Evaluation of the physiological properties of ventilatory ratio in a computational cardiopulmonary model and its clinical application in an acute respiratory distress syndrome population.

BACKGROUND: Owing to complexities of measuring dead space, ventilatory failure is difficult to quantify in critical care. A simple, novel index called ventilatory ratio (VR) can quantify ventilatory efficiency at the bedside. The study objectives were to evaluate physiological properties of VR and examine its clinical applicability in acute respiratory distress syndrome (ARDS) patients. METHODS: A validated computational model of cardiopulmonary physiology [Nottingham Physiology Simulator (NPS)] was used to evaluate VR ex vivo in three virtual patients with varying degrees of gas exchange defects. Arterial P(CO2) and mixed expired P(CO2) were obtained from the simulator while either dead space or CO2 production was altered in isolation. VR and deadspace fraction was calculated using these values. A retrospective analysis of a previously presented prospective ARDS database was then used to evaluate the clinical utility of VR. Basic characteristics of VR and its association with mortality were examined. RESULTS: The NPS showed that VR behaved in an intuitive manner as would be predicted by its physiological properties. When CO2 production was constant, there was strong positive correlation between dead space and VR (modified Pearson's r 0.98, P<0.01). The ARDS database had a mean VR of 1.47 (standard deviation 0.58). Non-survivors had a significantly higher VR compared with survivors [1.70 vs 1.34, mean difference 0.35, 95% confidence interval (CI) 0.16-0.56, P<0.01]. VR was an independent predictor of mortality (odds ratio 3.05, CI 1.35-6.91, P<0.01). CONCLUSIONS: VR is influenced by dead space and CO2 production. In ARDS, high VR was associated with increased mortality.

Histologic and ultrastructural changes in nonpulmonary organs during early hyperdynamic sepsis.

Previous studies describing the histologic elements of multi-system organ failure caused by bacterial sepsis may have been complicated by a significant interaction on tissue injury from either a preterminal low-flow state or the effects of therapy immediately before death. Therefore we evaluated the nonpulmonary histologic findings of sepsis during a 3-day period that followed cecal ligation and perforation. In this septic model, mean arterial perfusion pressures remained unchanged from baseline, systemic flows rose by 54%, and laboratory evidence of organ dysfunction including an elevation of the serum bilirubin levels and a depression of the serum total protein values was considered mild. Concurrently, development of the hyperdynamic central circulatory septic state was associated with widespread histologic changes in myocardium, striated muscle, liver, gut, and pancreas. Lesions common to these organs included high-protein interstitial and intracellular edema, mitochondrial destruction, and patchy cell necrosis. Lesions within the pancreas were exaggerated over those noted in other organs. Of all organs examined, only the liver demonstrated microvascular neutrophil accumulation. Unlike models of shock caused by sepsis, fibrin thrombi were not seen in the microvasculature of any organ. We conclude that tissue injury characterized by the accumulation of protein-rich extravascular fluid and the development of reversible and irreversible cell injury antedated significant multiple-system organ failure in this animal model of normotensive sepsis.

The effect of various sympathomimetics on the regional circulations in hyperdynamic sepsis.

Because sepsis is characterized by a depression in vascular reactivity, we hypothesized that changes in organ blood flows (Q) would differ between the nonseptic and septic state during the infusion of sympathomimetics. Therefore we examined the (sepsis x organ Q) interaction during the infusion of five sympathomimetics in 36 mature, awake sheep before and after cecal ligation and perforation produced hyperdynamic sepsis. A 3-hour infusion of dobutamine, norepinephrine, dopamine, dopexamine, or salbutamol was compared with that of placebo during both nonseptic and septic studies; drug infusion was titrated to an increase in cardiac index of greater than 20%. Increased plateau infusion doses of norepinephrine (+305%), salbutamol (+275%), dopamine (+70%), and dobutamine (+49%) were required to achieve predefined treatment guidelines during the septic versus nonseptic study. Few differences in the regional effects of individual sympathomimetics were found in the nonseptic study, although infusion of sympathomimetics was accompanied by a redistribution of systemic Q toward the heart and away from the brain, kidney, small intestine, liver, and pancreas. In the septic study, however, the sympathomimetic infusions were not accompanied by the redistribution of Q away from small intestine and liver that was demonstrated in the nonseptic study. Therefore (1) the depressed vascular reactivity in hyperdynamic sepsis altered the dose profile of exogenous sympathomimetics required to augment systemic Q, and (2) the (sepsis x sympathomimetic) interaction was characterized by a depression in the anticipated redistribution of organ Q from "nonvital" to "vital" circulations.

Measurement of tidal volume by using transthoracic impedance variations in rats.

The application of impedance pneumography for monitoring respiration in small animals has been limited by problems with calibration. With improved instrumentation, we describe the calibration of tidal volume in anesthetized rats. The detection of changes in voltage, reflecting the electrical impedance variations associated with respiration, was optimized by using disposable adhesive silver-silver chloride electrodes, advanced circuitry, and analog-to-digital recording instrumentation. We found a linear relationship between change in impedance and tidal volume in individual rats (R2 >/= 98%), which was strongly influenced by rat weight. Consequently, a calibration equation incorporating change in impedance and rat weight was derived to predict tidal volume. Comparison of the predicted and true tidal volumes revealed a mean R2 >/= 98%, slopes of approximately 1, intercepts of approximately 0, and bias of approximately 0.07 ml. The predicted volumes were not significantly affected by either frequency of respiration or pulmonary edema. We conclude that impedance pneumography provides a valuable tool for the noninvasive measurement of tidal volume in anesthetized rats.

A simple bedside approach to measurement of respiratory mechanics in critically ill patients.

OBJECTIVE: To describe and evaluate clinically applicable approaches to measurement of respiratory mechanics in critically ill patients. DATA SOURCES: Methodological and evaluation studies of respiratory mechanics in critically ill patients from relevant MEDLINE searches. SUMMARY OF REVIEW: In ventilated subjects clinically important respiratory system mechanics can be measured using airway pressure and flow data. However, since the respiratory system consists of the lung and chest wall, and chest wall mechanics can markedly alter respiratory system mechanics, it is preferable to compartmentalise these parameters with concurrent measurement of oesophageal, and preferably gastric pressure. Additional care must be taken with interpretation of these data since elastance and resistance may be influenced by frequency, volume, volume history and flow. Tissue viscoelasticity and non-homogeneity of regional time constants are responsible for stress adaptation, which can be measured simply, and accounts for some of these effects on elastance and resistance, and for a systematic difference between static and dynamic intrinsic PEEP. Elastance can be measured using the end-inspiratory occlusion technique, or from either static or dynamic volume-pressure curves. PEEP-mediated recruitment can be measured following referencing of these curves to FRC. Similarly, resistance can be measured from either end-inspiratory occlusion or dynamic pressure and flow data. CONCLUSIONS: Some of this information is available on modern ventilators, but greater insight requires measurement and manipulation of flow and pressure data using a pneumotachograph and pressure transducers. Given the importance of respiratory mechanics in the management of many critically ill patients, and given how poorly the respiratory system is monitored compared with the cardiovascular system, it is worth considering making this simple but additional effort.

Measurement of overinflation by multiple linear regression analysis in patients with acute lung injury.

Strategies to optimize alveolar recruitment and prevent lung overinflation are central to ventilatory management of patients with acute lung injury (ALI). The recent description of overinflation using multilinear regression analysis of airway pressure (Paw) and flow (V') data allows a functional assessment of lung mechanics. However, this technique has not been studied in ALI patients. During 15 positive end-expiratory pressure (PEEP) trials in 10 ALI patients, respiratory elastance was partitioned into volume-independent (E1) and volume-dependent (E2VT) components, where Paw=(E1+E2VT)V+RrsV'+Po; where V is volume, VT is tidal volume, Rrs is respiratory resistance and Po is static recoil pressure at end-expiration (equivalent to total PEEP). Then, %E2 was calculated as (100E2VT)/(E1+E2VT); a measure of lung overinflation when %E2>30%. Alveolar recruitment, assessed as a PEEP-induced increase in V>50 mL at a constant Paw occurred in 14 of 15 trials (299+/-34 mL, mean+/-SEM), but was independent of the degree of lung inflation. Lung overinflation was common (six of 15 clinically set PEEP levels) and occurred despite a dynamic elastic distending pressure (Pel,dyn) <30 cmH2O during 18 of 36 PEEP titrations. During a PEEP titration the resultant %E2 was directly related to delta(peak airway pressure-Po) (rs=0.86, p<0.001) and delta(Pel,dyn-Po) (rs=0.89, p<0.001). The 95% predictive intervals for a 2 cmH2O change in either driving pressure were %E2 values of 30.4-68.1% and 32.8-69.2%, respectively. Single or continuous measurement of %E2 (a measure of lung inflation) is a readily available method for titrating ventilatory parameters. Further, during a positive end-expiratory pressure titration a change in ventilatory driving pressure > or =2 cmH2O is indicative of overinflation.

Vasoactive drugs and the importance of renal perfusion pressure.

Despite the often multifactorial nature of renal insults in critically ill patients, inadequate renal blood flow (RBF) is common and frequently causes a reduction in the glomerular filtration rate (GFR). Renal autoregulation acts to maintain both the RBF and GFR constant across a broad range of renal perfusion pressure (RPP) levels; however, the lower limit of this range (approximately 80 mm Hg for RBF, and 10-15 mm Hg higher for GFR) is often above the RPP achieved in critically ill patients. Furthermore, renal autoregulation is often lost, resulting in a linear pressure-flow relationship in the "at-risk" kidney. Consequently, maintenance of an adequate RPP level is needed to optimize RBF. While this may require the use of vasopressor catecholamines with their attendant risk of renal vasoconstriction and a reduction in RBF, both laboratory studies and clinical data suggest that such reactions rarely occur with intravenous infusions of these drugs, and that RBF and renal function usually improve when RPP is augmented during shock. Preliminary data, using nitric oxide (NO.) synthase inhibitors to augment blood pressure, showed a detrimental effect on renal perfusion, perhaps due to the central role of NO. in the normal vasoregulation of the kidney. Dopaminergic agonists have been commonly used as renal vasodilators; however, their actions are complex and include a proximal tubular diuretic effect, renal vasodilation, and systemic hemodynamic effects. Their specific action to increase RBF and GFR has not been demonstrated in clinically relevant studies and no prospective randomized study has shown a reduction in the incidence of renal impairment or acute renal failure.

Renovascular interaction of epinephrine, dopamine, and intraperitoneal sepsis.

OBJECTIVE: To determine the effect of intraperitoneal sepsis on the systemic and renal actions of the continous infusion of epinephrine or dopamine, and during the concurrent administration of both drugs. DESIGN: Prospective, randomized study. SETTING: Laboratory at a university hospital. SUBJECTS: Seven conscious, chronically catheterized, adult merino sheep. INTERVENTIONS: Epinephrine at 40 micrograms/min or dopamine at 2 micrograms/kg/min, or both drugs concurrently were infused for 4 hrs on separate study days in healthy sheep. This protocol was then repeated following the induction of sepsis after the intraperitoneal injection of 10(11) Escherichia coli, 10(12) Bacteroides fragilis, and bran. MEASUREMENTS AND MAIN RESULTS: Systemic oxygen delivery (DO2) and consumption were measured using thermodilution cardiac output and measured oxygen content. Renal blood flow was measured using an electromagnetic flow transducer, and creatinine clearance was calculated as the quotient of renal blood flow and the renal extraction ratio of creatinine. Infusion of epinephrine augmented systemic DO2 and mean arterial pressure (MAP) during both healthy and septic studies. Systemic oxygen consumption was only increased during epinephrine infusion in the septic study. During the healthy animal study, renal blood flow was initially decreased during epinephrine infusion, but increased to 36% above baseline (p = .003). However, creatinine clearance remained unchanged. During the experimental sepsis study, the infusion of epinephrine had less marked effects on renal blood flow (unchanged from baseline), while an initial reduction (15 mins) in creatinine clearance (p = .04) was not sustained and had returned to baseline by 3 hrs. Dopamine alone produced no change in systemic oxygen variables or MAP during the studies on healthy or septic animals. Although dopamine produced renal vasodilation and an increase in renal blood flow in the healthy state, these results were not found during the septic state. In addition, concurrent infusion of dopamine with epinephrine did not alter the systemic or renal effects of epinephrine during the healthy or septic states. CONCLUSIONS: These results do not support the routine use of low-dose dopamine, and demonstrate a change in renovascular responses to catecholamines during intraperitoneal sepsis. The infusion of epinephrine at 40 micrograms/min had few deleterious effects on the kidney, and augmented both MAP and systemic DO2. Its role as a catecholamine in the management of sepsis may need to be reconsidered.

Non.Invasive Ventilation for Adult Acute Respiratory Failure. Part II.

OBJECTIVE: To discuss the clinical indications and complications of non-invasive ventilation. DATA SOURCES: A review of articles published in peer-reviewed journals from 1966 to 1998 and identified through a MEDLINE search on non-invasive ventilation. SUMMARY OF REVIEW: Non-invasive ventilation (NIV) has been used in patients with respiratory failure caused by cardiogenic pulmonary oedema, acute respiratory distress syndrome, acute asthma and chronic obstructive pulmonary disease. However, in patients with acute respiratory failure, it appears that acute cardiogenic pulmonary oedema and acute respiratory failure associated with Pneumocystis carinii pneumonia are the only disorders in which significant benefits have been associated with the use of the NIV mode of CPAP. The potential clinical benefit of CPAP in acute asthma and blunt chest trauma remains unclear. Pressure support ventilation is beneficial in patients with hypercapnic acute respiratory failure (ARF) secondary to respiratory muscle insufficiency, high inspiratory work loads, or reduced alveolar ventilation. It appears also to be associated with an improved outcome in COPD patients with hypercapnic ARF. CONCLUSIONS: Non-invasive ventilation using the modes of CPAP, PSV, BiPAP and NIPPV should be considered in patients with respiratory disorders who remain in acute respiratory failure despite conventional therapy, before considering invasive mechanical ventilation.

Non.invasive ventilation for adult acute respiratory failure. Part I.

OBJECTIVE: To detail the history, modes, physiological effects, and circuit geometry of non-invasive ventilation. DATA SOURCES: A review of articles published in peer-reviewed journals from 1966 to 1998 and identified through a MEDLINE search on non-invasive ventilation. SUMMARY OF REVIEW: Non-invasive ventilation (NIV) has been used for many years as an adjunct to standard therapy in patients with acute and chronic respiratory disorders. The newer modes of NIV which include continuous positive airway pressure (CPAP), pressure support ventilation (PSV), BiPAP (bi-level positive airway pressure) and controlled and assisted modes of intermittent non-invasive positive pressure ventilation (NIPPV) have additional advantages and are often used routinely in many respiratory diseases. These modes of ventilatory support have been found to improve arterial oxygenation, ventilation, work of breathing, and cardiac function, in patients with respiratory failure, although in normal subjects, respiration is often impaired.. CONCLUSIONS: Non-invasive ventilation using the modes of CPAP, PSV, BiPAP and NIPPV should be considered in patients with respiratory failure who are unresponsive to conventional therapy, before considering invasive mechanical ventilation.

Aerosol kinetics and bronchodilator efficacy during continuous positive airway pressure delivered by face mask.

BACKGROUND: Rates of fresh gas flow (FGF) commonly used when continuous positive airway pressure (CPAP) is delivered by face mask theoretically reduce the delivery and availability of therapeutic aerosols. As it may be hazardous for patients with acute respiratory failure to interrupt mask CPAP, the effects of CPAP on aerosol kinetics and bronchodilator efficacy were investigated. METHOD: The effect of CPAP at 10 cm H2O at a FGF rate of 50 l/min on the delivery of technetium labelled aerosol generated from a readily available jet nebuliser was measured using a bench model of spontaneous respiration. In a separate clinical study the bronchodilator responses to incremental doses of nebulised salbutamol were measured in nine stable asthmatic subjects in a random sequence of conventional nebulisation (control) or nebulisation whilst receiving CPAP via a tight fitting face mask. Each patient acted as his or her own control. RESULTS: CPAP significantly reduced total aerosol delivery to the face mask from 6.85 (1.52)% to 1.3 (0.37)% of the initial nebuliser charge. In the clinical study a significant bronchodilator response to nebulised salbutamol was seen during both conventional nebulisation and nebulisation whilst receiving CPAP by face mask. The shape of the dose-response curves and the magnitude of the total increase in the forced expiratory volume in one second (FEV1) was identical for CPAP and control conditions. CONCLUSIONS: Despite a reduction in aerosol presented to the proximal airway, the bronchodilator response to inhaled beta 2 agonists in stable asthmatic subjects was not affected when CPAP was delivered by face mask. Despite a high rate of FGF, nebulised beta 2 agonists are effective when administered in conjunction with CPAP delivered by face mask.

Dopamine and renal salvage in the critically ill patient.

Dopamine is a catecholamine used widely in critically ill patients and those undergoing major surgery, often as a 'renal protective' agent. Direct renal vasodilatation with 'low-dose' dopamine is the widely accepted basis for its use--hence the term 'renal dose' dopamine. However, recent evidence has revealed that the renal effects of this agent are far more complex. Moreover, some of these effects may be undesirable in the 'at-risk' kidney. The increased renal blood flow (RBF) of dopamine may be largely attributable to its inotropic (myocardial) action, even with low doses (i.e. less than 5 micrograms/kg/min). Similar increases in RBF can also be demonstrated with other (non-dopaminergic) inotropes. The early evidence for direct renal vasodilatation in response to dopamine has been brought into question by more recent research. The diuresis and natriuresis commonly seen following dopamine administration is now known to be due to a direct renal tubular (or 'diuretic') action. Furthermore, increasing knowledge regarding the pathophysiology of acute (ischaemic) renal failure, including RBF and the concept of 'oxygen supply and demand' in relation to tubular function, suggests that dopamine may mask important signs of renal ischaemia. Whether or not dopamine is truly beneficial to renal function currently remains unanswered. As it stands however, there is sufficient evidence to question its routine use in the setting of renal dysfunction in the critically ill patient.

Efficacy of pressure support in compensating for apparatus work.

Breathing through an endotracheal tube, connector, and ventilator demand valve imposes an added load on the respiratory muscles. As respiratory muscle fatigue is thought to be a frequent cause of ventilator dependence, we sought to examine the efficacy of five different ventilators in reducing this imposed work through the application of pressure support ventilation. Using a model of spontaneous breathing, we examined the apparatus work imposed by the Servo 900-C, Puritan Bennett 7200a, Engstrom Erica, Drager EV-A or Hamilton Veolar ventilators, a size 7.0 and 8.0 mm endotracheal tube, and inspiratory flow rates of 40 and 60 l/min. Pressure support of 0, 5, 10, 15, 20 and 30 cm H2O was tested at each experimental condition. Apparatus work was greater with increased inspiratory flow rate and decreased endotracheal tube size, and was lowest for the Servo 900-C and Puritan Bennett 7200a ventilators. Apparatus work fell in a curvilinear fashion when pressure support was applied, with no major difference noted between the five ventilators tested. At an inspiratory flow rate of 40 l/min, a pressure support of 5 and 8 cm H2O compensated for apparatus work through size 8.0 and 7.0 endotracheal tubes and the Servo 900-C and Puritan Bennett 7200a ventilators. However, the maximum negative pressure was greater for the Servo 900-C. The added work of breathing through endotracheal tubes and ventilator demand valves may be compensated for by the application of pressure support. The level of pressure support required depends on inspiratory flow rate, endotracheal tube size, and type of ventilator.

Optimizing fresh gas flow and circuit design for the delivery of continuous positive airway pressure.

OBJECTIVE: To examine the effect of varying circuit design and the fresh gas flow rate on the circuit work imposed by a continuous positive airway pressure (CPAP) circuit. DESIGN: Circuit work was measured during simulated inspiration (500 mL) with a lung model at inspiratory flow rates (V) of 40, 60, and 80 L/min during the administration of 10 cm H2O CPAP through either a modified Mapleson-A or modified Mapleson-D circuit, both alone and when connected to a face mask (i.e., simulating an intubated and nonintubated patient). Fresh gas flow was varied from 10 to 250 L/min. RESULTS: The minimum circuit work occurred at a fresh gas flow rate approximating V; however, circuit work was consistently lower for the modified Mapleson-A circuit compared with the modified Mapleson-D circuit. As the fresh gas flow rate was increased sequentially to 250 L/min, circuit work remained close to the minimum value for the modified Mapleson-A, but increased gradually with the modified Mapleson-D, e.g., from 0.017 kg.m/L at a fresh gas flow rate and V of 80 L/min to 0.035 kg.m/L at a fresh gas flow rate of 250 L/min and a V of 80 L/min. Rotation of the fresh gas flow inlet did not change the circuit work vs. fresh gas flow rate relationship. Addition of a face mask resulted in a smaller increase in circuit work for the modified Mapleson-D with increasing fresh gas flow rate. However, unlike the modified Mapleson-A circuit alone, the addition of a mask caused circuit work to increase with increasing fresh gas flow rate. CONCLUSIONS: The modified Mapleson-A circuit at a fresh gas flow rate equal to V minimizes circuit work, and hence represents an optimal CPAP circuit. The increases in circuit work at fresh gas flow rates above V that were found with the modified Mapleson-D circuit are not due to inertial differences, and are likely due to turbulent gas flow.

Serum surfactant protein-A levels in patients with acute cardiogenic pulmonary edema and adult respiratory distress syndrome.

Detection of alveolo-capillary damage has important implications for treatment modalities in ventilated patients. Although surfactant protein-A (SP-A) is normally only found in appreciable amounts in the lung, we describe significantly elevated concentrations in the sera of patients with acute cardiogenic pulmonary edema (median, 250 ng/ml; range, 180 to 364; n = 10) and in those with the adult respiratory distress syndrome (ARDS) (median, 378 ng/ml; range, 215 to 1,378; n = 15) relative to healthy control subjects (median, 175 ng/ml; range, 123 to 248; n = 15) and ventilated patients with no cardiorespiratory disease (median, 169 ng/ml; range, 126 to 253; n = 6) (p < 0.01, in all cases). Serum SP-A was inversely related to blood oxygenation and to static respiratory system compliance both at the time of the patient's entry into the study (p < 0.005, rs = -0.51, n = 31; p < 0.001, rs = 0.82, n = 17; respectively) and during the course of admission (p < 0.001, rs = -0.34, n = 168; p < 0.001, rs = -0.50, n = 111; respectively). In addition, we describe in detail three cases of ARDS where lung function either improved, remained static, or deteriorated. We conclude that serum SP-A is an acute indicator of lung function and alveolo-capillary membrane injury.

New generation ventilators.

Desirable features of new generation intensive care ventilators include the ability to ventilate a wide range of patient sizes, an uncomplicated control panel, an appropriate but not excessive variety of ventilatory patterns, adequate patient monitoring and alarm functions, and simplicity of cleaning and routine maintenance. Examples of currently available ventilators include the Servo 900-C, CPU-1, Engstrom Erica, Bear 5, Drager EV-A and Hamilton Veolar. The incorporation of microcomputer control into some of these ventilators has resulted in improved flexibility and a limited number of automatic responses to detected patient changes. However, the function of components provided to allow spontaneous ventilation, such as demand valves, requires considerable improvement. Current trends in ventilator design include further refinement of computer control and the provision of graphic displays showing the results of continuous sophisticated analysis of respiratory function. The extent to which these developments will prove clinically useful will require careful evaluation.

Partitioning lung and plasma proteins: circulating surfactant proteins as biomarkers of alveolocapillary permeability.

1. The alveolocapillary membrane faces an extraordinary task in partitioning the plasma and lung hypophase proteins, with a surface area approximately 50-fold that of the body and only 0.1-0.2 micron thick. 2. Lung permeability is compromised under a variety of circumstances and the delineation between physiological and pathological changes in permeability is not always clear. Although the tight junctions of the epithelium, rather than the endothelium, are regarded as the major barrier to fluid and protein flux, it is becoming apparent that the permeability of both are dynamically regulated. 3. Whereas increased permeability and the flux of plasma proteins into the alveolar compartment has dire consequences, fortuitously the flux of surfactant proteins from the airspaces into the circulation may provide a sensitive means of non-invasively monitoring the lung, with important implications for treatment modalities. 4. Surfactant proteins are unique in that they are present in the alveolar hypophase in high concentrations. They diffuse down their vast concentration gradients (approximately 1:1500-7000) into the circulation in a manner that reflects lung function and injury score. Surfactant proteins vary markedly in size (approximately 20-650 kDa) and changes in the relative amounts appear particularly diagnostic with regard to disease severity. Alveolar levels of surfactant proteins remain remarkably constant despite respiratory disease and, unlike the flux of plasma proteins into the alveolus, which may reach equilibrium in acute lung injury, the flux of surfactant proteins is unidirectional because of the concentration gradient and because they are rapidly cleared from the circulation. 5. Ultimately, the diagnostic usefulness of surfactant proteins as markers of alveolocapillary permeability will demand a sound understanding of their kinetics through the vascular compartment.

Endotoxin alters the systemic disposition of nitric oxide synthase inhibitors in the awake sheep.

1. We evaluated the haemodynamic effects and systemic disposition of the nitric oxide synthase (NOS) inhibitor NL-nitro-L-arginine (NOLA) after intravenous (i.v.) administration of two different doses (5 and 20 mg/kg) in awake healthy sheep and awake sheep given a continuous i.v. infusion of endotoxin (lipopolysaccharide, 12 ng/kg per h, i.v., for 18 h). In addition, we determined the systemic disposition of another NOS inhibitor, NL-nitro-L-arginine methylester (L-NAME; 20 mg/kg, i.v.) in awake healthy sheep only. 2. NL-Nitro-L-arginine produced a dose-dependent decrease in heart rate (HR) and cardiac output (CO) together with a dose-dependent increase in mean arterial pressure (MAP) and peripheral vascular resistance (PVR) when compared to baseline. In endotoxic sheep NOLA produced a greater increase in MAP and mean pulmonary arterial pressure (MPAP). 3. In healthy sheep there was a dose-related increase in total body clearance (Cl) of NOLA. The Cl increased from 0.028 L/min after the lower dose to 0.032 L/min after the higher dose. The infusion of endotoxin caused an increase in Cl of NOLA to 0.040 and 0.047 L/min, respectively, and a decrease in plasma slow half-life (t1/2) from 825 to 546 min and from 780 to 453 min, respectively. 4. NL-Nitro-L-arginine methylester was rapidly cleared from the plasma with a slow half-life of approximately 7.5 min and there was a simultaneous appearance of NOLA in the plasma. 5. These results support the view that nitric oxide has a significant role in regulating vascular tone in healthy and endotoxic sheep and indicate that the increases in Cl of NOLA with an increase in its dose and the presence of endotoxin will be important in influencing appropriate dosage regimens in clinical studies.

Surfactant proteins-A and -B are elevated in plasma of patients with acute respiratory failure.

Surfactant protein-A (SP-A) leaks into the circulation of patients with acute respiratory distress syndrome (ARDS) or acute cardiogenic pulmonary edema (APE) in a manner inversely related to lung function. Since surfactant protein-B (SP-B) is synthesized as a precursor considerably smaller than alveolar SP-A, we investigated whether it enters the circulation more readily. Reactivities consistent with SP-B proprotein (approximately 42 to approximately 45 kD) and the approximately 25 kD processing intermediate were detected in plasma. Plasma immunoreactive SP-B levels were significantly higher in ARDS (8,007+/-1,654 ng/ml [mean+/-SEM], n = 22) and APE (3,646+/-635 ng/ml, n = 10) patients compared with normal subjects (1,685+/-58 ng/ml, n = 33) and ventilated patients with no cardiorespiratory disease (1,829+/-184 ng/ml, n = 7). All groups had plasma SP-B/SP-A ratios approximately 6- to approximately 8-fold higher than in normal lavage or ARDS tracheal aspirate fluid, consistent with protein sieving. During admission, both plasma SP-B and the SP-B/SP-A ratio were inversely related to blood oxygenation (PaO2/FIO2) (p < 0.0001 and p < 0.025, n = 260 from 39 patients; Spearman) and static respiratory system compliance (deltaV/deltaP) (p < 0.0001 and p < 0.01, n = 168 from 25 patients). We describe in detail three patients and conclude that immunoreactive SP-B enters more readily than SP-A, is cleared acutely, and provides a better indicator of lung trauma.

Surfactant replacement therapy in ARDS: white knight or noise in the system?

Although one would predict that surfactant replacement therapy would be effective in acute respiratory distress syndrome (ARDS), a recent large trial proved unsuccessful, possibly reflecting the nature of the surfactant used. Given the importance of the unique proteins in the action of surfactant, these would seem vital components of any exogenous surfactant. The ability to identify patients at risk of ARDS and to characterise their surfactant might allow prophylactic treatment with a nebulised, complementary, tailor-made preparation of surfactant. Advanced cases might undergo bronchoscopic focal lavage to remove plasma proteins and inflammatory mediators prior to focal instillation of surfactant to areas of greatest need. Ventilation regimens might be adjusted both to minimise trauma and to conserve endogenous surfactant.