant-deficient states include exogenous surfactant (ES) and either partial (PLV) or total liquid ventilation (TLV) with perfluorochemical (PFC). Because of the additional air-lung and air-PFC interfaces introduced during PLV compared with TLV, we hypothesized that compliance would be worse during PLV than during TLV. Because surfactant is able to reduce interfacial tension between air and lung as well as between PFC and lung, we further hypothesized that compliance would improve with surfactant treatment before PLV. In excised preterm lamb lungs, we used Survanta for surfactant replacement and perflubron as the PFC. Compliance during PLV was intermediate between TLV and gas inflation, both with and without surfactant. Surfactant improved compliance during PLV, compared with PLV alone. Because of the force-balance equation governing the behavior of immiscible droplets on liquid surfaces, we predict that PFC droplets spread during PLV to cover the alveolar surface in surfactant-deficient lungs during most of lung inflation and deflation but that the PFC would retract into droplets in surfactant-sufficient lungs, except at end inspiration.     

Effects of ventilation on hyaluronan and protein concentration in pleural liquid of anesthetized and conscious rabbits

Use of animal power generally enables farmers in sub-Saharan Africa to increase agricultural production and improve the quality of life. Effective use of working animals depends on an understanding of the capabilities of the animals for work, their husbandry requirements and the factors which can influence their performance. These issues are reviewed in this paper in the context of the use of animal power in agriculture in sub-Saharan Africa. The type of animal used for work determines power available to the farmer. The performance of donkeys, horses and cattle have been compared in work tests. Equids are more suited to rapid low draught activities where their faster speed can be used to advantage. At higher draught forces, where speed is less important, the additional weight and power of cattle are an advantage. Use of heart rate recovery after work gives a reasonable indication of fatigue and fitness of equids, when test conditions are standardized. Although feed requirements for work are generally low, feed quality can be so poor that animals are unable to eat enough to meet energy needs for work, and so lose weight during the work season. However, improvements in work performance are not always seen following supplementary feeding in the dry season and the economics need to be considered in each case. Food availability, diseases and heat stress, the major constraints to performance of draught cattle and donkeys working in sub-Saharan Africa, are discussed.     

Distribution of pulmonary blood flow and total lung water during partial liquid ventilation in acute lung injury

BACKGROUND: Gas exchange is improved during partial liquid ventilation (PLV) with perfluorocarbon in animal models of acute lung injury. The mechanisms are not fully defined. We hypothesize that redistribution of pulmonary blood flow (PBF) along with redistribution of, and decrease in, total lung water (TLW) during PLV may improve oxygenation. METHODS: We characterized PBF and TLW in anesthetized adult dogs by using positron emission tomography with H2(15)O. Measurements of gas exchange, PBF, and TLW were made before and after acute lung injury was induced with intravenous oleic acid. The same measurements were made during PLV (with 30 ml/kg perfluorocarbon) and compared with gas ventilated (GV) controls. RESULTS: Oxygenation was significantly improved during PLV. PBF redistributed from the dependent zone of the lung to the nondependent zones, thus potentially improving ventilation/perfusion relationships. However, a similar pattern of PBF redistribution was observed during GV such that there was no significant difference between groups. TLW redistributed in a similar pattern during PLV. By quantitative measurements, PLV ameliorated the continued accumulation of TLW compared with GV animals. CONCLUSIONS: We conclude that PBF and TLW redistribution and attenuation of increases in TLW may contribute to the improvement in gas exchange during PLV in the setting of acute lung injury.     

Pediatric dermatology

Physicians who treat children will encounter dermatologic conditions in their daily practice. A general approach to the diagnosis and management of pediatric skin disease is discussed in this article, and specific common entities are summarized, with emphasis on diagnosis and treatment.     

Pediatric hypertension

This review focuses on recent hypertension literature relevant to pediatrics. In the past year there have been some new recommendations for the evaluation of hypertension and some new ways to look at blood pressure norms in the pediatric population. Furthermore, several useful reviews concerning pediatric hypertension have been published. There have also been striking experimental breakthroughs in hypertension, some of which will eventually translate into clinical advances. The following sections summarize and discuss some areas in pediatric hypertension with a critical appraisal of recent papers.     

Pediatric bronchoscopy

Endoscopic techniques for evaluation and management of airway and pulmonary problems in pediatric patients have matured greatly in the past decade, especially with the introduction of flexible instruments suitable for use in the smallest infants. Careful selection of the most appropriate instrument and technique by well-trained medical or surgical endoscopists will result in safe and effective diagnosis and treatment of a wide variety of conditions affecting the upper and lower respiratory tract.     

Pediatric trauma

Trauma is the leading cause of death in infants and children. Caring for the pediatric trauma victim requires a systematic approach which utilizes an understanding of the anatomic and pathophysiologic characteristics that make children different from adults. Child abuse frequently presents as trauma, making a high index of suspicion for mechanism and severity of injury an important component of trauma assessment. A basic approach to managing pediatric trauma with emphasis on initial stabilization is presented, followed by discussion of specific areas including head and neck trauma, chest trauma, abdominal trauma, and extremity trauma.