Acute (Adult) Respiratory Distress Syndrome A.L.I. Acute Lung Injury A.R.D.S. Acute (Adult) Respiratory Distress Syndrome Patologie che oggi si estrinsecano perché esiste la rianimazione. Un tempo i pazienti andavano invece incontro a rapidissima morte. Il loro quadro è ben distinguibile dalla forma pediatrica, che ha un’etiopatologia precisa (assenza di surfattante).

ACUTE RESPIRATORY DISTRESS SYNDROME IN ADULTS By D.G. Ashbaugh et al. The Lancet, 1967. “THE CLINICAL PATTERN: dispnea severa, tachipnea, cianosi refrattaria a ossigeno-terapia, perdita della compliance polmonare, diffuso infiltrato alveolare (bilaterale) visibile all’RX” Colpisce soggetti giovani e sani, in seguito a insulto verificatosi 2-3 giorni prima. Molti casi sono stati osservati durante la guerra del Vietnam (varie denominazioni: polmone del soldato, polmone da shock, polmone umido)

A L I - A R D S recommended definition AECC Am J Respir Crit Care Med 1994; 149: 818-24 … as a syndrome of inflammation and increased permeability that is associated with a constellation of clinical, radiological and physiologic abnormlities that cannot be explained by, but may coexist with, left atrial or pulmonary hypertension. It is associated most often with sepsis syndrome, aspiration primary pneumonia, or multiple trauma. ……..ALI and ARDS are acute in onset and persistent e.g. lasting days to weeks, are associated with one or more known factors, and are carachterized by arterial hypoxemia resistant to oxygen therapy alone and diffuse radiologic infiltrates. Caratteristica clinica: segni ABNORMI rispetto alle cause sottese

A L I and A R D S: Clinical Presentation Precipitating conditions Acute onset Tachypnea - Dyspnea (Respiratory DISTRESS) Progressive severe hypoxemia Chest radiograph with bilateral infiltrates No evidence of L.V. failure Plasma proteins in bronchial secretions in early stage

MAIN ETIOLOGIES OF A L I and A R D S DIRECT INJURY INDIRECT INJURY Inhalation and Aspiration * Sepsis syndrome Pulmonary infections Pancreatitis ** Lung contusion Shock Near Drowning Fat embolism Trauma (non thoracic) Reperfusion injury with or without fat embolism Massive blood transfusion Burns ECC (circol. extra corporea) *Oggi meno frequente. Soprattutto in donne gravide, in cui si ha un aumento di P gastrica, con risalita di materiale che può essere aspirato. **ARDS è complicanza frequentissima di pancreatite! Cataboliti tossici rilasciati durante la pancreatite raggiungono il torace attraverso il dotto toracico.

A L I and ARDS EPIDEMIOLOGY ARDS incidence 1.5 - 13.5 (28-30) cases / year / 100.000 inhab. ALI incidence 18 - 70 (35) cases / year / 100.000 inhab. ARDS mortality 41 - 65 % (25-51 % in specialised centers) from 60 %(initial studies) to 35%(present studies) A L I mortality 40- 60 % Heavy influence of comorbidity and poor functional reserve(age >70, sepsis, liver failure)

A L I A R D S.: fisiopatologia Esagerata risposta infiammatoria dopo un insulto esogeno maggiore, sia diretto(es trauma toracico, danno da inalazione) che indiretto(es peritonite, pancreatite, emorragia ustioni gravi etc) E’ un quadro non specifico. IL polmone è un organo poco fantasioso! Spesso,indipendentemente dal tipo di causa lesiva, reagisce in maniera stereotipata, con flogosi e alterazione dell’interfaccia alveolo-capillare.

The Normal Alveolus (Left-Hand Side) and the Injured Alveolus in the Acute Phase of Acute Lung Injury and the Acute Respiratory Distress Syndrome (Right-Hand Side) Figure 3. The Normal Alveolus (Left-Hand Side) and the Injured Alveolus in the Acute Phase of Acute Lung Injury and the Acute Respiratory Distress Syndrome (Right-Hand Side). In the acute phase of the syndrome (right-hand side), there is sloughing of both the bronchial and alveolar epithelial cells, with the formation of protein-rich hyaline membranes on the denuded basement membrane. Neutrophils are shown adhering to the injured capillary endothelium and marginating through the interstitium into the air space, which is filled with protein-rich edema fluid. In the air space, an alveloar macrophage is secreting cytokines, interleukin-1, 6, 8, and 10, (IL-1, 6, 8, and 10) and tumor necrosis factor {alpha} (TNF-{alpha}), which act locally to stimulate chemotaxis and activate neutrophils. Macrophages also secrete other cytokines, including interleukin-1, 6, and 10. Interleukin-1 can also stimulate the production of extracellular matrix by fibroblasts. Neutrophils can release oxidants, proteases, leukotrienes, and other proinflammatory molecules, such as platelet-activating factor (PAF). A number of antiinflammatory mediators are also present in the alveolar milieu, including interleukin-1-receptor antagonist, soluble tumor necrosis factor receptor, autoantibodies against interleukin-8, and cytokines such as interleukin-10 and 11 (not shown). The influx of protein-rich edema fluid into the alveolus has led to the inactivation of surfactant. MIF denotes macrophage inhibitory factor. Ware, L. B. et al. N Engl J Med 2000;342:1334-1349

1)Fase essudativa acuta 2)Fase subacuta proliferativa: Mechanisms Important in the Resolution of Acute Lung Injury and the Acute Respiratory Distress Syndrome Vari stadi evolutivi: 1)Fase essudativa acuta 2)Fase subacuta proliferativa: microtrombosi capillare, vasocostrizione su base ipossica determinano ipertensione polmonare. Polmone duro, da ridotta compliance 3) Fase risolutiva/cronicizzazione/fibrosi. Figure 4. Mechanisms Important in the Resolution of Acute Lung Injury and the Acute Respiratory Distress Syndrome. On the left side of the alveolus, the alveolar epithelium is being repopulated by the proliferation and differentiation of alveolar type II cells. Resorption of alveolar edema fluid is shown at the base of the alveolus, with sodium and chloride being transported through the apical membrane of type II cells. Sodium is taken up by the epithelial sodium channel (ENaC) and through the basolateral membrane of type II cells by the sodium pump (Na+/K+-ATPase). The relevant pathways for chloride transport are unclear. Water is shown moving through water channels, the aquaporins, located primarily on type I cells. Some water may also cross by a paracellular route. Soluble protein is probably cleared primarily by paracellular diffusion and secondarily by endocytosis by alveolar epithelial cells. Macrophages remove insoluble protein and apoptotic neutrophils by phagocytosis. On the right side of the alveolus, the gradual remodeling and resolution of intraalveolar and interstitial granulation tissue and fibrosis are shown. Ware, L. B. et al. N Engl J Med 2000;342:1334-1349

A L I A R D S ISTOLOGIA (fase acuta) : Aggregazione ed attivazione dei neutrofili e delle piastrine Distruzione endoteliale ed alveolare a chiazze Edema interstiziale poi Fibrosi (fase fibroproliferativa)

Findings on Light Microscopy and Electron Microscopy during the Acute Phase (Panels A and D) and the Fibrosing-Alveolitis Phase (Panels B, C, and E) of Acute Lung Injury and the Acute Respiratory Distress Syndrome Figure 2. Findings on Light Microscopy and Electron Microscopy during the Acute Phase (Panels A and D) and the Fibrosing-Alveolitis Phase (Panels B, C, and E) of Acute Lung Injury and the Acute Respiratory Distress Syndrome. Panel A shows a lung-biopsy specimen obtained from a patient two days after the onset of the syndrome as a result of the aspiration of gastric contents. Characteristic hyaline membranes are evident (arrow), with associated intraalveolar red cells and neutrophils, findings that are consistent with the pathological diagnosis of diffuse alveolar damage (hematoxylin and eosin, x90). Panels B and C show lung-biopsy specimens obtained 14 days after the onset of sepsis-associated acute lung injury and the acute respiratory distress syndrome. Panel B shows granulation tissue in the distal air spaces with a chronic inflammatory-cell infiltrate (hematoxylin and eosin, x60). Trichrome staining in Panel C reveals collagen deposition (dark blue areas) in the granulation tissue, a finding that is consistent with the deposition of extracellular matrix in the alveolar compartment (x60). Panel D shows a specimen of lung tissue from a patient who died four days after the onset of acute lung injury and the acute respiratory distress syndrome; there is injury to both the capillary endothelium and the alveolar epithelium. There is an intravascular neutrophil (LC) in the capillary (C). Vacuolization and swelling of the endothelium (EN) are apparent. Loss of alveolar epithelial cells is also apparent, with the formation of hyaline membranes on the epithelial side of the basement membrane (BM*). Panel E shows a specimen of lung tissue obtained from a patient during the fibrosing-alveolitis phase in which there is evidence of reepithelialization of the epithelial barrier with alveolar epithelial type II cells. The arrow indicates a typical type II cell with microvilli and lamellar bodies containing surfactant. The epithelial cell immediately adjacent to this cell is in the process of changing to a type I cell, with flattening, loss of lamellar bodies, and microvilli. The interstitium is thickened, with deposition of collagen (C). Panels A, B, and C were supplied by Dr. Martha Warnock. Panel D was reprinted from Bachofen and Weibel20 with the permission of the publisher. Panel E was reprinted from Anderson and Thielen21 with the permission of the publisher. Ware, L. B. et al. N Engl J Med 2000;342:1334-1349

L’addensamento si localizza prevalentemente a livello delle porzioni più declivi (posteriormente, se paziente allettato) e a questo livello determina una compressione a carico degli alveoli, che collassano. La loro riespansione può essere ottenuta utilizzando la PEEP. Questo addenzamento può variare rapidamente di posizione se faccio girare il pz (DD con focolaio pneumonico, che è invece fisso)

 Ventilation Blood flow and Ventilation (l/min) Blood flow dead space shunt  0.01 0.1 1 10 100 Ventilation/Perfusion ratio

Patterns of Va/Q distribution in patients with ARDS Reyes A et al. Am Rev Respir Dis 1988;137:1062

Edema da permeabilità (lesionale) A.L.I. and A.R.D.S. sono caratterizzate da infiammazione polmonare ed endoteliale con conseguente: Edema da permeabilità (lesionale) Perdita e disfunzione del surfattante con conseguente atelettasia e riduzione della compliance Mismatch ventilazione/perfusione con conseguente shunt dx-sx ed ipossiemia Ipertensione arteriosa polmonare

LE ARDS NON SONO TUTTE UGUALI -Primarie Danno primitivo polmonare (polmonite, contusione,ab ingestis,etc) Secondarie Danno primitivo extrapolmonare (sepsi addominale,politrasfusione,autoimmune, etc.)

PRIMARY ARDS La TC mette in evidenza i bronchi abnormemente dilatati (perché a valle il polmone è poco compliante) e marcata epatizzazione del parenchima.

SECONDARY ARDS

Evoluzione del concetto fisiopatologico : - da Polmone rigido (stiff lung) - a Polmone piccolo (baby lung)

Pressure Volume Curves Se il polmone è poco compliante è necessario utilizzare una P maggiore per raggiungere un medesimo volume, rispetto a un polmone sano. Da qui deriva l’utilità della ventilazione assistita.

rigidità alveolare (sovradistensione) meccanica parete toracica (IAP) Cosa esprime la Cpl,rs ? n° alveoli aperti (baby lung) rigidità alveolare (sovradistensione) meccanica parete toracica (IAP) (Cpl,rs normale = 1,2-1,5 ml/cmH2O/Kg)

A L I - A R D S treatment goals GOAL MEANS To improve gas exchange FiO2, MV, iNO, drugs, positioning To reduce (eliminate) WOB (lavoro) MV To reduce EVLW(edema) Keep negative fluid balance To keep adequate tissue oxygenation DO2 /VO2 balance To prevent fibrosis Steroids To avoid complications Good I C U

PEEP 0 SP PEEP 5 PEEP 10 5 10 Ma attenzione! Se ventilo in modo scorretto posso danneggiare un polmone già molto delicato. E’ essenziale trattare il polmone il più dolcemente possibile, non eccedendo con la ventilazione.

Primary ARDS: effect of PEEP

Secondary ARDS: effect of PEEP

and systemic inflammation Mechanical ventilation can cause (worsen) ALI and ARDS ( Barotrauma, Volotrauma and Ventilator Induced Lung Injury) and systemic inflammation (biotrauma concept)

Ventilator Induced (Associated) Lung Injury V I L I (V A L I) Pinhu et al Lancet 2003;361:332-340

Low mortality associated with low volume pressure limited ventilation with permissive hypercapnia in severe ARDS Hickling KG, Henderson SJ, Jackson R Intensive Care Med 1990; 16: 372-377 SIMV, Vt ridotto fino a 5 ml/Kg Ppicco max 30 (40) cmH2O PEEP per ossigenazione sufficiente a FiO2 0.6 Mortalità intraospedaliera 18.6%

Probability of Survival and of Being Discharged Home and Breathing without Assistance during the First 180 Days after Randomization in Patients with Acute Lung Injury and the Acute Respiratory Distress Syndrome Figure 1. Probability of Survival and of Being Discharged Home and Breathing without Assistance during the First 180 Days after Randomization in Patients with Acute Lung Injury and the Acute Respiratory Distress Syndrome. The status at 180 days or at the end of the study was known for all but nine patients. Data on these 9 patients and on 22 additional patients who were hospitalized at the time of the fourth interim analysis were censored. The Acute Respiratory Distress Syndrome Network, N Engl J Med 2000;342:1301-1308

Clinical Impact 6 ml/kg of Vt : “the end of the story”???? Treat the lung AS GENTLE AS POSSIBLE !!!

Perché addensamenti posteriori ? PRONAZIONE

Kaplan-Meier Estimates of Survival at Six Months Figure 1. Kaplan-Meier Estimates of Survival at Six Months. The status at 183 days was known for all but seven patients (four in the prone group and three in the supine group). The difference between groups was not significant (P=0.65 by the log-rank test). Gattinoni, L. et al. N Engl J Med 2001;345:568-573

Effect of prone positioning on the survival of patients with acute respiratory failure – Gattinoni L et al. N Eng J Med 2001;345:568-73

A L I - A R D S treatment goals GOAL MEANS To improve gas exchange FiO2, MV, iNO, drugs, positioning To reduce (eliminate) WOB MV To reduce EVLW Keep negative fluid balance To keep adequate tissue oxygenation DO2 /VO2 balance To prevent fibrosis Steroids To avoid complications Good I C U