Influence of age on surfactant isolated from healthy horses maintained on pasture.

BACKGROUND: Surfactant alterations are described in horses after exercise, anesthesia, and prolonged transport, in horses with recurrent airway obstruction, and in neonatal foals. The effect of horse age or bronchoalveolar lavage fluid (BALF) sample characteristics on surfactant is unknown. OBJECTIVES: To evaluate surfactant phospholipid composition and function in healthy horses, and to investigate the influence of age and BALF sample characteristics on surfactant. ANIMALS: Seventeen healthy horses 6-25 years of age maintained on pasture year-round. METHODS: BALF was collected by standard procedures and was assessed for recovery volume, nucleated cell count (NCC), and cytology. Cell-free BALF was separated into crude surfactant pellet (CSP) and surfactant supernatant (Supe) by ultracentrifugation. Phospholipid and protein content were determined from both fractions. CSP phospholipid composition was analyzed by high-performance liquid chromatography with an evaporative light scatter detector. Surface tension of CSP was evaluated with a pulsating bubble surfactometer. Regression analysis was used to evaluate associations between age, BALF sample characteristics, and surfactant variables. RESULTS: Results and conclusions were derived from 15 horses. Increasing age was associated with decreased phospholipid content in CSP but not Supe. Age did not affect protein content of CSP or Supe, or surfactant phospholipid composition or function. Age-related surfactant changes were unaffected by BALF recovery percentage, NCC, and cytological profile. CONCLUSIONS AND CLINICAL IMPORTANCE: Older horses have decreased surfactant phospholipid content, which might be because of age-related pulmonary changes. Surfactant composition is unaffected by BALF sample characteristics at a BALF recovery percentage of at least 50%.

Role of lung surfactant in respiratory disease: current knowledge in large animal medicine.

Lung surfactant is produced by type II alveolar cells as a mixture of phospholipids, surfactant proteins, and neutral lipids. Surfactant lowers alveolar surface tension and is crucial for the prevention of alveolar collapse. In addition, surfactant contributes to smaller airway patency and improves mucociliary clearance. Surfactant-specific proteins are part of the innate immune defense mechanisms of the lung. Lung surfactant alterations have been described in a number of respiratory diseases. Surfactant deficiency (quantitative deficit of surfactant) in premature animals causes neonatal respiratory distress syndrome. Surfactant dysfunction (qualitative changes in surfactant) has been implicated in the pathophysiology of acute respiratory distress syndrome and asthma. Analysis of surfactant from amniotic fluid allows assessment of fetal lung maturity (FLM) in the human fetus and exogenous surfactant replacement therapy is part of the standard care in premature human infants. In contrast to human medicine, use and success of FLM testing or surfactant replacement therapy remain limited in veterinary medicine. Lung surfactant has been studied in large animal models of human disease. However, only a few reports exist on lung surfactant alterations in naturally occurring respiratory disease in large animals. This article gives a general review on the role of lung surfactant in respiratory disease followed by an overview of our current knowledge on surfactant in large animal veterinary medicine.

Abnormalities in lung surfactant in horses clinically affected with recurrent airway obstruction (RAO).

BACKGROUND: Abnormalities in lung surfactant are well described in human respiratory diseases including asthma, but are poorly described in horses. HYPOTHESIS: Lung surfactant is abnormal in horses with clinical signs of recurrent airway obstruction (RAO). ANIMALS: Six healthy horses and 5 horses with RAO. METHODS: Bronchoalveolar lavage fluid (BALF) was obtained from all horses by standard procedures. Cell-free BALF was separated into crude surfactant pellets (CSP) and supernatant via ultracentrifugation. Phospholipid and protein content was analyzed from both of these fractions. Phospholipid composition of CSP was determined using high-performance liquid chromatography with an evaporative light scatter detector. Surface tension of CSP was measured with a pulsating bubble surfactometer. RESULTS: Compared with healthy horses, surfactant from RAO-affected horses was characterized by significantly decreased phospholipid content in total surfactant (median; range: 23.2; 14.7-62.2 microg/mL BALF versus 172; 111-267 microg/mL BALF, P = .0062) and CSP (20.2; 6.4-48.9 microL/mL BALF versus 155; 94.4-248 microg/mL BALF, P = .0062), and a significantly lower percentage of phosphatidylglycerol (PG) (4.5; 3.6-5.6% versus 6.6; 4.1-7.6%, P = .028). Furthermore, the ratio between the percentages of phosphatidylcholine and PG was significantly higher in RAO-affected horses than in healthy horses (20.9; 16.6: 25.9 versus 13.9; 11.8-22.8, P = .045). CONCLUSIONS AND CLINICAL IMPORTANCE: This study demonstrates that surfactant from RAO-affected horses is abnormal. Further studies are needed to determine if these abnormalities are related to an increased tendency for bronchoconstriction and to a decreased ability to clear airway mucus in RAO-affected horses.

Acute respiratory distress syndrome: pharmacological treatment options in development.

The acute respiratory distress syndrome (ARDS) is a clinical syndrome with primarily supportive management options. Despite extensive basic and clinical investigations, multiple pharmacological and nonpharmacological modalities have been unsuccessful in decreasing mortality. Nonetheless, these efforts have substantially heightened our understanding of ARDS pathophysiology. Investigators continue to create new and more complex therapeutic strategies that may have significant clinical impact. Several pharmacological agents for ARDS are in development and have shown either great promise or are at most, under phase II evaluation. The order in which therapeutic options are presented in this review highlights therapeutic options other than the anti-inflammatory approach. In addition to the anti-inflammatory category, vasodilators, surfactant therapy, immunonutrition and partial liquid ventilation are all being evaluated. Within the anti-inflammatory category. new mechanistic approaches include the 'anti-inflammatory nature' of interleukin-10, the inhibitory aspects of lysophosphatidic acid on endothelial cell permeability, and the use of recombinant human anti-coagulant proteins (activated protein C and tissue factor pathway inhibitor) to reduce the inflammatory cycle that contributes to microvascular thrombi. Previous work with surfactant in ARDS had its limitations, however, these trials were of sufficient success to spawn 2 new synthetic compounds. These new synthetic surfactants incorporate mixtures of phosphatidylcholine and phosphatidylglycerol (the key phospholipids within endogenous surfactant) and either recombinant surfactant protein C or an analogue of surfactant protein B. Recently, the ARDS Network's low tidal volume study has broken the cycle of decades of negative ARDS trials and demonstrated an improvement in mortality. Through better mechanistic approach and study design, investigator compliance with exclusion criteria, and better understanding of the complexities of patient management, the next pharmacological ARDS trials will hopefully be successful and lead to further reductions in patient mortality.

Venous air embolism from central venous catheterization: a need for increased physician awareness.

OBJECTIVES: To report a series of patients with clinically diagnosed venous air embolism (VAE) and major sequelae as a complication of the use of central venous catheters (CVCs), to survey health care professionals' practices regarding CVCs, and to implement an educational intervention for optimizing approaches to CVC insertion and removal. SETTING: Tertiary care, university-based 806-bed medical center. INTERVENTIONS: We surveyed 140 physicians and 53 critical care nurses to appraise their awareness of the proper management and complications of CVCs. We then designed, delivered, and measured the effects of a multidisciplinary educational intervention given to 106 incoming house officers. MEASUREMENTS AND MAIN RESULTS: Although most physicians (127, 91%) chose the Trendelenburg position for CVC insertion, only 42 physicians (30%) reported concern for VAE. On CVC removal, only 36 physicians (26%) cited concern for VAE. Some physicians (13, 9%) reported elevating the head of the bed during CVC removal, possibly increasing the risk of VAE. Awareness of VAE or its prevention did not correlate with the level of physician training, experience, or specialty. After the educational intervention, concern for and awareness of proper methods of prevention of VAE improved (p < .001). At 6-month follow-up, reported use of the Trendelenburg position continued, but concern cited for VAE had returned to baseline. CONCLUSIONS: There is inadequate awareness of VAE as a complication of CVC use. Focused instruction can improve appreciation of this potentially fatal complication and knowledge of its prevention, but the effect declines rapidly. To achieve a more sustained improvement, a more intensive, hands-on, periodic educational program will likely be necessary, as well as reinforcement through enhanced supervision of CVC insertion and removal practices.

Bronchopulmonary segmental lavage with Surfaxin (KL(4)-surfactant) for acute respiratory distress syndrome.

We performed a trial to assess the safety and tolerability of sequential bronchopulmonary segmental lavage with a dilute synthetic surfactant (Surfaxin) in 12 adults with ARDS. Patients received one of three dosing regimens in which aliquots of Surfaxin were administered via a wedged bronchoscope to each of the 19 bronchopulmonary segments. Suctioning was performed 10-30 s after instillation of individual aliquots. Group 1 patients (n = 3) received one 30-ml aliquot of a 2.5-mg/ml concentration of Surfaxin in each segment, followed by a second 30-ml aliquot with a 10-mg/ml concentration. Group 2 patients (n = 4) received two 30-ml aliquots of the 2.5-mg/ml concentration followed by a third lavage with the 10-mg/ml concentration. Group 3 patients (n = 5) received therapy identical to that received by patients in Group 2 and were eligible for repeat dosing 6 to 24 h later. All patients tolerated the procedure. There were no serious adverse experiences ascribed to either the procedure or the surfactant. In the 96 h after treatment initiation, FI(O(2)) decreased from 0.80 to 0.52 and PEEP decreased from 10.3 to 7.6 cm H(2)O. Bronchoscopic "cleansing" of the lungs with dilute Surfaxin may offer a safe and feasible approach to improving outcomes in patients with ARDS. Wiswell TE, Smith RM, Katz LB, Mastroianni L, Wong DY, Willms D, Heard S, Wilson M, Hite RD, Anzueto A, Revak SD, Cochrane CG. Bronchopulmonary segmental lavage with Surfaxin (KL(4)-surfactant) for acute respiratory distress syndrome.

Hydrolysis of surfactant-associated phosphatidylcholine by mammalian secretory phospholipases A2.

Hydrolysis of surfactant-associated phospholipids by secretory phospholipases A2 is an important potential mechanism for surfactant dysfunction in inflammatory lung diseases. In these conditions, airway secretory phospholipase A2 (sPLA2) activity is increased, but the type of sPLA2 and its impact on surfactant function are not well understood. We examined in vitro the effect of multiple secretory phospholipases A2 on surfactant, including their ability to 1) release free fatty acids, 2) release lysophospholipids, and 3) increase the minimum surface tension (gammamin) on a pulsating bubble surfactometer. Natural porcine surfactant and Survanta were exposed to mammalian group I (recombinant porcine pancreatic) and group II (recombinant human) secretory phospholipases A2. Our results demonstrate that mammalian group I sPLA2 hydrolyzes phosphatidylcholine (PC), producing free fatty acids and lysophosphatidylcholine, and increases gammamin. In contrast, mammalian group II sPLA2 demonstrates limited hydrolysis of PC and does not increase gammamin. Group I and group II secretory phospholipases A2 from snake venom hydrolyze PC and inhibit surfactant function. In summary, mammalian secretory phospholipases A2 from groups I and II differ significantly from each other and from snake venom in their ability to hydrolyze surfactant-associated PC.

Bovine surfactant therapy for patients with acute respiratory distress syndrome.

Lung surfactant is deficient in patients with acute respiratory distress syndrome (ARDS). We performed a randomized, prospective, controlled, open-label clinical study of administration of a bovine surfactant to patients with ARDS to obtain preliminary information about its safety and efficacy. Patients received either surfactant by endotracheal instillation in addition to standard therapy or standard therapy only. Three different groups of patients receiving surfactant were studied: patients receiving up to eight doses of 50 mg phospholipids/kg, those receiving up to eight doses of 100 mg phospholipids/kg, and those receiving up to four doses of 100 mg phospholipids/kg. Outcome measures included ventilatory support parameters, arterial blood gases, organ system failures, bronchoalveolar lavage (BAL) analyses, immunologic analyses, survival, and adverse events during the 28-d study period. Fifty-nine study patients were evaluable; 43 in the surfactant group and 16 in the control group. The FI(O2) at 120 h after treatment began was significantly decreased only for patients who received up to four doses of 100 mg phospholipids/kg surfactant as compared with control patients (p = 0.011). Mortality in the same group of patients was 18.8%, as compared with 43.8% in the control group (p = 0.075). The surfactant instillation was generally well tolerated, and no safety concerns were identified. This pilot study presents preliminary evidence that surfactant might have therapeutic benefit for patients with ARDS, and provides rationale for further clinical study of this agent.

Acute effects of a single dose of porcine surfactant on patients with the adult respiratory distress syndrome.

In an attempt to restore functional surfactant to the lungs of patients with the adult respiratory distress syndrome (ARDS), we have treated six patients within the first 2 days of the onset of ARDS with a single dose of hydrophobic components of porcine surfactant. Surfactant (4 g in 50 ml) delivered via a bronchoscope in aliquots to each of the lobar bronchi was well tolerated and caused a modest transient improvement in gas exchange. No significant changes in chest radiograph or lung compliance were detected. Analysis of bronchoalveolar lavage (BAL) fluid showed no change in albumin, alpha-1-proteinase inhibitor specific activity, or cell count. Bronchoalveolar lavage phospholipid concentrations were elevated 3 h after surfactant administration relative to preadministration levels and fell by 24 h. In addition, in two patients we found reduced inhibition of surfactant function in BAL after surfactant replacement. These observations suggest a role for surfactant replacement in the treatment of patients with ARDS and support the need for continuing investigation.