ALI and ARDS: the european experience

A quick review of the literature and some preliminary data from the ALIVE project

prepared by

Luca Brazzi* and Guido Bertolini°

* Istituto di Anestesia e Rianimazione, Ospedale Maggiore IRCCS, Milano – Italy

° Istituto di Ricerche Farmacologiche "Mario Negri": Centro di Ricerche Cliniche per le Malattie Rare Aldo e Cele Daccò – Ranica (Bergamo), Italy.

A QUICK REVIEW OF THE LITERATURE

Introduction

Since its first description, more than 25 years ago (1), the Adult Respiratory Distress Syndrome (ARDS) has received more attention than any single entity in critical care medicine. It was initially described in 12 patients and it consists of an acute, severe alteration in lung structure and function characterised by hypoxemia, low-compliance lungs with low functional residual capacity and diffuse radiographic infiltrates due to increased lung microvascular permeability.

A wide variety of conditions have been reported to be associated with ARDS (Table I). There are direct injuries, such as aspiration of gastric contents or inhalation of toxic gases, in which a toxic substance directly damages lung epithelium or indirect injuries, such as severe sepsis and major trauma, that affect lung tissue via a blood-born systemic inflammation.

Table I: Major clinical disorders associated with ARDS

Direct lung injury Indirect lung injury

Thoracic trauma Severe sepsis

Aspiration Severe shock

Toxic gas inhalation Major trauma

Pulmonary infection Drug overdose

Emboli Blood transfusions

Radiation Pancreatitis

Drugs inalation Severe neurological injury

Reperfusion injury Post-cardiopulmonary bypass

Near-drowning Diabetic ketoacidosis

Independently from its origin, ARDS is usually a composite manifestations of an evolving, severe diffuse lung injury, especially to the parenchyma. Chest radiographs show widespread alveolar infiltrations caused by increased-permeability pulmonary edema and atelectasis. Physiologic complications include hypoxemia from right to left shunting of blood and decrease pulmonary compliance from filling and closure of alveoli and increased surface forces. Hyaline membranes, proteinaceous pulmonary edema and intraalveolar hemorrhage are usually prominent histologic findings.

Definitions

Since the clinical presentation of patients with ARDS has changed little from its original description in 1967, the development of physiologic indices for an accurate definition of the syndrome has been essential for the standardisation of “entry criteria” into various clinical studies.

Initially, Ashbaugh and Petty (1) proposed, as criteria for ARDS definition, the presence of severe dyspnea, tachypnea, cyanosis that is refractory to oxygen therapy, loss of lung compliance and diffuse alveolar infiltration on chest x-ray. Bone et al. in 1976 (2) used a PaO2/FiO2 ratio lower than 150 to define the level of hypoximia needed to classify patients as affected by ARDS. In 1979, the National heart, Lung and Blood Institute revised the criteria and defined them more strictly as to select patients to be enrolled in a collaborative study (3). Two operative definitions to select patients with ARDS were designed: the first to enhance specificity (not including temporary conditions) - the fast entry criteria - included a PaO2 lower than 50 mmHg for more than two hours with a FiO2 equal to 1 and a PEEP level equal to or higher than 5 cm H2O; the second, not to limit sensibility (including very severe cases) - the slow entry criteria - included a PaO2 lower than 50 mmHg for more than twelve hours with a FiO2 equal to 0.6, a PEEP level equal to or higher than 5 cm H2O and a shunt fraction higher than 30% after 48 hours of maximal medical therapy.

The non cardiogenic origin of the pulmonary oedema was introduced, as a necessary characteristics in the definition of ARDS, by Pepe et al. (4) that, in 1982, defined ARDS as a clinical picture satisfying all the following criteria: 1) PaO2 less than 75 mmHg with FiO2 of 0.5 or greater; 2) new diffuse bilateral infiltrates on chest roentgenography; 3) pulmonary artery wedge pressure less than 18 mmHg.

These criteria were revised again in 1983 by Bell et al. (5) and Fein et al. (6) who enrolled patients in their studies on ARDS according to the following: 1) diffuse radiographic infiltrates; 2) hypoxemia requiring a FiO2 equal or higher than 0.5 to maintain a partial arterial oxygen pressure greater than 50 mmHg and 3) a pulmonary artery wedge pressure lower than 15 mmHg. Fowler et al. (7), introduced, among the criteria, the need of a total static pulmonary compliance value equal to or lower than 50 ml/cm H2O together with a pulmonary capillary wedge pressure lower than or equal to 12 mmHg and an arterial to alveolar PO2 ratio lower than or equal to 0.2. Up till 1988 no major revision were introduced and the criteria published in literature to define ARDS all moved around a combination of the aspects reported above. In 1988 a new approach to the definition of ARDS was designed by Murray et al. (8) who developed a “lung injury score” (LIS) to quantify, albeit roughly, the presence, severity and evolution of acute and chronic damage involving lung parenchyma. Different components were taken into account and different values were attributed to these components according to the degree of abnormality of them (Table II). Three level in severity of lung injury were defined: 1) absence of lung injury (LIS=0); 2) mild to moderate lung injury (LIS=0.1-2.5); 3) severe lung injury (ARDS) (LIS > 2.5).

TABLE II: Components and individual values of LIS*

1. Chest roentgenogram score

No alveolar consolidation 0

Alveolar consolidation confined to 1 quadrant 1

Alveolar consolidation confined to 1 quadrants 2

Alveolar consolidation confined to 1 quadrants 3

Alveolar consolidation in all 4 quadrants 4

2. Hypoxemia score

PaO2 / FiO2 equal to or higher than 300 0

PaO2 / FiO2 between 225 and 299 1

PaO2 / FiO2 between 175 and 224 2

PaO2 / FiO2 between 100 and 174 3

PaO2 / FiO2 lower than 100 4

3. PEEP score (when ventilated)

PEEP equal to or higher than 5 cm H2O 0

PEEP between 6 and 8 cm H2O 1

PEEP between 9 and 11 cm H2O 2

PEEP between 12 and 14 cm H2O 3

PEEP equal to or higher than 15 cm H2O 4

4. Respiratory system compliance score (when available)

Compliance equal to or higher than 80 ml/cm H2O 0

Compliance between 60 and 79 ml/cm H2O 1

Compliance between 40 and 59 ml/cm H2O 2

Compliance between 20 and 39 ml/cm H2O 3

Compliance equal to or lower than 19 ml/cm H2O 4

The final value is obtained by dividing the aggregate sum by the number of components that were used.

Legend: PaO2 / FiO2 = arterial oxygen tension to inspired oxygen concentration ratio; PEEP = positive end-expiratory pressure

* From Murray JF et al. Am Rev Respir Dis 1988; 138: 720-723.

Recently, the Committee of the American-European Consensus Conference on ARDS recommended that ARDS is now to be described as a particularly severe subset of Acute Lung Injury (ALI), which in turn is defined as a “syndrome of inflammation and increased permeability that is associated with a constellation of clinical, radiologic and physiologic abnormalities that cannot be explained by, but may coexist with, left arterial or pulmonary capillary hypertension” (9).The criteria proposed to define ALI and ARDS were: 1) acute onset; 2) presence of bilateral infiltrates seen on frontal chest radiograph; 3) pulmonary artery wedge pressure equal to or lower than 18 mmHg or no clinical evidence of left atrial hypertension being the only difference between the two syndromes the PaO2 / FiO2 cut-point that is 300 mm Hg (equal to or lower than) to define ALI and 200 mm Hg (equal to or lower than) to define ARDS.

Risk factors

ARDS occurs following a variety of overwhelming insults or risk factors. As reported above, some of the non-pulmonary conditions associated with ARDS are shock, sepsis, non-pulmonary trauma, drug overdose, pancreatitis, uraemia, eclampsia, central nervous system disease, emboli, burns and massive transfusion. Those pulmonary conditions associated with ARDS include aspiration, lung contusion, infection, radiation, toxic gases and near-drowning. The incidence of these pathological conditions has been reported differently according either to the admitting policy of the different hospitals or to their clinical speciality practice. Different studies reported data regarding incidence of ARDS according to pre-existing prognostic factors (Table III). Pepe et al. (10), Fowler et al. (11) and Hudson et al. (12) reported on multiple risk factors, which included aspiration, bacteremia/sepsis, cardiopulmonary bypass, DIC, fractures, multiple contusion, shock and trauma.

TABLE III: Distribution of risk factors for ARDS

	Pepe AmJSurg1982;144:124	Fowler AnnIntMed1983;98:593	Mancebo CCM1987;15:243	Villar ARRD1989;140: 814	Suchyta Chest1992;101:1074	Hudson AJRCCM1995;151:293	Milberg JAMA1995;273:306	Heffner AJRCCM1995;152:1518
Pts. ARDS / Total (%)	46/136 (34)	68/936 (7)	35/35 (100)	74/1997 (4)	215/215 (100)	179/695 (26)	918/918 (100)	50/50(100)
Cardiopulmonary bypass		4/237 (2)
Burn		2/87 (2)
Bacteriemia		9/239 (4)
Massive blood transfusion	19/42 (45)	9/197 (5)				28/77 (36)	48/918 (5)	4/50 (8)
Bone fractures	15/34 (44)	2/38 (5)			7/63 (11)
Pneumonia		10/84 (12)	9/35 (25)	5/74 (7)	76/215 (35)			20/50 (40)
DIC		2/9 (22)
Pulmonary aspiration	10/32 (31)	16/45 (36)		9/74 (12)	25/215 (11)	13/59 (22)	85/918 (9)	5/50 (10)
Sepsis	9/19 (47)	6/35 (17)	30/74 (41)	31/215 (14)	56/136 (41)	340/918 (37)	9/50 (18)
Major trauma		4/35 (11)	14/74 (19)	20/215 (9)		230/918 (25)	6/50 (12)
Drug overdose		1/35 (2)	3/74 (4)		14/164 (8)	54/918 (6)
Near drowning	3/4 (75)		1/74 (1)		2/6 (33)		1/50 (2)
Pulmonary contusion	19/50 (38)				12/55 (22)
Abdominal surgery			4/74 (5)
Thoracic surgery			2/74 (3)
Post-anoxic coma			2/74 (3)
Cerebral hemorrage			2/74 (3)
Pancreatitis	1/1 (100)	5/35 (4)
Prolonged hypothension	2/4 (50)
Shock		2/35 (5)					3/50 (6)
Fat embolism							1/5 (2)
Smoke inhalation							1/5 (2)
Peritonitis		7/35 (20)		43/215 (20)
LES		1/35 (2)
Others				20/215 (9)

Hudson et al. (12) reported the highest incidence of ARDS with sepsis, trauma, multiple transfusions and aspiration. Pepe et al. (10) observed the highest incidence of ARDS with sepsis, aspiration and multiple transfusions while Fowler et al (11) noted the highest incidence with pneumonia, DIC and pulmonary aspiration. Villard and Slutsky (13) performed a population-based prospective cohort study in which they examined the incidence of ARDS on an isolated island with a single large hospital. They found that the most common predisposing factor for the development of ARDS was sepsis even if the results of this study may not be generalizable to large metropolitan centres, given that the incidence of blunt trauma as well as other ARDS risk factors are presumably not comparable. Mancebo and Artigas (14) found that sepsis and trauma are the most common causes of ARDS whereas Suchyta et al. (15) and Heffner et al. (16) found pneumonia as the major cause for ARDS. Lastly, Milberg et al. (17) studying 918 patients with ARDS reported that the primary causes for the syndrome were sepsis in 37% and major trauma in 25% of the cases.

Recently, Garber et al (18) published the results of a systematic overview of incidence and risk factor of ARDS. Seventy-seven articles examining ARDS risk factors were identified. The strongest evidence supporting a cause-effect relationship between ARDS and risk factor was identified for sepsis, trauma, multiple transfusions, aspiration of gastric contents, pulmonary contusion, pneumonia and smoke inhalation. The weakest evidence was identified for disseminated intravascular coagulation, fat embolism and cardiopulmonary bypass even if the authors themselves suggested that, being the great majority of the existing studies not prospective cohort studies, we still have to cast doubts regarding the real relationships between risk factors and ARDS.

Incidence and outcome

Due to the fact that different criteria to define ARDS exist, it has always been difficult to estimate the crude incidence and the outcome of the ARDS either in US or outside. The 1972 report of the National Heart and Lung Institute Task Force on Respiratory Diseases suggested that there were about 150.000 cases of ARDS per year in the United States (19) that would represent an incidence of 60 case / 100.000 population per year. Even if this figure has been cited in a number of subsequent articles and textbooks, different studies, afterwards, started casting doubts regarding the validity and the reproducibility of this estimate (Table IV).

TABLE IV: Incidence and mortality of ARDS in the existing literature

Author Publication Patients Incidence Mortality rate

year (*100.000 population / year) (%)

Fowler (20) 1983 88 5.2 65

Webster (21) 1988 139 4.5 38

Evans (22) 1988 62 25 60

Villar (23)* 1989 30 / 74 1.5 / 3.5 70 / 50

Thomsen (24) 1995 110 / 83 8.3 / 4.8 --

Lewandowski (25) 1995 17 3 58.8

* Data reported according to two different definitions for ARDS

Fowler and colleagues (20) prospectively studied ARDS patients in three Denver, Colorado hospitals. Using the following definitions: PaO2 / PAO2 £ 0.2; bilateral lung infiltrates on a chest radiograph; no heart failure or evidence of fluid overload; total static thoracic compliance £ 50 ml/cmH2O and age ³ 12 yrs, they identified 88 patients as having ARDS. They did not calculate an ARDS incidence with respect to any outpatient population even if, subsequently, Villar and Slutsky used their data to calculate an ARDS incidence of 4.8 patients / 100.000 population per year with a mortality rate of 65% (23).

Webster and collegues (21), in 1988, studied the incidence of ARDS in one British health region with a population of 3.599.400. They did not use a standard definition but accepted the diagnosis by the consultant in charge of the intensive therapy unit. Most consultant used an oxygenation criteria with PaO2 of > 8 Kpa while receiving an FiO2 = 0.5. No lower age limit was reported in their study, which recorded an incidence of 4.5 / 100.000 per year with a mortality rate of 38%.

Evans and associates reported an incidence of ARDS in San Francisco, California of 25 patients per 100.000 population per year (22) with a mortality rate of 60%. They used the combination of a PaO2 / FiO2 ratio £ 150, diffuse infiltrates involving all four quadrants of the chest radiograph, and either a pulmonary wedge pressure £ 18 mmHg or no clinical evidence of elevated left atrial pressure as diagnostic criteria for ARDS. They published data in an abstract covering the first 4 months of a planned 12 months study. To our knowledge, only these preliminary data are available.

Villard and Slutky (23) in 1989 in a prospective cohort study investigated the incidence of ARDS in the Canary Islands (a population of 700.000). The study was performed over a two years period. The definition of ARDS was quite strict requiring a recognized predisposing illness and a PaO2 < 55 mmHg while receiving an FiO2 > 0.5 on 5 cm H2O of PEEP without improvement in 24 hrs. The authors did present data on an alternative oxygenation criterion using a PaO2/FiO2 ratio of less than 150 but the 24 hrs period without improvement remained. Patients < 15 yrs of age were excluded, although the denominator was not adjusted to reflect this exclusion as were patients with chronic obstructive pulmonary disease (COPD) who also developed ARDS. An incidence of ARDS of 1.5 / 100.000 population per year was identified using the more severe definition and 3.5 /100.000 population per year using the more liberal oxygenation definitions. The mortality rate of the patients included in the stringent criteria group was 70%, whereas the mortality rate of all of the ARDS patients as identified by the less stringent criteria was 50%.

Thomsen and Morris (24) carried out a prospective cohort study over 1 year in the state of Utah (population 1.720.000). Their definition of ARDS included an oxygenation criteria of PaO2 / PAO2 > 0.2 roughly equivalent to a PaO2 / FiO2 > 110. They excluded patients > 12 yrs of age but did not adjust denominator to reflect this exclusion but did report that 75% of the population was > 12 yrs. of age so that the reader could make this adjusting. They calculated a lower limit of incidence, by using only the screened and identified Utah patients (4.8 / 100.000 population per year) and an upper limit by adjusting for estimates in non-screened hospitals and patients hospitalised in neighbouring states (8.3 / 100.000 population per year).

Lewandowski and co-authors (25) in 1995 reported a prospective cohort study of the incidence of ARDS in Berlin, Germany (population 3.440.000). The diagnosis of ARDS was limited to patients aged 14 or greater but the denominator was not corrected for this. They based the definition on the Murray Lung Injury Score (LIS) (greater than 2.5) and also required that patients be on mechanical ventilation for > 24 hrs. They found the incidence of ARDS was 3.0 / 100.000 population per year with a mortality rate of 58.8%.

In summary, all the subsequent studies have reported an incidence of ARDS that was an order of magnitude lower than estimated by the NIH in 1972. However, it is likely that, at least in some of these last cases, there is a major unrepresentativness of the true incidence of ARDS due to problems of definitions and study methodology. Among these lasts can certainly be remembered: an incomplete screening (24), the use of a retrospective questionaire with no set criteria for the definition of ARDS (21), a too short study period of two months (25), the exclusion of patients under the age of 12 to 15 without correction of the denominator (23-25) or without stating any age limitation (21).

As regards mortality rate data, it is important to remember that in their seminal description of the adult respiratory distress syndrome (ARDS), Ashbaugh and colleagues (1) reported that 7 of 12 patients died. Despite nearly 3 decades of progress in the supportive care of patients with respiratory failure, recent studies and reviews continue to report mortality figures ranging between 40 and 70% in patients with ARDS. Moreover, a recent study (26), designed to evaluate changes in the outcome and severity of ARDS (as indicated by PaO2 / FiO2 ratio or lung injury scores) over the past three decades, evidenced that the mortality of ARDS patients remained constant throughout the period studied and sustained the hypothesis that the observed differences in outcome could mainly be attributed to differences in the severity of underlying disease and in the number of accompanying organ dysfunctions, oftenly not reported in the considered papers.

the EUROPEAN “ALIVE” project

ALIVE (ALI verification of epidemiology) is a prospective, multicentric and multinational cohort study designed to provide an epidemiological description of the aetiologies and case-mix, therapies/intervention used, and outcome of patients having ALI or ARDS in European ICUS. The specific objectives of the study are:

· · to provide an estimate of the within-ICU incidence and occurrence of these two syndromes in participating ICUs across Europe;

· · to describe the case-mix of patients, and aetiologies associated with occurrence of ALI/ARDS;

· · to assess the relationship between the two syndrome, and explore whether there is a continuum between ALI and ARDS;

· · to assess the relationship between specific markers of respiratory failure (i.e. PaO2 / FiO2 and short- and long-term mortality in patients with ALI/ARDS);

· · to examine and evaluate prognostic factors and assess the capability of existing generic severity of illness scoring systems in describing and monitoring the clinical condition and outcome of patients with ALI/ARDS;

· · to describe the use of specific therapies and management strategies in patients with ALI/ARDS and explore their relationship to outcomes.

The study was launched on February 1999 in 78 ICUs belonging to 9 European Countries (Belgium, France, Germany, Iceland, Italy, Portugal, Spain, Switzerland and U.K.). The recruitment period lasted two months, during which all patients admitted to the participating ICUs for a period of time higher than 4 hrs were included. The causes of ALI/ARDS were recorded and several scoring systems (SAPS II, McCabe, LOD) used to characterising patients on admission and at time of occurrence of ALI/ARDS, if different. All patients were followed-up until discharge or death and hospital outcome was recorded.

The analyses of recruited data will provide further and significant insights in the epidemiology of these important diseases.

References

1) 1) Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress in adults. Lancet 1967; 2: 319-323.

2) 2) Bone RC, Francis PB, Pierce AK. Intravascular coagulation associated with the adult respiratory distress syndrome. Am J Med 1976; 61: 585-589.

3) 3) National Heart, Lung and Blood Institute, Division of Lung Disease. Extracorporeal support for respiratory insufficiency: a collaborative study. Bethesda, MD, NIH.

4) 4) Pepe PE, Potkin RT, Reus DH, Hudson LD, Carrico CJ. Clinical predictors of the adult respiratory distress syndrome. Am J Surg 1982; 144: 124-130.

5) 5) Bell RC, Coalson JJ, Smith JD, Johanson WG. Multiple organ system failure and infection in adult respiratory distress syndrome. Ann Intern Med 1983; 99: 293-298.

6) 6) Fein AM, Lippmann M, Holtzman H, Eliraz A, Goldberg SK. The risk factors, incidence and prognosis of ARDS following septicemia. Chest 1983; 83: 40-42.

7) 7) Fowler AA, Hamman RF, Zorbe GO, Benson KN, hyers TM. Adult respiratory distress syndrome: prognosis after onset. Am Rev Respir Dis 1985; 132: 472-478.

8) 8) Murray JF, Matthay MA, Luce JM, Flick MR. An expanded definition of the adult respiratory distress syndrome. Am Rev Respir Dis 1988; 138: 720-723.

9) 9) Bernard GR, Artigas A, Brigham KL, et al. Report of the American-European consensus conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994; 149: 818-824.

10) 10)Pepe PE, Potkin RT, Holtman Reus D, Hudson LD, Carrico CJ. Clinical predictors of the adult respiratory distress syndrome. Am J Surg 1982; 144: 124-130.

11) 11)Fowler AA, Hamman RF, Good JT, et al. Adult respiratory distress syndrome: risk with common predispositions Ann Intern Med 1983; 98: 593-597.

12) 12)Hudson LD, Milberg JA, Anardi D, et al. Clinical risks for development of the acute respiratory distress syndrome. Am J Respir Crit Med 1995; 151: 293-301.

13) 13)Villar J, Slutsky AS. The incidence of the adult respiratory distress syndrome. Am Rev Respir Dis 1989; 140: 814-816.

14) 14)Mancebo J, Artigas A. A clinical study of the adult respiratory distress syndrome. Crit Care Med 1987; 15: 243-246.

15) 15)Suchyta MR, Clemmer TP, Elliott CG, et al. The adult respiratory distress syndrome. A report of survival and modifying factors. Chest 1992; 101: 1074-1079.

16) 16)Heffner JE, Brown LK, Barbieri CA, et al. Prospective validation of an acute respiratory distress syndrome predictive score. Am J Respir Crit Care Med 1995; 152: 1518-1526.

17) 17)Milberg JA, Davis DR, Steinberg KP, Hudson LD. Improved survival of patients with acute respiratory distress syndrome (ARDS): 1983-1993. JAMA 1995; 273: 306-309.

18) 18)Garber BG, Hèbert PC, Yelle JD, et al. Adult respiratory distress syndrome: a systematic overview of incidence and risk factors. Crit Care Med 1996; 24: 687-695.

19) 19)National Heart and Lung Institute, National Institutes of Health. 1972. Respiratory distress syndrome: task force report on problems, research approaches, needs. U.S. Government Printing Office, Washington, DC. 1972 DHEW publication No. (NIH) 73-432: 165-180.

20) 20)Fowler AA, Hamman RF, Good JT, et al. Adult respiratory distress syndrome: risk with common predispositions. Ann Intern Med 1983; 98: 593-597.

21) 21)Webster NR, Cohen AT, Nunn JF. Adult respiratory distress syndrome-haw many cases in the UK ? Anaesthesia 1988; 43: 923-926.

22) 22)Evans BH, Wachter RM, Wiener-Kronish JP, Luce JM. Incidence of the adult respiratory distress syndrome in an urban population. Am Rev Respi Dis 1988; 137: A469.

23) 23)Villard J, Slutsky AS. The incidence of the adult respiratory distress syndrome. Am Rev Respir Dis 1989; 140: 814-816.

24) 24)Thomsen GE, Morris AH. Incidence of the adult respiratory distress syndrome in the state of Utah. Am J Respir Crit Care Med 1995; 152: 965-971.

25) 25)Lewandowski K, Metz J, Deutschmann, et al. Incidence, severity and mortality of acute respiratory failure in Berlin, Germany. Am J Respir Crit Care Med 1995; 151: 1121-1125.

26) 26) Krafft P, Fridrich P, Pernerstorfer T, et al. The adult respiratory distress syndrome: definitions, severity and clinical outcome. Intensive Care Med 1996; 22: 519-529.