Acute Severe Asthma: Pathophysiology and Pathobiology of Gas Exchange Abnormalities

Home , Acute (medicine), Acute severe asthma, Bohr effect, Dead space (physiology), Haldane Effect, Mucus

SERIES 'CLINICAL PHYSIOLOGY IN RESPIRATORY INTENSIVE CARE' Edited by A. Rossi and C. Roussos Number 16 in this Series Acute severe asthma: pathophysiology and pathobiology of gas exchange abnormalities

R. Rodriguez-Roisin

Acute severe asthma: pathophysiology and pathobiology of gas exchange abnormali- Servei de Pneumologia i Al.lèrgia Resp- ties. R. Rodriguez-Roisin. ERS Journals Ltd 1997. iratòria, Dept de Medicina, Hospital Clínic, ABSTRACT: Acute severe asthma, or "status asthmaticus", is a devastating clin- Universitat de Barcelona, Barcelona, Spain ical condition ultimately resulting in life-threatening hypoxaemia. The pivotal Correspondence: R. Rodriguez-Roisin, intrapulmonary mechanism of this condition is profound ventilation/perfusion Servei de Pneumologia i Al. lèrgia Respira- (V ’A/Q ’) mismatch, characterized by a predominant bimodal blood flow pattern tòria, Dept de Medicina, Hospital Clínic, reflecting a marked deterioration (increase) of the dispersion of pulmonary blood Universitat de Barcelona, Barcelona, Spain flow. This V’A/Q’ profile is consistent with the presence of numerous alveolar units with low V’A/Q’ ratios, in which ventilation is markedly reduced, although never Keywords: Airway mediators, anti-asth- abolished, but perfusion is maintained. Further V’A/Q’ worsening whilst breath- ma drugs, bronchial circulation, fatal and near-fatal asthma, platelet activating fac- ing 100% O2 suggests the presence of an underlying vigorous hypoxic vascular response. Of equal importance, gas exchange disturbances are poorly related to tor, ventilation-perfusion mismatching the severity of reduced maximal airflow rates. Received: April 8 1997 Inhaled platelet-activating factor (PAF), both in normal individuals and asth- Accepted for publication April 16 1997 matic patients, results in moderate-to-severe disturbance of V’A/Q’ status, a finding that is probably related to altered microvascular permeability within the Supported by Grants from the Comissionat airway wall. Salbutamol, but not ipratropium bromide, prevented all PAF-induced per a Universitats i Recerca (1995 SGR systemic and lung function abnormalities, possibly because venoconstriction in the 00446) de la Generalitat de Catalunya and bronchial circulation was antagonized. Taken together, these findings support the the Fondo de Investigación Sanitaria (FIS) hypothesis that platelet-activating factor may play a critical role in the pathobi- 97/0126. ology of severe acute exacerbations of asthma. Eur Respir J 1997; 10: 1359Ð1371.

Bronchial asthma is a chronic disease that causes aemia with or without hypercapnia [1]. All asthmatic widespread narrowing of the conducting airways. It is patients are susceptible and at risk of developing acute universally accepted that short-term variability of air- severe asthma (ASA) (status asthmaticus), a life-threat- way narrowing is the hallmark of bronchial asthma. ening condition leading to impending acute severe res- Airway inflammation and bronchial hyperresponsive- piratory failure and even, to death [2]. Near-fatal or fatal ness, together with airflow obstruction, are pivotal patho- asthma is a catastrophic, devastating clinical condition genetic components of asthma and have been included that occurs despite increased understanding of its patho- in its current definition. Although airway inflammation physiology and pathogenesis, a better awareness of the and reactivity are not unique to asthma and may be com- main therapeutic guidelines, and important current ach- mon in other chronic airway conditions, the critical ievements in the preventive and educational aspects of issue in bronchial asthma is the specific type of airway asthma. inflammation and its interplay with airway responsiveness. Clinical framework In patients with asthma, during acute attacks, arterial oxygen and carbon dioxide (Pa,O2 and Pa,CO2) values can One important, but difficult, question to answer is range from nearly normal or slightly abnormal to extre- how and why asthmatic patients die during an episode mely altered, ultimately resulting in profound hypox- of severe exacerbation, particularly outside a medical

Previous articles in this series: No. 1: S.K. Pingleton. Enteral nutrition in patients with respiratory disease. Eur Respir J 1996; 9: 364Ð370. No. 2: R. Dhand, M.J. Tobin. Bronchodilator delivery with metered-dose inhalers in mechanically-ventilated patients. Eur Respir J 1996; 9: 585Ð595. No. 3: N. Ambrosino. Noninvasive mechanical ventilation in acute respiratory failure. Eur Respir J 1996; 9: 795Ð807. No. 4: P. Pelosi, S. Crotti, L. Brazzi, L. Gattinoni. Computed tomography in adult respiratory distress syndrome: what has it taught us? Eur Respir J 1996; 9: 1055Ð1062. No. 5: H. Burchardi. New strategies in mechanical ventilation for acute lung injury. Eur Respir J 1996; 9: 1063Ð1072. No. 6: V.M. Ranieri, M. Dambrosio, N. Brienza. Intrinsic PEEP and cardiopulmonary interactions in patients with COPD and acute ventilatory failure. Eur Respir J 1996; 9: 1283Ð1292. No. 7: A. Corrado, M. Gorini, G. Villella, E. De Paola. Negative pressure ventilation in the treatment of acute respiratory failure: an old noninvasive technique reconsidered. Eur Respir J 1996; 9: 1531Ð1544. No. 8: A. Torres, M. El-Ebiary, N. Soler, C. Montón, N. Fàbregas, C. Hernández. Stomach as a source of colonization of the respiratory tract during mechanical ventilation: association with ventilator-associated pneumonia. Eur Respir J 1996; 9: 1729Ð1735. No. 9: J. Mancebo. Weaning from mechanical ventilation. Eur Respir J 1996; 9: 1923Ð1931. No. 10: D. Georgopoulos, C. Roussos. Control of breathing in mechanically ventilated patients. Eur Respir J 1996; 9: 2151Ð2160. No. 11: T. Vassilakopoulos, S. Zakynthinos, Ch. Roussos. Respiratory muscles and weaning failure. Eur Respir J 1996; 9: 2383Ð2400. No. 12: G.U. Meduri. The role of the host defence response in the progression and outcome of ARDS: pathophysiological correlations and response to glucocorticoid treatment. Eur Respir J 1996; 9: 2650Ð2670. No. 13: H.E. Fessler. Heart-lung interactions: applications in the critically ill. Eur Respir J 1997; 10: 226Ð237. No. 14: S. Singh, T.W. Evans. Nitric oxide, the biological mediator of the decade: fact or fiction. Eur Respir J 1997; 10: 699Ð707. No. 15: W.T. McNicholas. Impact of sleep in respiratory failure. Eur Respir J 1997; 10: 920Ð933. 1360 R. RODRIGUEZ-ROISIN environment. Conceivably, the mechanisms involved categorized by SUR et al. [12] as "sudden-onset" fatal may be multifactorial. However, in a study of 10 patients asthma, as opposed to the more common "slow-onset" with asthma, who reached the hospital in respiratory form, to highlight a different aetiopathogenic mecha- arrest or had overt respiratory failure within less than nism and, possibly, a specific underlying structural de- 30 min after admission to the casualty room in spite of rangement of the airway. vigorous conventional medical therapy, MOLFINO et al. Respiratory alkalosis is the most common acid-base [3] postulated that the near-fatal nature of these exac- abnormality in severe acute conditions, although, as erbations was the result of severe asphyxia. At the time asthma worsens, this results in respiratory or mixed aci- of respiratory arrest, while oxygen was given by T-tube dosis due to hypercapnia and associated lactic acidosis or breathing bag mask, these patients exhibited extreme in peripheral tissues. Patients with more severe CO2 hypercapnia, Pa,CO2 >8.0 kPa (60 mmHg) in all cases, retention (Pa,CO2 >12.0 kPa (90 mmHg)) and respiratory and intense mixed acidosis. It was concluded that the acidosis (pH <7.0) can show dramatic subconjunctival near-fatal nature of these episodes of ASA was the result haemorrhage, possibly due to sudden and severe con- of severe asphyxia, i.e. unconsciousness or death result- gestion of blood flow into the territory of the superior ing from lack of oxygen, rather than cardiac arrhyth- vena cava, resulting from raised intrathoracic airway mias related to the side-effects of antiasthma drugs, more pressures in order to overcome massive and widespread β specifically 2-agonists. The asphyxia or hypoxaemia airway narrowing [13]. Although not common, its pre- hypothesis, previously suggested by others [4], would sentation should alert physicians as a sign of impend- point to undertreatment rather than overtreatment, which ing ASA. had been indicated by detrimental cardiac effects as one Similarly, patients with an acute exacerbation of asth- of the principal factors implicated in the increased num- ma, who have become profoundly hypercarbic and hypox- ber of patients with fatal asthma. aemic, may have critically raised intracranial pressure How common are abnormal arterial blood gas tensions [14]. It has recently been proposed that acute intracra- in patients with ASA? A review based on the analysis nial pressure-induced uncal herniation and third cranial of routine gas exchange data in over 350 critically sick nerve palsy, causing a single dilated pupil, can be devel- patients in the 1970s revealed that only 2% had Pa,O2 oped by a combination of acute hypercapnia, cerebral values <6.7 kPa (50 mmHg), while 13% of patients had hypoxia and high intrathoracic pressures. It can be ex- a Pa,CO2 of 6.0Ð8.0 kPa (45Ð60 mmHg) and only 4% of pected that extreme hypercapnia would create maximal patients >8.0 kPa (60 mmHg) [2]. Nevertheless, the cerebral vasodilation, hence increasing intracranial vol- clinical severity of the attacks was variable, with no uni- ume and causing hypoxaemia, acidosis, marked cellular form criteria among the different reports published. For swelling and, as a consequence of elevated intrathoracic instance, in a more recent study in patients with ASA, pressure, limitation of cerebral venous drainage [14]. within the first 24 h of their admission to the hospital, In many historical studies using respiratory gas ten- five out of ten patients (of whom only one required sion [15, 16], a positive linear relationship has been mechanical ventilation) had Pa,O2 values <6.7 kPa (50 shown between Pa,O2, or a hyperbolic relationship bet- mmHg) and two had Pa,CO2 levels >6.0 kPa (45 mmHg) ween Pa,CO2, and forced expiratory volume in one sec- whilst breathing room air [5]. In another study [6], in- ond (FEV1). However, FEV1 above 1.0 L is not a reliable cluding 18 patients with ASA, Pa,O2 was <6.7 kPa (50 predictor of the Pa,O2, and this is also true for the rela- mmHg) in two patients and Pa,CO2 >6.0 kPa (45 mmHg) tionship between Pa,CO2 and FEV1. In principle, the in two out of nine patients admitted to hospital (within less than 6 h) under similar breathing conditions. Pat- 200 ients with ASA presenting with hypercapnia when attend- ing the hospital had features of more severe persistent asthma and more severe airway narrowing; had a longer 150 duration of asthma; were more prone to require maintenance treatment both with β-adrenergic agonists and steroids; and were less likely to have been previously 100 in and discharged from the emergency room [7]. These % baseline data are compatible with the view that hypercapnia in ASA can evolve rapidly, and is not necessarily related to 50 a prolonged attack. Patients with sudden "asphyxic" asthma, defined as a rapidly progressing attack associated with extreme res- 0 piratory failure needing mechanical support very quick- 0 2 468 1428 ly (within less than 3 h of the onset of symptoms) [8], Time course days ❍ show a severe mixed acidosis with intense hypercap- Fig. 1. Ð Time course of changes in FEV1 ( ), Pa,O2 ( ) nia. This condition may be caused either by massive and V'A/Q' mismatch ( ) (as assessed by the dispersion of pulmonary blood flow), expressed as percentage of change from admis- inhalation of airborne soybean dust [9] or thunderstorm sion, in a representative patient with ASA while breathing room air. activity [10], or associated with sensitivity and expo- Note that the improvement of FEV1 precedes that of Pa,O2 and V'A/Q' sure to other allergens, such as Alternaria alternata imbalance. FEV1 increases immediately and progressively during hos- [11], or a stressful event, with a higher incidence of res- pitalization, whereas the two gas exchange indices remain unchanged, piratory arrest but a more rapid remission, with a short- to markedly improve after discharge. This pattern was shown in 7 of the 8 patients studied. FEV1: forced expiratory volume in one sec- er duration of mechanical ventilation. These fulminant, ond; Pa,O2: arterial oxygen tension; V 'A/Q ': alveolar ventilation/per- calamitous, dismal presentations of ASA have been fusion; ASA: acute severe asthma. (Taken with permission from [5]). GAS EXCHANGE IN ACUTE SEVERE ASTHMA 1361

greater the airway obstruction the worse the gas exchange; Pa,CO2, but increased values of alveolar-arterial differ- and yet this need not be the case. In a sequential study ence in oxygen tension (P(A-a),O2) values [1, 20]. This of patients with ASA, we identified a complete dissoci- is due to the buffering effect that an inordinately high ation between airflow rates and gas exchange markers, cardiac output, which is a distinctive feature of many both while admitted to hospital and during remission critically ill asthmatic patients, has on Pa,O2 [20]. Alter- after discharge [5]. Moreover, airflow rates recovered natively, patients with life-threatening ASA, with [21] more readily than gas exchange disturbances during or without [5, 6, 18] the need for mechanical ventila- hospitalization, the latter improving only after discharge tion, exhibit the most grossly abnormal profile of the (fig. 1). Similarly, in children admitted to hospital for V'A/Q' spectrum, namely a bimodal pattern of the pul- ASA, arterial O2 saturation (Sa,O2) is low at admission, monary blood flow distribution (fig. 2). Accordingly, a and reflects bronchodilation with salbutamol only when O2 saturation is low. Sa,O2 recovers more slowly than a) 1.5 airway function, and also more quickly in younger chil- 30% dren than in older children [17]. Lack of improvement dead or worsening of gas exchange [18], whilst airflow rates space increase following the conventional administration of 1.0 different classes of bronchodilators in patients with ASA, is further compelling evidence of this intriguing dissociation of behaviour between spirometry and pulmonary gas exchange. 0.5 0% shunt Pathophysiology 0

In recent years, there has been major progress in -1 b) 0.75 understanding the pathophysiological mechanisms of pulmonary gas exchange in bronchial asthma, largely thro- 27% dead ugh the information provided by the multiple inert gas space elimination technique (MIGET), a robust tool for the 0.50 quantitative and qualitative assessment of the distribution of V'A/Q' ratios in the lung [1, 19]. Of equal importance, MIGET provides a quantum leap forward to unravelling the complex interaction among the different 0.25 intrapulmonary determinants, namely V'A/Q' imbalance, 0% increased intrapulmonary shunt and alveolar-to-end- shunt

capillary diffusion limitation to O2, and extrapulmonary and blood flow L·min Ventilation 0 determinants (essentially inspired O2 fraction (FI,O2), overall ventilation, cardiac output and O2 consumption) c) 0.50 that modulate the physiological blood gas values in the clinical arena [19]. 33% At present, it is largely undisputed that V'A/Q' mis- dead match is the pivotal mechanism leading to abnormal space arterial blood gas values, being the primary factor that modulates the varying levels of arterial hypoxaemia. 0.25 Carbon dioxide retention during ASA can also be, in part, associated with V 'A/Q ' inequality, although it is likely that alveolar hypoventilation related to respira- 0% tory muscle fatigue and/or weakness can also play a key shunt role. However, detecting respiratory fatigue in patients with critically life-threatening asthma is not easy with 0 the technology currently available. By contrast, both 00.001 0.01 0.1 1 10 100 increased intrapulmonary shunting and alveolar-to-end- Ventilation-perfusion ratio capillary diffusion limitation to O2, the two other intrapulmonary factors influencing pulmonary gas exchange, Fig. 2. Ð Three profiles of V'A/Q' distribution plotted against a V'A/ are conspicuously marginal. Q' ratio on a log scale while breathing room air (FI,O2 0.40, during A wide variety of V 'A/Q ' inequalities has been de- mechanical support): a) normal; b) ASA while breathing spontaneous; monstrated in the different categories of asthma. At one c) ASA during mechanical ventilation. The narrowing unimodal, well-centred and symmetrical distribution in a healthy young indi- end of the spectrum, patients with mild-to-moderate vidual differs from the predominant bimodel blood flow pattern of asthma may have nearly normal, mildly broadened uni- the two patients with ASA. The dispersion of ventilation is discrete- modal distributions of the pulmonary perfusion, hence ly broadened, intrapulmonary shunt is conspicuously lacking, and increasing the dispersion of blood flow, i.e. a functional dead space is normal in the abnormal V'A/Q' distributions. Note that there are no major V'A/Q' profile differences between the two latter. outcome of V'A/Q' inequality sensitive to areas of both FI,O2: inspired oxygen fraction. For further definitions see legend to below normal and low V'A/Q' ratio, with normal or near- figure 1. ❍ : ventilation; : blood flow. (Taken with per- ly normal Pa,O2 and a normal or slightly decreased mission from [16, 19]). 1362 R. RODRIGUEZ-ROISIN large percentage of cardiac output is distributed to alve- increases of intrapulmonary shunting (in general, below olar units with poor or very poor V'A/Q' ratios, in keep- 5% of cardiac output), it is not uncommon to observe ing with the presence of numerous alveoli in which the presence of high V'A/Q' units, alone or combined ventilation is moderately to extremely reduced, altho- with the former profile, possibly influenced by under- ugh always patent, while perfusion is preserved or even lying gas-trapping, lung hyperinflation, intrinsic posi- increased. In between, there can be patients with mod- tive end-expiratory pressure (PEEPi), and also areas of erate-to-severe persistent categories of asthma [1] with pulmonary emphysema [23]. varying degrees of V'A/Q' heterogeneity, albeit always Overall, V 'A/Q ' inequalities in patients with ASA affecting the dispersion of pulmonary perfusion more concur with the historical concept of gas exchange ab- profoundly, according to the underlying severity of the normalities [15]. In the classical three-compartment structural derangement. lung model, the effects both of an increased venous ad- In general, the more severe the attack of asthma the mixture ratio (Q'S/Q'T) and physiological dead space/tidal worse the V'A/Q' imbalance. Accordingly, patients with volume ratio (VD/VT) were considered to reflect the stable asthma, either with intermittent or persistent forms, gross extent of the underlying V'A/Q' abnormalities. The have broadened unimodal pattern of pulmonary blood increased Q'S/Q'T keeps pace with the presence of in- flow [1], whilst those presenting with acute severe or creased areas of low V 'A/Q ' ratios, i.e. increased dis- fulminant forms [21] generate a predominantly bimodal persion of pulmonary blood flow. However, while the blood flow profile as the most distinctive V'A/Q' pattern. virtual absence of areas of high V'A/Q' ratio, including However, it is likely that the high inspired O2 concen- inert dead space, is consistent with previous studies in trations that may, at least in part, mitigate hypoxic adult asthma, this is an unexpected feature in patients pulmonary vasoconstriction (HPV), and the added phar- with ASA, in whom gas-trapping, with increased intra- macological effects of high doses of β-adrenergic ago- alveolar pressures induced by check-valve mechanisms, nists and methylxanthines, with potential pulmonary could be present. Hyperinflation would reduce perfu- vasodilating effects, may both contribute to an increase sion of such lung areas, thus inducing the development in the presence of areas with low V'A/Q' ratios. Teleologi- of areas with high V'A/Q' ratio, by causing formation cally, HPV is a phenomenon that minimizes the amount of West's zones 1, where alveolar pressure exceeds pul- of V'A/Q' heterogeneity, and hence the ensuing hypox- monary capillary pressure [24]. aemia. Conceivably, in patients with severe persistent At first glance, inert dead space is always slightly asthma, the severity of widespread airway narrowing is lower than that calculated with the Bohr equation, be- akin to a small V'A/Q' mismatch, because distal small cause the latter does not include the dead space-like airways may be either remodelled or distressed by less effects of lung units with a carbon dioxide tension inflammatory changes or have a more vigorous HPV, (PCO2) less than the Pa,CO2 [19]. Increased overall ven- or both [1]. In contrast, in ASA, the airway inflamma- tilation augments physiological dead space, other things tory involvement may be more dynamic and probably being equal. However, the absence of an increased inert located both proximally and distally, hence resulting in dead space shown in ASA still remains elusive. High a preferentially bimodal pattern of pulmonary perfusion. V'A/Q' regions have been demonstrated only in children In a canine model of multiple airway occlusion, LEE with low FEV1 after exercise-induced asthma [25], the et al. [22] showed that when small airways (1.6 mm in contention being that both gas-trapping and lung hyper- diameter) are occluded, collateral ventilation to distal inflation would provoke areas of high V'A/Q' ratio. alveolar units is so efficient that ventilation is only Because arterial hypoxaemia is essentially provoked slightly altered; however, as occlusion becomes more by V'A/Q' mismatching, a clinical implication of prac- proximal, collateral ventilation is less effective until, tical relevance is that it can be corrected promptly by with beads 4.8 mm in diameter, the ventilation of dis- increases in FI,O2 (i.e. 0.24Ð0.40), without major unex- tal units is so poor that a bimodal V'A/Q' pattern deve- pected side-effects. While breathing 100% O2, it is of lops. Although anatomical differences between human note that, from a pathophysiological viewpoint, there is and dog lung need to be considered, these experimen- further worsening of V'A/Q', solely as a consequence of tal findings suggest that the bimodal blood flow profile marked increase in the dispersion of blood flow. This seen in human asthma concurs with near complete ob- suggests that HPV is attenuated even in the absence struction of some airways, and that the levels of airway of accompanying pulmonary haemodynamic changes. narrowing may affect the V'A/Q' pattern. Through the mechanisms of vascular recruitment and A cardinal point of clinical interest is that, irrespec- dilatation, the pulmonary vascular bed may redistribute tive of the extent of V'A/Q' abnormalities, whilst breath- blood flow without influencing standard flow-pressure ing room air or low FI,O2, the presence of increased outcomes, but still provoking further worsening in some intrapulmonary shunt is always trivial, even in the most of the markers of V'A/Q' imbalance. life-threatening conditions of ASA. The distribution In contrast, the distribution of alveolar ventilation de- (dispersion) of alveolar ventilation, representing basi- creases (improves) during mechanical ventilation but cally lung regions above normal and high V'A/Q' ratio, increases (worsens) during spontaneous breathing, pos- is minimally increased (impaired), at least compared to sibly reflecting a different hypoxic vascular response the deterioration of the distribution of blood flow, and related to ventilatory support, since blood flow can be inert dead space is not increased. redistributed to areas with high or low V 'A/Q ' ratios, During severe acute exacerbations or even under sta- respectively. Moreover, in patients with ASA needing ble clinical conditions, patients with chronic obstruc- mechanical ventilation, a moderate amount of increas- tive pulmonary disease (COPD) may exhibit a similar ed intrapulmonary shunt is shown (below 10% of cardiac low V 'A/Q ' pattern. However, with mild-to-moderate output) upon breathing 100% O2 [21], an uncommon GAS EXCHANGE IN ACUTE SEVERE ASTHMA 1363 finding in patients with chronic obstructive and restric- V 'A/Q ' imbalance in hyperventilated normal canine tive respiratory diseases [26]. This points to the deve- lungs is pH-mediated and is not a function of PCO2 per lopment of reabsorption atelectasis and/or to a marked se [35]. increase in regional blood flow of small pre-existing The hypoxic pulmonary pressor tone was almost intrapulmonary shunts [21]. completely abrogated with elevation of pH to 7.60 by a

During high FI,O2, there were significant increases metabolic alkalosis, and a respiratory alkalosis at a simi- in Pa,O2 (>60 kPa (450 mmHg)) and also in Pa,CO2, lar pH resulted in a 70% decrement of the HPV respon- although much less dramatic (of the order of 0.4Ð0.7 se [36]. Of equal importance, increases in extracellular kPa (3Ð5 mmHg)). Taken together, these arterial blood pH may also adversely disturb pulmonary gas exchange gas findings suggest further V 'A/Q ' worsening, altho- by causing deterioration in pulmonary mechanics and ugh the additional influence of a Haldane effect is also the distribution of ventilation. Hypocapnia induces bron- plausible. In patients with COPD, irrespective of the choconstriction of airways of all sizes and reduces col- need for mechanical ventilation, 100% O2 breathing al- lateral ventilation, a mechanism of vital importance in ways results in deterioration (increase) in the dispersion the maintenance of the V 'A/Q ' balance [37]. Calcium of blood flow, without altering the basal modest levels channels are important both in hypocapnia-induced con- of shunt, hence suggesting release of HPV [27]. However, traction of airway smooth muscle and hypoxic vascular in some critical cases of ASA, increases and decreases contraction of the lungs. Because calcium channels are in Pa,CO2 have been reported with application and remo- pH-dependent, it has been hypothesized that changes val of 100% O2, suggesting a depressant effect on ven- in calcium influx may profoundly influence the under- tilation similar to that observed in patients with COPD lying alkalosis-induced changes in V'A/Q' heterogene- [2]. However, this behaviour appears to be similar to ity [35]. that shown by near-fatal cases of asthma during epi- Approximately 90% of the variation in both Pa,O2 and sodes of respiratory arrest [3], and may merely reflect P(A-a),O2 values is accounted for by V'A/Q' imbalance profound alveolar hypoventilation due to extreme res- in patients with asthma [20]. However, baseline Pa,O2 piratory muscle fatigue. values can be considered exceptionally high consider- Although some experimental studies have suggested ing the underlying degree of V 'A/Q ' inequality. This that variations in FI,O2 may influence airway responses suggests that some well-known extrapulmonary factors, to bronchoconstrictor and bronchodilator stimuli [28], such as cardiac output or overall minute ventilation, or acute hyperoxia does not enhance the immediate bron- both, modulate Pa,O2 in addition to V'A/Q' mismatch [38, chodilator response to nebulized β-adrenergic agonists 39]. In critical ASA patients, both cardiac output and in stable asthmatic patients [29]. However, the poten- minute ventilation tend to be increased for reasons that tial influence of 100% O2 breathing on airway tone and are not yet completely understood, thus optimizing the the response of V 'A/Q ' heterogeneity in patients with baseline values of Pa,O2, which would otherwise be ASA should also be taken into account, as bronchial much lower due to the deleterious effects of V'A/Q' in- hyperresponsiveness can be minimized in patients with equalities. This helps to increase Pa,O2 in patients with asthma [30]. A hyperoxic bronchodilator response could asthma, either at baseline or following therapeutic inter- increase regional ventilation in poorly-ventilated alve- ventions with bronchodilators [1, 18]. olar units, hence increasing local blood flow and improv- This hyperkinetic status could be related, at least in ing gas exchange. A local reduction of pulmonary blood part, to the increased levels of exhaled nitric oxide (NO) flow without influencing the hypoxic vascular response found in patients with ASA [40, 41]. High levels of has been observed in response to canine antigen chal- exhaled NO, reflecting induction of NO synthase, may lenge [31]. This would tend to reduce the impact of have proinflammatory effects, since NO is a potent vaso- local V'A/Q' mismatch, other things being equal. dilator and can enhance plasma exudation from bron- It has been shown experimentally in normal lungs chial vessels. Patients with asthma show a greater V'A/Q' that hypocapnia can cause a deterioration of V'A/Q' rela- mismatch than patients with idiopathic pulmonary fib- tionships, suggesting that HPV is abrogated; in contrast, rosis [26] or heart failure [39]. However, Pa,O2 is much hypercapnia does not result in significant changes in lower in the latter two conditions, usually due to a low V'A/Q' heterogeneity [32]. In patients with severe acute cardiac output together with a mild-to-modest V 'A/Q ' respiratory failure needing mechanical ventilation, meta- heterogeneity, rather than as a consequence of extreme bolic alkalosis further disturbs V'A/Q' imbalance; and, V 'A/Q ' mismatch alone. Although there are different conversely, reversing this effect with hydrochloric acid mechanisms by which cardiac output can modulate pul-

(HCl) results in an improvement in Sa,O2 [33], possibly monary gas exchange, one of the most influential is via related to the pH of the circulating blood rather than to its effect on mixed venous oxygen tension (Pv,O2), since the nature of HCl. The acidosis-induced amelioration low cardiac output reduces Pa,O2, other things being of gas exchange has been attributed to a dual mecha- equal [38, 39]. nism: firstly, to a shift of the oxyhaemoglobin dissoci- As described above (see "Clinical framework"), the ation curve caused by the Bohr effect; secondly, and supposition that there is a peculiar dissociation between more importantly, to an improvement of V 'A/Q ' mis- spirometry and gas exchange in asthma has been streng- match, possibly by enhancing HPV through a redistri- thened by more recent findings, in which differences bution of blood flow away from hypoxic lung areas. in the time course and severity of bronchoconstriction Altogether, these findings are compatible with the con- and gas exchange were shown in patients with ASA cept that acidosis and alkalosis, respectively, enhance according to whether they were admitted to hospital or and mitigate the hypoxic vascular response of the lungs discharged home [6]. Whilst hospitalized patients, in [34]. Likewise, it has been shown that hypocapnia-induced general, showed greater functional abnormalities than 1364 R. RODRIGUEZ-ROISIN

a) Bronchial asthma 100

80 Spirometric Gas exchange 60 abnormalities abnormalities

40 Central Distal airway narrowing airway narrowing 20 ' au

Q '/

p<0.05 V 0 Bronchoconstriction Airway Inflammation

and b) 1 Fig. 4. Ð Pathophysiological interactions between airflow obstruc- 100 tion and gas exchange abnormalities in asthma. FEV

80 Conceivably, these exciting findings reflect two different pathophysiological phenomena, and are consistent with the view that spirometric abnormalities reflect 60 reduction of airway calibre in larger and middle-sized bronchi, whilst gas exchange abnormalities, more spec- 40 ifically V'A/Q' mismatch, refer predominantly to structural changes in distal, small airways. Thus, the latter 20 changes could be more preferentially related to airway inflammation rather than to airflow obstruction per se p=0.32 (fig. 4). Overall, airway narrowing and pulmonary gas 0 exchange are poorly related, both in individual patients 1 3–5 14 21 28 and within a clinically similar category of asthma pati- Time course days ents across the entire spectrum of asthma severity [20].

Fig. 3. Ð Time courses of improvement of FEV1 ( ❍ ) and From this weak relationship between spirometry and V'A/Q' inequality ( ) (as assessed by the dispersion of pul- gas exchange, it is clear that closer attention should be monary blood flow): a) in patients with ASA in hospital; and b) in given to gas exchange abnormalities in the clinical man- patients discharged home, while breathing room air. Variables are agement of these patients. Moreover, these findings expressed in special arbitrary units (au): 100=the least abnormal value; 0=the most abnormal value. When hospitalized patients appro- indicate that spirometric data alone may provide neither ached their maximal improvement in FEV1 at Week 2, V'A/ Q' mis- an adequate delineation of clinical remission, nor a clear match was still at 60% of its best value; by contrast, in discharged identification of those patients at risk of developing ser- patients both spirometric and gas exchange abnormalities are similar ious gas exchange deterioration [20]. Accordingly, it and overlap. For definitions see legend to figure 1. (Taken with permission from [6]). would be worthwhile to optimize knowledge of the relative importance of bronchoconstriction, inflammatory those sent home, only the former exhibited a more rapid oedema, microvascular leakage and luminal mucous se- and efficient recovery of spirometric changes compared cretion within airways on gas exchange, because the to V'A/Q' inequalities (fig. 3). From these data, it can pharmacological approach to these different pathophys- be postulated that patients with ASA who are discharg- iological features would clearly be different [20]. Never- ed from the emergency room have less airway inflam- theless, it is extremely difficult to establish a true cause matory changes and, with adequate therapy, improve and effect relationship in human asthma to support this more readily than those hospitalized, who in turn need dissociation between airflow rates and gas exchange out- more time to improve their functional status as they comes. have more severe airway inflammation. These findings also support the concept that the more severe the attack of asthma, the more severe the obstructive narrowing in Pathology distal airways for a given degree of widespread airway narrowing. In a model of bronchoconstriction in the Gas exchange disturbances are broadly consistent with rabbit, similar V'A/Q' abnormalities to those shown in postmortem lung findings in patients with ASA. In such human asthma, but without increased airway resistance, patients, the degree of widespread bronchoconstriction, have been simulated with nebulized isotonic saline [42]. together with the varying airway inflammatory events, Suffice it to say, that this reinforces the intriguing dis- leads to the development of extensive areas of alveolar sociation between spirometric and gas exchange find- units in which ventilation is critically reduced but per- ings in the setting of asthma. In contrast, in a sequential fusion is maintained. As mentioned above (see "Patho- study in patients with an acute exacerbation of COPD, physiology"), increased intrapulmonary shunting is BARBERË et al. [23] observed a parallel behaviour of re- conspicuously negligible, possibly because the presence duced maximal airflow rates and ventilation-perfusion of collateral ventilation, from relatively undisturbed ad- disturbances. jacent alveoli, preserves regional ventilation beyond the GAS EXCHANGE IN ACUTE SEVERE ASTHMA 1365 distal occluded airways. Two other mechanisms must increased airway inflammation. This can be attributed also be borne in mind to explain the practical absence to a combination of lesions that may occur during an in- of shunt: firstly, the finding that airway obstruction can flammatory process, including vascular hyperaemia, plas- never be functionally complete; and, secondly, the ex- ma exudate, and inflammatory cell infiltrate. Another ceptional efficacy of an active HPV. interesting finding was that part of the airway lumen was In a seminal study, DUNNILL [43] described the classi- occluded and part was empty, such that these patients cal findings in patients dying of ASA. The airways were could be considered intermediate between those having characteristically blocked by viscous, tenacious mucus mucous plugging and those showing dry airways, as within an acutely distended lung parenchyma; gross em- described by REID [45]. Likewise, the muscular pul- physema was absent. Many airways were completely monary arteries close to occluded and inflamed airways occluded by mucous plugging, composed of eosinophils did not show the morphological changes of chronic hy- and epithelial cells. Histologically, there was an incre- poxia, and yet, there was an extreme inflammatory wall ase in smooth airway muscle with hyperplasia and hy- involvement that was particularly remarkable at the sites pertrophy in the major airways. Shedding of the ciliated of contact of vessels and airways. This may support bronchial wall cells, mainly eosinophils, was prominent the notion that the severe inflammatory airway process and attributed to a transudation of oedematous fluid from spreads over the neighbouring vessel, as has been shown the submucosa. Apart from the bronchial infiltration of in patients with early COPD [46]. Whether or not these eosinophils, the most extraordinary finding in the air- inflammatory changes may influence the hypoxic vas- way wall was "...the dilatation of the capillary blood cular response of these vessels remains to be determined. vessels, often possessing rather swollen endothelial Interestingly, using both endobronchial and trans- cells, closely applied to the basement membrane. The bronchial biopsies, KRAFT et al. [47] have recently dem- connective tissue in which these vessels lie consists of onstrated that, in patients with stable persistent asthma, strands of widely separated collagen giving the impres- the inflammatory response involves not only proximal sion of oedema. Moreover, the mucosa overlying these airways but also distal airways, more specifically the areas often shows oedema with separation of the cells..." alveolar tissue. Similarly, marked goblet cell hyperpla- (fig. 5). This quote, more than any other, appears to be sia in peripheral airways has been suggested as a pre- one of the best descriptions of the abnormally increa- dominant characteristic feature of patients who die of a sed airway vascular permeability in asthma. severe attack of asthma [48]. Marked goblet cell hyper- Recent postmortem lung studies have further exten- plasia may be involved in the intraluminal accumula- ded some of the correlations between pathology and tion of large amounts of mucus in peripheral airways, both clinical and physiological findings. SAETTA et al. and is likely to produce impairment of mucociliary trans- [44] showed that the calibre of bronchioles was narrow- port and ion transport across the epithelium, and epithe- er than that of controls. Bronchioles of fatal asthmatic lial damage. Mucus retention is enhanced by a decrease patients had increased luminal occlusion, smooth mus- in the number and length of the cilia in peripheral air- cle thickness, and inflammatory infiltrate, and mononu- ways and in the rate of mucus transport with increas- clear cells and eosinophils contributed together to this ing airway branching [48]. It has been shown that "sudden-onset" fatal asthma is immuno- logically distinct from "slow-onset" asthma, the latter having more eosinophils and fewer neutrophils in the airway submucosa. This suggests perhaps, two different pa- thological entities triggered by different inflammatory stimuli and resulting in distinct mechanisms of extreme airway narrowing [12]. These findings are akin to those shown by AZZAWI et al. [49], who reported that levels of activated eosinophils were significantly higher in asthmatic patients whose fatal attack had a duration of more than 24 h compared with those who died suddenly. These sudden fatal episodes may occur against a background of persistent airway inflammation and structural derangement; moreover, those with the most extreme structural chang- Fig. 5. Ð Histological section of airway (A) plugging in a patient with fatal asthma. There is thick- es, such as mucous gland hypetro- ening of the reticular basement membrane, a subepithelial zone of inflammatory cells surrounded by increased amounts of bronchial smooth muscle, and marked dilatation of the network of bronchial phy, will have the most devastating vessels and their engorgement with blood (arrows). Internal scale bar=100 µm. (With kind permission of response [50]. Patients with fatal P.K. Jeffery, Lung Pathology Unit, National Heart & Lung Institute, Imperial College, London, UK). soybean asthma have diminished 1366 R. RODRIGUEZ-ROISIN numbers of CD3+ and CD8+ T-cells in the airway epi- such as histamine, the cysteinyl leukotrienes, LTC4, LTD4 thelium and submucosa compared with fatal asthma cases and LTE4, and PAF, and also neural-derived mediators, [51]. However, there were no differences in the num- e.g. substance P (SP), neurokinin A and B (NKA, NKB), bers of mast cells, eosinophils and neutrophils in rela- and calcitonin gene-related peptide (CGRP). PAF is a tion to basal asthma severity or to the pattern of fatal phospholipid that induces neutropenia, bronchoconstric- attack. No differences have been observed between sud- tion, and abnormal airway microvascular leakage, pos- den-onset soybean epidemic asthma and slow-onset sibly through postcapillary venoconstriction in the nonepidemic asthma patients both in the degree of sev- tracheobronchial circulation. Thus, microvascular leak- erity and extent of V'A/Q' im-balance [9, 21]. age of plasma is an inflammatory hallmark of para- mount relevance in asthma, generally referred to as Pathobiology abnormally increased vascular permeability. A substan- tially increased number of PAF receptors are reported Despite the fact that overall airway structural chang- in the lungs of asthmatic individuals [52]. Collectively, es concur essentially with the development of V'A/Q' ab- all these findings lend further support to the view that normalities, the intrinsic mechanism by which V'A/Q' PAF may be of particular relevance to the pathogene- heterogeneity may occur in bronchial asthma still resis of asthma. mains uncertain. It is currently believed that multiple Because of its wide range of vascular effects, we pos- mediators and their interactions are implicated in the tulated that PAF could disturb pulmonary gas exchange pathogenesis of asthma. A vast literature exists to sup- in patients with mild asthma. Challenge with a small port the view that, in the inflamed airway, a large num- dose (12 µg) of PAF moderately increased the resis- ber of chemically different cell mediators are released tance of the respiratory system (Rrs) within 5 min after from many sources. The way in which these substances inhalation [53]. Simultaneously, Pa,O2 decreased slightly, provoke smooth muscle contraction and disrupt airway while there was a significant increase in the P(A-a),O2, liquid balance illustrates a complex mechanism, where- changes that were caused entirely by V'A/Q' heterogene- by inflammation can cause influx of plasma into the air- ity, in a pattern similar to that commonly shown in pati- way wall and lumen by acting directly on endothelial ents with varying categories of asthma (fig. 6). Similar and epithelial permeability. findings, although using a higher dose of PAF (24 µg), Although new inflammatory mediators are contin- were replicated in healthy individuals [54]. ually being detected, numerous vasoactive agents have The question arises as to whether PAF-induced V'A/Q' already been identified, including cell-derived mediators, imbalance may be related to bronchoconstriction or a) 9 b) 110

8 100

·s 7 -1 90

O·L 6 2 * * * mmHg 80 5 2 * a,O cmH P rs 70

R 4 3 60 0 0 c) 70 d) 20 60 50 15 2 ' 40 * Q '/ 10

V * (A-a),O 30 * P 20 5 10 0 0 Baseline 5 15 45 Baseline 5 15 45 Post-PAF min Post-PAF min

Fig. 6. Ð Individual time course of the four most relevant functional outcomes (V 'A/Q ' mismatch is represented by a dimensionless overall index of V'A/Q' heterogeneity), altered by PAF challenge in six patients with mild asthma. a) resistance of the respiratory system (Rrs); b) arterial oxygen tension (Pa,O2); c) alveolar-arterial difference in oxygen tension (P(A-a),O2); d) ventilation/perfusion (V'A/Q') mismatch. PAF-induced V'A/Q' relationships were extremely disturbed in one patient but less so in four, and were unchanged in the remaining patient. Solid bars repre- sent means. *: p<0.05 versus baseline. PAF: platelet-activating factor. (Taken with permission from [50]). GAS EXCHANGE IN ACUTE SEVERE ASTHMA 1367

250 Thirdly, pretreatment with inhaled salbutamol (300 µg) profoundly blocked PAF-induced effects on pul- 200 monary neutrophil sequestration [60, 61], Rrs and gas exchange disturbances, as well as systemic effects, namely, facial flushing, dyspnoea, feeling of warmth 150 and cough, both in normal humans [62] and in patients with mild asthma [63]. These findings are unlikely to 100 be interpreted as a smooth muscle relaxation alone, and contrast, in some aspects, with former data showing that a lower dose of salbutamol (200 µg) in normal subjects

Gas exchange % baseline 50

∆ failed to prevent PAF-induced disturbances [64]. Sim- ilarly, we have shown that pretreatment with inhaled 0 ipratropium bromide, at a maximal bronchodilating dos- 0 25 50 75 100 125 age (80 µg), antagonized only the PAF-induced increases ∆ Rrs % baseline of Rrs without altering neutropenia, gas exchange abnor- Fig. 7. Ð Plots of gas exchange indices and Rrs before and after PAF malities or systemic effects [63]. ( ) and methacholine ( ), expressed as percentage change (∆%) from baseline, in two populations of mild asthmatics. Values If the effects of PAF in our asthma model are pref- are presented as mean±SEM. Gas exchange responses, representing erentially related to enhanced microvascular exudation either increases in P(A-a),O2 or V 'A/Q ' mismatch (as assessed by an of protein-rich plasma, then the protective role shown overall index of V 'A/Q ' heterogeneity), were of the same order of by salbutamol supports the view that the effect of this magnitude. For further explanation, see text. For definitions see leg- β end to figure 6. (Taken with permission from [50]). 2-adrenergic agonist may be accomplished by preven- ting postcapillary venoconstriction of the bronchial cir- altered microvascular-epithelial plasma exudation. It culation. Mediators that increase abnormal vascular is of note, however, that the effects of inflammatory med- permeability operate directly on the venular wall endothe- iators on vascular permeability may, in part, induce lium [65Ð68], possibly by altering normal cell-to-cell bronchoconstriction through airway smooth muscle contact at distinct locations in the wall of the postcap- plasma-derived peptides. Therefore, both mechanisms illary venules (7–80 µm in diameter). The mechanism may conceivably contribute together to widespread air- of this interendothelial gap (hole) formation has been way narrowing, hence leading to the development of widely accepted as a contractile phenomenon provok- V'A/Q' inequality. However, we suggest that the PAF- ing wide clefts intercellularly, irrespective of the chem- induced V'A/Q' abnormalities are related more to altered ical composition of the mediator and whether the target airway vascular permeability than to airway constric- is within or around the vessel. tion, based on several pieces of information. These gap junctions are unique to endothelial chang- The first evidence is based on the comparison of the es after exposure to intravenous histamine [69]. The tar- immediate effects of methacholine (MCh) [55] (which get cells for inflammatory mediators have, thus, been has a primary effect on airway smooth muscle) and PAF identified as venular endothelial cells, and their con- on Rrs and gas exchange markers (both arterial blood traction has been suggested to support mediator-induced gas values and V'A/Q' inequalities) in patients with mild leakage of molecules and other substances. Non-sieved asthma (fig. 7). The slope was shifted rightwards and plasma would escape, via these holes in the venular downwards after MCh, as a markedly increased Rrs was wall, into extravascular sites, under the influence of the associated with moderate worsening of gas exchange, hydrostatic pressure gradient, hence abolishing the col- but leftwards and upwards after PAF, as mild increa- loidal osmotic pressure gradient between the lumen of ses of Rrs combined with moderate deterioration of gas the microvessels and the interstitial space of the airway exchange. This indicates that MCh-induced intense wall [68]. Bronchial blood flow changes will alter both bronchoconstriction per se does not cause much V 'A/ the delivery of plasma and white cells and the micro- Q' imbalance and, alternatively, that the effect of PAF vascular hydrostatic pressure; similarly, the bronchial on V'A/Q' relationships is unlikely to be explained on circulation may be extremely augmented in the inflam- the basis of profound bronchoconstriction alone. Asth- ed airway, hence increasing the hydrostatic pressure in matic patients develop greater airway obstruction after venules, resulting in local exudation and subsequent PAF challenge (30 µg as a single dose) than normal sub- hyperaemia [70]. The hydrostatic pressure of the bron- jects; however, MCh is much more sensitive than PAF chial microvasculature depends both on the arterial and at discriminating between asthmatic and healthy sub- venous pressures and also on the ratio of post- to pre- jects [56]. microvascular resistance [70]. Secondly, RUBIN et al. [57] demonstrated that inhaled Plasma exudate in the lumen of the airway in asthma PAF, at doses similar to those we have used in healthy may contribute to epithelial sloughing, disturbances in individuals [54], induced very little change in FEV1, of mucociliary transport, narrowing of distal airways and the order of 5% in normals and 10% in asthmatics, in mucous plugging. Alternatively, exuded plasma may comparison to relatively larger increases in more sen- produce airway inflammation and constriction, since it sitive tests of airway dysfunction. Although PAF may includes potent mediators, and both chemoattractant in- produce airway narrowing by inducing bronchial wall gredients and plasma proteins may facilitate the release oedema in addition to airway smooth muscle contrac- of mediators by the numerous airway inflammatory tion, PAF has either no effect [58] or discrete but varia- cells involved in asthma in the presence of stimuli that ble effects on the contraction of isolated human airways would otherwise be harmless to the cells. Exuded plas- [59]. ma may, thus, by a direct effect on a variety of target 1368 R. RODRIGUEZ-ROISIN

β cells and by recruitment and conditioning of inflam- long-acting 2-agonist induced a similar effective anti- matory cells, enhance the process that escalates and sus- oedema effect, whether plasma exudation was increased tains airway inflammation [67]. by cell-mediated mediators (PAF) or neuron-mediated β The relative absence of airway oedema usually obser- mediators (SP) [75]. In contrast, another long-acting 2- ved in histological specimens may be explained, in part, agonist, salmeterol, given over a 1 week period, did not by migration of plasma exudate into the airway lumen. inhibit the effects of PAF inhalation in normal indivi- Furthermore, abnormal airway microvascular leakage duals, possibly because of the induction of tachyphy- may amplify the bronchoconstrictor response by several laxis related to repeated dosing [77]. The absence of a mechanisms, such as increasing mucosal and/or sub- transient increase of pulmonary artery pressure after mucosal thickness, interfering with the mechanical pro- PAF challenge in our PAF model both in normal man perties of the airway wall, uncoupling of the airway [54] and asthmatic patients [53] does not preclude a ven- from the surrounding lung parenchyma, and/or filling oconstrictor effect of inhaled PAF, since, as mentioned of airway interstitial spaces, which together result in above (see "Pathophysiology"), HPV can be attenuated decreased calibre and increased resistance of the distal without necessarily inducing pulmonary haemodyna- airways [69]. Nevertheless, it is not possible to differ- mic changes by itself [21]. entiate the relative contribution of a leaky microvas- Alternatively, the transient sequestration of neutro- culature, vascular engorgement and/or fluid shift from phils within the pulmonary circulation after PAF [60, neighbouring cellular compartments to the extracellular 61], whose intrinsic mechanism remains to be deter- engorgement [69]. Mild oedema within the airway wall mined, also provides indirect evidence of a release of the would only marginally decrease the baseline airway cal- venular smooth muscle tone by salbutamol, hence redu- ibre, but could profoundly increase airflow resistance cing leucocyte transit time and their trapping within during simultaneous bronchoconstriction. Experimen- the pulmonary capillary network. By the same token, tal engorgement of the bronchial vasculature in a sheep salbutamol could also prevent the ensuing release of model led to an increase in the vascular area in regions other mediators into the pulmonary circulation, with within and around the smooth muscle layer, whilst the potential local vasodilator effects that can disturb the associated reduction of luminal area only followed in V'A/Q' balance [62, 63]. It is important to point out that, the presence of airway smooth muscle tone [71]. This irrespective of the baseline V 'A/Q ' status, the well- suggests that vascular hyperaemia induces a reflex effect known pulmonary vasodilator effect of salbutamol can on the airways and by itself plays only a marginal role still be compatiable with its impact on further V'A/Q' on airway narrowing. worsening shown in ASA [18]. Adherence of white cells Likewise, the venular endothelial cell can be the target to the endothelium, with subsequent migration across the for drugs with antiexudative effects by direct vascular vascular wall, is a prominent feature of the inflamma- antipermeability mechanisms [72]. Bronchodilators, such tory response. Although we ignore the potential effects β as 2-agonists and theophylline, may have the ability to of salbutamol on cellular adhesion at the endothelial minimize or antagonize airway inflammatory challenge- level, other plausible mechanisms, such as lung hyper- induced plasma exudation responses [73]. Conceivably, inflation due to PAF-induced bronchoconstriction cau- salbutamol, but not ipratropium bromide, could dimin- sing capillary compression, are unlikely to play a key ish hydrostatic pressure in the airway capillary network, role. Development of areas of high V 'A/Q ' has never hence reducing the degree of airway submucosal and been observed, either in normals [54] or asthmatics [53] adventitial swelling and the subsequent reduction of cal- after inhalation of PAF; neither has diffusion limi- ibre in distal airways, resulting in V'A/Q' heterogene- tation for O2 potentially induced by neutrophil lung ity [63]. Moreover, salbutamol causes vasodilation that sequestration. Finally, the abolition by salbutamol of the can increase the post- to premicrovascular resistance PAF-induced systemic effects, attributed to the subse- ratio of the bronchial circulation [70], hence decreasing quent release of other substances possibly derived from the hydrostatic pressure and subsequent plasma exuda- neutrophils, could also be related to its preventive effects tion. Based on the hypothesis of endothelial contraction, on pulmonary neutrophil kinetics. salbutamol would, thus, have enhanced the ability of Increased plasma levels of PAF have been documen- endothelial cells to minimize and/or close PAF-induced ted during mild exacerbations of asthma both in adults gap junctions, probably by facilitating their relaxation. [78] and children [79], whereas decreased in vivo and Although this contention also concurs with the inhibi- in vitro productions of PAF have been shown in chil- β tory effects of 2-agonists, in the guinea-pig, on PAF- dren after immunotherapy [79]. Moreover, we have seen induced [74, 75] and histamine-induced [76] disrupted the salutary effect of a new PAF receptor antagonist, airway permeability and acute plasma exudation, the SR 27417A, on PAF-induced lung function abnorma- efficacy of its potent airway relaxant influence on smooth lities, including systemic effects and neutropenia (unpub- muscle cannot be overlooked. The prevention of vascu- lished data). These findings confirm that these types of lar leakage provoked by some drugs cannot be expec- drugs specifically antagonize leakage produced by cor- ted to have a rapid reversal, possibly because the rate responding agonists. However, because postcapillary of resolution of interstitial fluid is dependent mainly on venules harbour specific receptors for a wide variety of the relatively slow lymphatic drainage. However, if the inflammatory mediators, it is unlikely that a single med- enhanced bronchomotor tone is dependent on a contin- iator antagonist alone can display an effective overall uous supply of activated plasma proteins from adjacent anti-exudative therapeutic response in asthma. The effi- leaky microvessels, then an anti-oedema effect might cacy shown by SR 27417A is at variance with the ap- reverse the airway narrowing more rapidly. parent negative data formerly observed with other Similarly, in the rat trachea, acute inhalation of a classes of PAF antagonist, which did not provide definite GAS EXCHANGE IN ACUTE SEVERE ASTHMA 1369 evidence that PAF is a vital mediator in asthma [80]. 8. Wasserfallen JB, Schaller MD, Feihl F, Perret C. Sud- This suggests that the effects of PAF antagonists should den asphyxic asthma: a distinct entity? Am Rev Respir be investigated in other categories of asthma, for in- Dis 1990; 142: 108Ð111. stance in patients with ASA [81], or that other func- 9. Ferrer A, Torres A, Roca J, Sunyer J, Antó JM, Rodriguez- tional outcomes, such as gas exchange markers, should Roisin R. Characteristics of patients with soybean dust- be used to better identify the potential anti-oedema induced acute severe asthma requiring mechanical effect of the airways. ventilation. Eur Respir J 1990; 3: 429Ð433. 10. Murray V, Venables K, Laing-Morton T, Partridge M, Williams D. Epidemic of asthma possibly related to Concluding remarks thunderstorms. BMJ 1994; 309: 131Ð132. 11. O'Hallaren MT, Yunginger JW, Offord KP, et al. Exposure Both in normal subjects and in patients with asth- to an aeroallergen as a possible precipitating factor in ma, challenge with platelet-activating factor induces re- respiratory arrest in young patients with asthma. N markable gas exchange abnormalities due to ventilation/ Engl J Med 1991; 324: 359Ð363. perfusion mismatch, a hallmark of primary clinical rele- 12. Sur S, Crotty TB, Kephart GM, et al. Sudden-onset fatal vance in acute severe asthma, similar to those detected asthma. A distinct entity with few eosinophils and rel- in patients with moderate-to-severe categories of asthma. atively more neutrophils in the airway submucosa. Am Of equal importance, a highly recommended corner- Rev Respir Dis 1993; 148: 713Ð719. stone of the therapeutic guidelines of asthma, salbuta- 13. Rodriguez-Roisin R, Torres A, Agusti AGN, Ussetti P, mol, but not ipratropium bromide, has been shown to Agusti-Vidal A. Subconjunctival haemorrhage: a feature of acute severe asthma. Postgrad Med J 1983; 61: be highly effective in inhibiting all platelet-activating 579Ð581. factor-induced systemic, neutropenic, lung mechanical 14. Dimond JP, Palazzo MGA. An unconscious man with and gas exchange responses. Collectively, these find- asthma and a fixed, dilated pupil. Lancet 1997; 349: 98. ings could support the supposition that endogenous rel- 15. McFadden ER Jr, Lyons HA. Arterial blood gas ten- ease of platelet-activating factor may be incriminated in sions in asthma. N Engl J Med 1968; 278: 1027Ð1032. the gas exchange disturbances seen during acute severe 16. Tai E, Read J. Arterial-blood gas tension in asthma. asthma. Lancet 1967; i: 644Ð646. The generally accepted criteria for judging the rele- 17. Mihatsch W, Geelhoed GC, Landau LI, LeSouëf PN. vance of a mediator in asthma should be: 1) produced Time course of change in oxygen saturation and peak by cells involved in the asthmatic damage; 2) capable expiratory flow rate in children admitted to hospital of mimicking some aspects of its pathophysiology; 3) with acute asthma. Thorax 1990; 45: 438Ð441. recoverable naturally or induced by disease; and 4) ame- 18. Ballester E, Reyes A, Roca J, Guitart R, Wagner PD, liorating the disease through inhibition of its action or Rodriguez-Roisin R. Ventilation-perfusion mismatching synthesis [82]. This tentative pathogenic notion of plate- in acute severe asthma: effects of salbutamol and 100% let-activating factor needs to be further investigated to oxygen. Thorax 1989; 44: 258Ð267. thoroughly support whether or not this inflammatory 19. Roca J, Wagner PD. Contributions of multiple inert gas mediator plays a putative role in the pathobiology of elimination technique to pulmonary medicine. 1. Princi- asthma, a hypothesis often invoked but never conclusi- ples and information content of the multiple inert gas vely proven. elimination technique. Thorax 1994; 49: 815Ð824. 20. Wagner PD, Hedenstierna G, Rodriguez-Roisin R. Gas exchange, expiratory flow obstruction and the clinical spectrum of asthma. Eur Respir J 1996; 9: 1278Ð1282. References 21. Rodriguez-Roisin R, Ballester E, Torres A, Roca J, Wagner PD. Mechanisms of abnormal gas exchange in 1. Rodriguez-Roisin R, Roca J. Contributions of multiple patients with status asthmaticus needing mechanical inert gas elimination technique to pulmonary medicine. ventilation. Am Rev Respir Dis 1989; 139: 732Ð739. 3. Bronchial asthma. Thorax 1994; 49: 1027Ð1033. 22. Lee LN, Ueno O, Wagner PD, West JB. Pulmonary gas 2. McFadden ER Jr, Hejal R. Asthma. Lancet 1995; 345: exchange after multiple airway occlusion by beads in 1215Ð1220. the dog. Am Rev Respir Dis 1989; 140: 1216Ð1221. 3. Molfino NA, Nannini LJ, Martelli AN, Slutsky AS. Res- 23. Barberà JA, Roca J, Ferrer A, et al. Mechanisms of piratory arrest in near-fatal asthma. N Engl J Med 1991; abnormal gas exchange during acute exacerbations of 324: 285Ð288. chronic obstructive pulmonary disease. Eur Respir J 4. Rebuck AS, Read J. Assessment and management of 1997; 10: 1285Ð1291. severe asthma. Am J Med 1971; 51: 788Ð798. 24. West JB, Dollery CT, Naimark A. Distribution of blood 5. Roca J, Ramis LI, Rodriguez-Roisin R, Ballester E, flow in isolated lung: relation to vascular and alveolar Montserrat JM, Wagner PD. Serial relationships bet- pressures. J Appl Physiol 1964; 19: 713Ð724. ween ventilation-perfusion inequality and spirometry in 25. Freyschuss U, Hedelin G, Hedenstierna G. Ventilation- acute severe asthma requiring hospitalization. Am Rev perfusion relationships during exercise-induced asthma Respir Dis 1988; 137: 1055Ð1061. in children. Am Rev Respir Dis 1984; 130: 888Ð894. 6. Ferrer A, Roca J, Wagner PD, Lopez FA, Rodriguez- 26. Agustí AGN, Barberà JA. Contributions of multiple Roisin R. Airway obstruction and ventilation-perfusion inert gas elimination technique to pulmonary medicine. relationships in acute severe asthma. Am Rev Respir 2. Chronic pulmonary disease: chronic obstructive pul- Dis 1993; 147: 579Ð584. monary disease and idiopathic pulmonary fibrosis. Thorax 7. Mountain RD, Sahn SA. Clinical features and outcome 1994; 49: 924Ð932. in patients with acute asthma presenting with hyper- 27. Rodriguez-Roisin R, Roca J. Gas exchange in COPD. capnia. Am Rev Respir Dis 1988; 138: 535Ð539. In: Calverley PMA, Pride NB, eds. Chronic Obstructive 1370 R. RODRIGUEZ-ROISIN

Pulmonary Disease. London, Chapman & Hall, 1994; 46. Barberà JA, Riverola A, Roca J, et al. Pulmonary vas- pp. 161Ð184. cular abnormalities and ventilation-perfusion relation- 28. Clayton RA, Nally JE, Thomson NC, McGrath JC. The ships in mild chronic obstructive pulmonary disease. Am effect of oxygen tension on responses evoked by metha- J Respir Crit Care Med 1994; 149: 423Ð429. choline and bronchodilators in isolated bovine bronchial 47. Kraft M, Djukanovic R, Wilson S, Holgate ST, Martin rings. Pulm Pharmacol 1996; 9: 123Ð128. RJ. Alveolar tissue inflammation in asthma. Am J Res- 29. Dagge KD, Thomson LJ, Ramsay SG, Thomson NC. pir Crit Care Med 1996; 154: 1505Ð1510. Effect of acute hypoxia on the bronchodilator response 48. Aikawa T, Shimura S, Sasaki H, Ebina M, Takishima to salbutamol in stable asthmatic patients. Thorax 1996; T. Marked goblet cell hyperplasia with mucus accumu- 51: 853Ð854. lation in the airways of patients who died of acute 30. Inoue H, Inoue C, Okayama M, Sekizawa K, Hida W, severe asthma attack. Chest 1992; 101: 916Ð921. Takishima Y. Breathing 30 percent oxygen attenuates 49. Azzawi M, Johnston PW, Majumdar S, Kay AB, Jeffery bronchial responsiveness to methacholine in asthmatic PK. T-lymphocytes and activated eosinophils in airway patients. Eur Respir J 1989; 2: 506Ð512. mucosa in fatal asthma and cystic fibrosis. Am Rev 31. Grant BJB, Fortune JB, West JB. Effect of local anti- Respir Dis 1992; 145: 1477Ð1482. gen inhalation and hypoxia on lobar blood flow in aller- 50. Carroll N, Carello S, Cooke C, James A. Airway struc- gic dogs. Am Rev Respir Dis 1980; 122: 39Ð46. ture and inflammatory cells in fatal attacks of asthma. 32. Domino KB, Swenson ER, Polissar NL, Lu Y, Eisenstein Eur Respir J 1996; 9: 709Ð715. BL, Hlastala MP. Effect of inspired CO2 on ventilation 51. Synek M, Antó JM, Beasley R, et al. Immunopathology and perfusion heterogeneity in hyperventilated dogs. J of fatal soybean dust-induced asthma. Eur Respir J Appl Physiol 1993; 75: 1306Ð1314. 1996; 9: 54Ð57. 33. Brimioulle S, Kahn RJ. Effects of metabolic acidosis on 52. Shirasaki H, Nishikawa M, Adcock JM, et al. Expres- pulmonary gas exchange. Am Rev Respir Dis 1990; 141: sion of platelet-activating factor receptor mRNA in human 1185Ð1189. and guinea-pigs. Am J Respir Cell Mol Biol 1994; 10: 34. Nattie EE. Gas exchange in acid-base disturbances. In: 533Ð537. Fahri LE, Tenney SM, eds. Handbook of Physiology. 53. Félez MA, Roca J, Barberà JA, et al. Inhaled platelet- Vol. 4. The Respiratory System: Gas Exchange. Bethe- activating factor worsens gas exchange in mild asthma. sda; American Physiological Society, 1987; pp. 421Ð438. Am J Respir Crit Care Med 1994; 150: 369Ð373. 35. Domino KB, Swenson ER, Hlastala MP. Hypocapnia- 54. Rodriguez-Roisin R, Félez MA, Chung FK, et al. Plate- induced ventilation-perfusion mismatch: a direct CO2- let-activating factor causes ventilation-perfusion mis- or pH-mediated effect? Am J Respir Crit Care Med match in humans. J Clin Invest 1994; 93: 188Ð194. 1995; 152: 1534Ð1539. 55. Rodriguez-Roisin R, Ferrer A, Navajas D, Agustí AGN, 36. Brimioulle S, Lejeune P, Vachiéry JL, Leeman M, Mélot Wagner PD, Roca J. Ventilation-perfusion mismatch C, Naeije R. Effect of acidosis and alkalosis on hypox- after methacholine challenge in patients with mild bron- ic pulmonary vasoconstriction in dogs. Am J Physiol chial asthma. Am Rev Respir Dis 1991; 144: 88Ð94. 1990; 258: H347ÐH353. 56. Louis RE, Radermecker MF. Acute bronchial obstruc- 37. Traystman RJ, Terry PB, Menkes HA. Carbon dioxide, tion following inhalation of PAF in asthmatic and nor- a major determinant of collateral ventilation. J Appl mal subjects: comparison with methacholine. Eur Respir Physiol: Respirat Environ Exercise Physiol 1978; 45: J 1996; 9: 1414Ð1420. 69Ð74. 57. Rubin AE, Smith LJ, Patterson R. The bronchoconstrictor 38. Rodriguez-Roisin R, Wagner PD. Clinical relevance of properties of platelet-activating factor in humans. Am ventilation-perfusion inequality determined by inert gas Rev Respir Dis 1987; 136: 1145Ð1151. elimination. Eur Respir J 1990; 3: 469Ð482. 58. Schellenberg RR. Airway responses to platelet-activat- 39. Wagner PD, Rodriguez-Roisin R. Clinical advances in ing factor. Am Rev Respir Dis 1987; 136: S28ÐS32. pulmonary gas exchange. Am Rev Respir Dis 1991; 143: 59. Johnson PRA, Black JL, Armour CL. Platelet-activa- 883Ð888. ting factor-induced contraction of human isolated bron- 40. Kharitonov SA, Yates D, Robbins RA, Logan-Sinclair chus. Eur Respir J 1992; 5: 970Ð974. R, Shinebourne EA, Barnes PJ. Increased nitric oxide 60. Tam FWK, Clague J, Dixon CM, et al. Inhaled platelet- in exhaled air of asthmatic patients. Lancet 1994; 343: activating factor causes pulmonary neutrophil seques- 133Ð135. tration in normal humans. Am Rev Respir Dis 1992; 146: 41. Massaro AF, Gaston B, Kita D, Fanta C, Stamler JS, 1003Ð1008. Drazen JM. Expired nitric oxide levels during treatment 61. Masclans JR, Barberà JA, MacNee W, et al. Salbutamol of acute asthma. Am J Respir Crit Care Med 1995; 152: reduces pulmonary neutrophil sequestration of platelet- 800Ð802. activating factor in humans. Am J Respir Crit Care Med 42. Lagerstrand L, Dahlbäck M, Hedenstierna G. Gas ex- 1996; 154: 529Ð532. change during simulated airway secretion in the anaes- 62. Roca J, Félez MA, Chung KF, et al. Salbutamol in- thesized rabbit. Eur Respir J 1992; 5: 1215Ð1222. hibits pulmonary effects of platelet-activating factor in 43. Dunnill MS. The pathology of asthma, with special ref- man. Am J Respir Crit Care Med 1995; 151: 1740Ð1745. erence to changes in the bronchial mucosa. J Clin 63. Díaz O, Barberà JA, Marrades R, Chung KF, Roca J, Pathol 1960; 13: 27Ð33. Rodriguez-Roisin R. Inhibition of PAF-induced gas 44. Saetta M, Di Stefano A, Rosina C, Thiene G, Fabbri exchange defects by beta-adrenergic agonists in mild LM. Quantitative structural analysis of peripheral air- asthma is not due to bronchodilation. Am J Respir Crit ways and arteries in sudden fatal asthma. Am Rev Res- Care Med 1997; (In press). pir Dis 1991; 143: 138Ð143. 64. Chung KF, Dent G, Barnes PJ. Effects of salbutamol 45. Reid LM. The presence or absence of bronchial mu- on bronchoconstriction, bronchial hyperresponsiveness, cus in fatal asthma. Allergy J Clin Immunol 1987; 80 and leucocyte responses induced by platelet-activating (Suppl.): 415Ð419. factor in man. Thorax 1988; 44: 102Ð107. GAS EXCHANGE IN ACUTE SEVERE ASTHMA 1371

65. McDonald DM. Neurogenic inflammation in the respi- formoterol in rat trachea does not depend on capsaicin- ratory tract: actions of the sensory nerve mediators on sensitive sensory nerves. Am J Respir Crit Care Med blood vessels and epithelium of the airway mucosa. Am 1994; 149: 232Ð238. β Rev Respir Dis 1987; 136: S65ÐS67. 75. Sakamoto T, Barnes PJ, Chung KF. Effect of 2- 66. McDonald DM. The ultrastructure and permeability of adrenoceptor agonists against platelet-activating factor- tracheobronchial vessels in health and disease. Eur Res- induced airway microvascular leakage in the guinea-pig. pir J 1990; 3 (Suppl. 12): 572sÐ585s. Agents Actions 1993; 40: 50Ð56. 67. Persson CGA. Role of plasma exudation in asthmatic 76. Tokuyama K, Lötvall JO, Löfdahl CG, Barnes PJ, airways. Lancet 1986; ii: 1126Ð1128. Chung KF. Inhaled formoterol inhibits histamine-induced 68. Persson CGA, Erjefält JS, Andersson M, Greiff L, airflow obstruction and airway microvascular leakage. Svensson C. Extravasation, lamina propria and lumen- Eur J Pharmacol 1991; 193: 35Ð39. al entry of bulk plasma in mucosal defence, inflamma- 77. Spring J, Johnston SR, Seale J, Ind PW. Failure of sal- tion and repair. Pulm Pharmacol 1996; 9: 129Ð139. meterol to inhibit white cell responses and broncho- 69. Yager D, Butler J, Bastacky J, Israel E, Smith G, Drazen constriction induced by platelet-activating factor. Thorax JM. Amplification of airway constriction due to liquid 1992; 47: 948Ð951. filling of airway interstices. J Appl Physiol 1989; 66: 78. Kurosawa M, Yamashita T, Kurimoto F. Increased lev- 2873Ð2884. els of platelet-activating factor in bronchial asthmatic 70. Persson CGA. Plasma exudation and asthma. Lung patients with active symptoms. Allergy 1994; 49: 60Ð 1988; 166: 1Ð23. 63. 71. Wagner EW, Mitzner W. Effects of bronchial vascular 79. Kue-Hsiung H, Cheng-Koon Ng. Increased plasma plate- engorgement on airway dimensions. J Appl Physiol 1996; let-activating factor in children with acute asthmatic 81: 293Ð301. attacks and decreased in vivo and in vitro production of 72. Erjefält JS, Svensjö E. Vascular responses and their sup- platelet-activating factor after immunotherapy. J Aller- pression: drugs interfering with venular permeability. gy Clin Immunol 1993; 91: 650Ð657. In: Bonta IL, Bray MA, Parnham MJ, eds. Handbook 80. Kuitert L, Barnes NC. PAF and asthma: time for ap- of Inflammation. Vol. 5. Amsterdam, Elsevier, 1985; praisal? Clin Exp Allergy 1995; 25: 1159Ð1162. pp. 61Ð82. 81. Nadel JA. Genetics reveals importance of platelet-acti- 73. Erjefält JS, Persson CGA. Pharmacological control of vating factor in asthma and possibly other inflamma- plasma exudation into tracheobronchial airways. Am tory states. J Clin Invest 1996; 97: 2689Ð2690. Rev Respir Dis 1991; 143: 1008Ð1014. 82. Drazen J. What are the clinical benefits of a selective 74. Sulakvelidze I, McDonald DM. Anti-edema action of approach? Eur Respir Rev 1994; 6: 402Ð404.