Sixteen rabbits were anaesthetized and subjected to saline lavage of the lungs to produce surfactant deficiency. This resulted in an arterial oxygen tension of less than 12 kPa on 100% inspired oxygen and an inflection point on the pressure-volume curve at a pressure of 8-12 mmHg. After lavage the animals were randomly assigned to receive either conventional mechanical ventilation (CMV) with a positive end-expiratory pressure (PEEP) of 1-2 mmHg (group I - low PEEP) or CMV with PEEP equal to the inflection point pressure (group II - high PEEP). Mean airway pressures were kept at 14-16 mmHg in both groups by increasing the inspiratory:expiratory time ratios in the low PEEP group. The 5-h protocol was completed by 4 animals in group I and 6 animals in group II, early death usually being associated with a metabolic acidosis. On 100% oxygen, the mean PaO2 at 2-h post-lavage was 15.2 +/- 8.3 kPa in group I and 39.6 +/- 21.8 kPa in group II. Group I had much lower end-expiratory lung volumes (3.0 +/- 1.5 ml above FRC) than group II (34.9 +/- 12.2 ml above FRC). Histological examination of the lungs revealed significantly less hyaline membrane formation in group II (p = 0.001). Thus, the prevention of alveolar collapse by the use of high PEEP levels appears to reduce lung damage in this preparation.

Lung lavage was performed in 16 anaesthetized rabbits to produce surfactant-deficient lungs. This resulted in alveolar collapse, an arterial PO2 of less than 15 kPa on 100% oxygen and an inflection point on the inspiratory limb of the pressure-volume curve at an airway pressure of 8-10 mm Hg. One group of eight animals was then ventilated with a positive end-expiratory pressure (PEEP) equal to the pressure at the inflection point, whilst the second group of eight was ventilated with a PEEP 5 mm Hg less than the inflection point. Animals in the high PEEP group had a significantly greater arterial PO2 than those in the low PEEP group, but the mean survival time for each group was similar. However, there was a significantly greater incidence of hyaline membranes in the low PEEP group. Various mechanisms to explain these findings are discussed.

The first pass uptake, metabolism and recovery of bupivacaine were examined in an intact rabbit lung model using a multiple indicator technique with rapid sequential sampling. The rabbits were allocated to an acidotic group (pH 7.0-7.1) (n = 8) and a control group (n = 10) with normal pH. Bupivacaine recovery rates were not significantly different: median 93.2% (range 48.9-116.5%) and 94.5% (54.9-123.1%) in control and acidotic groups, respectively. Median peak percentage fractional concentrations of bupivacaine were greater in the acidotic group: 6.22% (2.5-7.65%) vs 4.1% (2.5-6.7%) (P less than 0.05). Median maximum instantaneous pulmonary percentage extraction was less in the acidotic animals than in animals with normal pH: 81.2% (47.1-91.9%) vs 91.0% (82.6-94.5%) (P less than 0.01). Median normalized mean percentage transit time was less in the acidotic group (245.3% (163.4-465.3%)) than in the control group (423.9% (313.9-740.4%)) (P less than 0.01). There was no evidence for bupivacaine metabolism by the lung. The results suggest that acidosis reduced bupivacaine lung uptake and increased its rate of passage through the lung, but did not influence overall drug recovery rates. This has clinical implications for bupivacaine related cardiac and cerebral toxicity.

A double indicator technique has been used in an in situ isolated perfused rabbit lung model to examine the first pass effect of the lung on systemic bupivacaine concentrations. Bupivacaine (0.5 mg/kg) was given in two consecutive boluses to six in situ isolated perfused New Zealand White rabbit lung preparations. The mean recovery (first bolus) of bupivacaine was 62.6% +/- 6.3 (S.E.M.), and 63.7% +/- 10.2 (second bolus), suggesting bupivacaine accumulation in the lung. The average mean transit time for bupivacaine was 280.5% +/- 24.1 and 264.8% +/- 36.7 longer than ICG (Indocyanine Green) following the first and second boluses respectively (P less than 0.01). There were no differences in the first pass effect of the lung between the first and second boluses of bupivacaine. The profiles of the bupivacaine concentrations suggest that uptake is followed by accumulation and later back diffusion. This has implications for conditions that decrease the uptake and therefore increase the risk of systemic toxicity.

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