Aerosolised prostacyclin in adult
`respiratory distress syndrome
`
`We studied the effects of aerosolised prostacyclin (PGI2) in
`three patients with acute severe adult respiratory distress
`syndrome. 17-50 ng/kg per min, nebulised into the afferent
`limb of the ventilator circuit, decreased mean pulmonary artery
`pressure (SEM) from 40 3 (13 5) to 32-0 (3 8) mm Hg
`(pulmonary vascular resistance fell by 30%); systemic arterial
`pressure decreased slightly from 76 8 (2-2) to 74 5 (6 1)
`mm Hg. Concomitantly, the ratio of arterial oxygen partial
`pressure to the fraction of inspired oxygen increased from 120
`(19) to 173 (18), mainly due to redistribution of blood flow
`from shunt areas to regions of normal ventilation-perfusion. All
`effects were reversed on drug withdrawal.
`Lancet 1993; 342: 961-62
`
`See Commentary page 941
`
`Essential features of adult respiratory distress syndrome
`(ARDS) include pulmonary hypertension (its level being
`related to the severity of microvascular injury), high-
`permeability lung oedema, and ventilation (VA)-perfusion
`(Q) mismatch with a predominance of right-to-left
`shunting of venous blood. Infused vasodilatory
`prostanoids, such as prostacyclin (PG 12) and prostaglandin
`E, (PGE,), have decreased lung microvascular pressure and
`thereby reduced pulmonary fluid filtration and right heart
`afterload. 1,2 However, the lack of selectivity of infused
`prostanoids has meant that vasorelaxation occurs in both
`pulmonary and systemic vessels, and also in ventilated and
`non-ventilated lung regions. Results of investigations with
`inhaled nitric oxide in an experimental model of ARD S,3 in
`patients with severe ARDS,4 and in patients with
`pulmonary hypertension5,6 have suggested that this method
`of administration can overcome a vasodilator’s lack of
`selectivity; vasorelaxation was restricted to the pulmonary
`circulation, and the improvement in arterial oxygenation
`indicated that vasodilation was predominantly in well-
`ventilated lung areas. We describe the effect of aerosolised
`PGI2, a substance of known efficacy, on haemodynamics
`and gas exchange in three patients with severe ARDS.
`The patients’ underlying diseases were haemorrhagic
`necrotising pancreatitis (X, 62 years; 3 days’ mechanical
`ventilation), septicaemia with Candida albicans and pre-existing
`pulmonary hypertension (Y, 22 years; 2 days’ ventilation), and
`widespread acute pulmonary Wegener’s granulomatosis with
`nosocomial pneumonia (Z, 53 years, 2 days’ ventilation). All
`patients had arterial oxygen partial pressure/fraction of inspired
`oxygen (pa02/Fi02) values of less than 150 (A, 105/0-8; B, 98/0-7;
`C, 81/1-0) despite optimum ventilator settings for more than 24 h.
`Routine monitoring included use of thermodilution pulmonary-
`artery and femoral-artery catheters. Gas exchange was assessed by
`the multiple inert-gas-elimination technique.? VA/Q distributions
`
`were calculated from the retention and excretion values of sulphur
`hexalfluoride, ethane, cyclopropane, halothane, diethyl ether, and
`acetone. Shunt-flow was defined as the fraction of blood perfusing
`unventilated lung regions (Vp/Q ratio<0-005),
`low VA/0 was
`defined as the fraction of blood perfusion in poorly ventilated
`regions (where 0-005 < VA/Q ratio < 0-1), 0-1 to 10 was taken as the
`normal range of VA/Q ratios. PGI2 (Flolan, dissolved in glycine
`buffer) was aerosolised with a jet nebuliser, which was driven with
`oxygen at a pressure of 82 kPa. This nebuliser delivered aerosol
`particles with a mass median aerodynamic diameter of 2-7 11m
`(geometric standard deviation 2-1), as determined by a differential
`mobility analyser that was connected to a condensation nucleus
`counter. The aerosol was introduced into the afferent limb of the
`ventilator circuit. Oxygen in the aerosol mixture was balanced by
`reduction of both the pre-set ventilator tidal volume and the Fi02
`to maintain alveolar ventilation and inspired oxygen concentration
`(continuously monitored). Glycine buffer vehicle was aerosolised
`to obtain baseline values. Next, the PGI2 concentration in the
`buffer fluid was increased stepwise until there was a decrease in
`pulmonary artery pressure (PAP). PG 12 administration started at 5
`ng/kg per min and was increased to 17 (Y) and 50 (X and Z) ng/kg
`per min. Haemodynamics and gas exchange were assessed again
`(At in figure 1; done 25 min [Y] and 35 min [X and Z] after onset of
`PGI2 aerosol administration), and after 30 min continuous
`treatment with the maximum PGI2 dose (A2 in figure 1). The
`vehicle was then administered, and measurements made 60 and 120
`min after drug withdrawal. In the one patient with pre-existing
`
`Figure 1: Influence of PGI2 aerosol on haemodynamics and gas
`exchange
`PAP and SAP (mm Hg), cardiac output (CO, L/min), pa02/Fi02, and
`shunt-flow (% of perfusion) were assessed under baseline conditions
`( - 30, 0 min), during inhalation of PGI2 aerosol (Al, A,) and after
`withdrawal of the drug ( + 60, + 120 min) (8, patient X; ", Y; 8, Z).
`
`961
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`vasodilation, together with reduced shunt-flow and
`improved arterial oxygenation, in patients with severe
`ARDS strongly suggest that the trans bronchial route of
`application allows targeting of prostanoid activity to lung
`vessels in well-ventilated areas. As a consequence,
`redistribution of blood flow from non-ventilated to aerosol-
`accessible areas occurs, together with improved matching
`of ventilation and perfusion. The doses of nebulised PGI2
`needed to induce substantial pulmonary vasodilation
`(17-50 ng/kg per min) are only slightly greater than those
`reported for intravenous PGI2 (5-35 ng/kg per min).2,9 This
`finding is remarkable, since the aerosol fraction deposited
`in the alveolar spaces is estimated to range from 10 to 20%.
`The efficacy of aerosolised PG 12 we observed compares
`favourably with that of inhaled nitric oxide in a larger group
`of patients with ARDS.4 There was, however, a larger
`decrease in systemic vascular resistance during PGI2
`aerosolisation than during nitric oxide inhalation. The
`action of nitric oxide is assumed to be completely restricted
`to the lung vasculature because of instantaneous binding to
`haemoglobin and inactivation on entry to the vascular
`compartment 3,4 but an increase in the dose of aerosolised
`PGI2 might cause "spillover" of the prostanoid into the
`systemic circulation. Titration of aerosolised PGI2 in
`individual patients might be necessary to produce selective
`vasodilation in well-ventilated lung areas.
`
`We thank Dr J Gebhart for measuring particle size.
`
`1
`
`References
`M&eacute;lot CH, Lejeune PH, Leeman M, Moraine J-J, Naeije R.
`Prostaglandin E1 in the adult respiratory distress syndrome. Benefit for
`pulmonary hypertension and cost for pulmonary gas exchange. Am
`Rev Respir Dis 1989; 139: 106-16.
`2 Radermacher P, Santak B, W&uuml;st HJ, Tarrow J, Falke KJ, Prostacyclin
`and right ventricular functions in patients with pulmonary
`hypertension associated with ARDS. Intensive Care Med 1990; 16:
`227-32.
`3 Frostell C, Fratacci M-D, Wain JC, Jones R, Zapol WM. Inhaled
`nitric oxide. A selective pulmonary vasodilator reversing hypoxic
`pulmonary vasoconstriction. Circulation 1991; 83: 2038-47.
`4 Rossaint R, Falke KJ, L&oacute;pez F, Slama K, Pison U, Zapol WM.
`Inhaled nitric oxide for the adult respiratory distress syndrome. N Engl
`J Med 1993; 328: 399-405.
`5 Pepke-Zaba J, Higenbottam TW, Dinh-Xuan AT. Stone D, Wallwork
`J. Inhaled nitric oxide as a cause of selective pulmonary vasodilatation
`in pulmonary hypertension. Lancet 1991; 338: 1173-74.
`6 Kinsella JP, Neish SR, Shaffer E, Abman SH. Low-dose inhalational
`nitric oxide in persistent pulmonary hypertension of the newborn.
`Lancet 1992; 340: 819-20.
`7 Wagner PD, Saltzman HA, West JB. Measurement of continuous
`distributions of ventilation-perfusion ratios: theory. J Appl Physiol
`1974; 36: 588-99.
`8 Bihari D, Smithies M, Gimson A, Tinker J. The effects of vasodilation
`with prostacyclin on oxygen delivery and uptake in critically ill
`patients. N Engl J Med 1987; 317: 397-403.
`9 Higenbottam T. The place of prostacyclin in the clinical management
`of primary pulmonary hypertension. Am Rev Respir Dis 1987; 136:
`782-85.
`10 Hardy CC, Bradding P, Robinson C, Holgate ST. Bronchconstrictor
`and anti-bronchoconstrictor properties of inhaled prostacyclin in
`asthma. J Appl Physiol 1988; 64: 1567-74.
`
`Department of Internal Medicine, Justus-Liebig University Glessen,
`Klinikstrasse 36, D-6300 Glessen, Germany (D Walmrath MD,
`T Schneider MD, J Pilch MD, F Grimminger MD, Prof W Seeger MD)
`Correspondence to: Prof Werner Seeger
`
`Figure 2: Sequential application of PGI, via Intravenous and
`transbronchial route
`In a patient with pulmonary hypertension and septic ARDS (Y),
`haemodynamics and gas exchange were measured during an initial 30
`min baseline period, after 30 min infusion of PGI, (10 ng/kg per min), 30
`min after withdrawal of the intravenous PGI, (baseline 2), and 25 min
`after onset of administration PGIZ aerosol of up to 17 ng/kg per min.
`
`pulmonary hypertension (Y), the aerosolisation period was
`preceded by a therapeutic trial of intravenous PGI2 to reduce
`pulmonary vascular resistance (PVR).
`PGIz reduced PAP in all patients (figure 1, mean [SEM]
`of all PAP values 40-3 [13’5] mm Hg at baseline and 32 0
`[3’8] during PGI2 aerosol administration). Since cardiac
`output and pulmonary capillary wedge pressure were
`almost unchanged, this PAP reduction reflected a great
`decrease in pulmonary vascular resistance (from 385 [101] ]
`to 270 [53] dyn.s/cm - 5). However, a substantial decrease in
`arterial pressure occurred in only one patient, and the mean
`value decreased only slightly from 76-8 (2-2) to 74 5 (6.1)
`mm Hg. Pa02/Fi02, an index of the efficiency of arterial
`oxygenation, greatly increased in response to PGI2 aerosol
`administration in all patients (mean baseline values 119-5
`[19 3] at baseline and 173 [17 7] during aerosol
`administration 173 [17 ’7]). The multiple inert-gas analysis
`showed that this beneficial effect was mainly due to a
`pronounced reduction in the shunt fraction (figure 1).
`Blood flow was redistributed to normal VA/Q areas in two
`of the patients (increases of 5 6 and 8 6 % ), and to both low
`areas (increased by 12-5%) and normal VA/0 areas
`(increased by 2-7%) in patient Z. Deadspace ventilation,
`arterial pH, and carbon dioxide concentration remained
`constant within narrow ranges. After PGI2 withdrawal,
`PAP and gas-exchange variables returned to pre-treatment
`values within 60 min. In contrast to the effects of PGI2 2
`aerosol, a therapeutic trial with intravenous PG 12
`administration increased shunt-flow (figure 2) and induced
`pulmonary vasodilation.
`The vasomotor and cellular effects of short and long term
`intravenous administration of PGI2 are well known.8.9
`Previous investigations that used aerosolised PGI2 in
`1 J.1g/kg per min)
`human beings (nebulised doses up to >
`addressed the bronchodilatory effect of this agent;10
`detailed studies of its effect on lung vasculature have not
`been reported. Our observations of pulmonary
`
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`Liquidia's Exhibit 1048
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