Acute lung injury (ALI) and Acute respiratory distress syndrome ...
Acute lung injury (ALI) and Acute respiratory distress syndrome ...
Acute lung injury (ALI) and Acute respiratory distress syndrome ...
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<strong>Acute</strong> <strong>lung</strong> <strong>injury</strong> (<strong>ALI</strong>) <strong>and</strong><br />
<strong>Acute</strong> <strong>respiratory</strong> <strong>distress</strong> <strong>syndrome</strong><br />
(ARDS)<br />
Arthur P. Wheeler, MD<br />
Associate Professor of Medicine<br />
Director, Medical ICU<br />
Division of Allergy, Pulmonary <strong>and</strong> Critical Care Medicine<br />
V<strong>and</strong>erbilt University<br />
Commercial disclosures: none<br />
Research Support: NO1-HR-46054-64, NO1-16146-54
• 21 yo female WKU student<br />
• Previously healthy<br />
• Admitted with Gullian-Barre<br />
• Day 5 aspiration-induced ARDS<br />
• Ventilation<br />
– Tidal volume 10 ml/kg<br />
–FiO 2 0.8<br />
– PEEP 15<br />
– PIP 70 cm H 2 0<br />
– Adjustments made to normalize blood gases
• Day 23 bilateral tension<br />
pneumothoraces<br />
– Multiple (4+3) chest tubes<br />
– Large bilateral (R>L) cystic<br />
areas<br />
– Pneumomediastinum<br />
– Interstitial emphysema
• Day 52 air-hunger, suddenly sat upright<br />
– New seizure<br />
– Livedo reticularis right hemi-thorax, h<strong>and</strong>, <strong>and</strong> face<br />
– ECG: acute inferior myocardial infarction<br />
– Head CT: multiple new infarcts<br />
• Day 70 autopsy:<br />
– Severe <strong>lung</strong> <strong>injury</strong> with prominent cystic changes,<br />
extensive fibrosis <strong>and</strong> foci of infection<br />
– Multiple myocardial infarcts, intact atrial septum<br />
– Multiple CNS infarcts c/w emboli<br />
Marini JJ Ann Intern Med 1989; 110: 699
<strong>Acute</strong> <strong>lung</strong> <strong>injury</strong> (<strong>ALI</strong>)<br />
<strong>Acute</strong> <strong>respiratory</strong> <strong>distress</strong> <strong>syndrome</strong><br />
• <strong>Acute</strong> onset<br />
• Profound hypoxemia<br />
• Radiograph of<br />
pulmonary edema<br />
• No evidence of left<br />
atrial hypertension<br />
• “Stiff” or “small” <strong>lung</strong>s<br />
• Predisposing cause<br />
(ARDS)<br />
Bernard GR. Am J Resp Crit Care 1994; 149: 818
Causes of <strong>ALI</strong><br />
Severe<br />
sepsis<br />
26%<br />
Aspiration<br />
15%<br />
Trauma<br />
Pneumonia<br />
11%<br />
35%<br />
Other<br />
13%<br />
ARDS Network N Engl J Med 2000; 342:1301<br />
Drowning<br />
Pancreatitis<br />
Reperfusion<br />
Salicylate <strong>and</strong> narcotic OD<br />
Fat / amniotic fluid embolism<br />
Smoke / chemical inhalation
Mortality rate of <strong>ALI</strong>/ARDS<br />
100<br />
80<br />
Mortality (%)<br />
60<br />
40<br />
20<br />
0<br />
83 84 85 86 87 88 89 90 91 92 93<br />
Milberg J JAMA 1995;273:306
Supportive care for all patients<br />
• DVT prophylaxis<br />
• Gastrointestinal bleeding prophylaxis<br />
• Elevate HOB to 30 degrees<br />
• H<strong>and</strong> washing<br />
• Catheters inserted using full barrier precautions with<br />
chlorhexidine.<br />
• Sedation <strong>and</strong> analgesia protocols.<br />
• Reduction in transfusion thresholds.<br />
• St<strong>and</strong>ardized feeding protocols.<br />
• Contrast nephropathy avoidance.<br />
• Bedsore prevention program.
Causes of death<br />
Multiple<br />
organ failure<br />
Severe<br />
sepsis<br />
Underlying<br />
<strong>injury</strong> /<br />
illness<br />
Lung failure<br />
Montgomery AB Am Rev Respir Dis. 1985;132:485
Epithelial <strong>injury</strong><br />
Protein rich<br />
edema fluid<br />
Inflammatoryhemorrhagic<br />
infiltrate<br />
Increased<br />
vascular<br />
permeability<br />
Adapted from Ware LB, N Engl J Med. 2000; 342:1334<br />
Activated<br />
coagulation
<strong>ALI</strong> is heterogeneous<br />
Near normal<br />
Marginal<br />
Non-functional<br />
Maunder R, JAMA 1986; 255:2463
Major questions in <strong>ALI</strong> in the 1990’s<br />
• What is the best way to ventilate the <strong>lung</strong><br />
• Does attenuating inflammation offer benefit<br />
• What should be done with fluids
ARDSnet<br />
Mass General<br />
Washington<br />
San Francisco<br />
Philadelphia<br />
Baltimore<br />
NHLBI<br />
Utah<br />
Denver<br />
Michigan<br />
V<strong>and</strong>erbillt<br />
Clevel<strong>and</strong><br />
Duke<br />
NIH NHLBI ARDS Clinical Trials Network
Ventilation
Airway pressures<br />
Airway<br />
Pressure<br />
Peak inspiratory<br />
pressure (PIP)<br />
Plateau pressure<br />
PEEP<br />
Time
Mechanisms of ventilation induced<br />
<strong>lung</strong> <strong>injury</strong><br />
• Healthy animals developed <strong>lung</strong> <strong>injury</strong> if ventilated<br />
with PIP > 40 cm H 2 O “Barotrauma”<br />
– Kolobow Am Rev Resp Dis 135:312, 1987<br />
• Identical pressures did not cause <strong>injury</strong> if <strong>lung</strong><br />
expansion was restricted “Volutrauma”<br />
– Hern<strong>and</strong>ez J Appl Physiol 1989 66:2364<br />
• PEEP attenuated the <strong>injury</strong> of high pressure<br />
ventilation “Repetitive opening <strong>injury</strong>”<br />
– Webb Am Rev Resp Dis 1974; 110: 556
Ventilation can cause systemic<br />
inflammation: “biotrauma”<br />
1200<br />
600<br />
1000<br />
500<br />
BAL<br />
TNF<br />
(pg/ml)<br />
800<br />
600<br />
400<br />
BAL<br />
IL-6<br />
(pg/ml)<br />
400<br />
300<br />
200<br />
200<br />
100<br />
0<br />
Control MVHP MVZP HVZP<br />
0<br />
Control MVHP MVZP HVZP<br />
Tremblay J Clin Invest 1997; 99:944
Inadequate<br />
Tidal Volume<br />
or PEEP<br />
Large<br />
Tidal Volume<br />
or Inadequate<br />
PEEP<br />
Consequences:<br />
• Atelectasis<br />
• Hypoxemia<br />
• Hypercapnia<br />
<strong>ALI</strong><br />
Before Ventilation<br />
Consequences:<br />
• V/Q mismatch<br />
TNF<br />
IL-6, etc<br />
• Alveolar-capillary <strong>injury</strong><br />
• “Barotrauma”<br />
• Inflammation
Tidal volume in practice<br />
50<br />
40<br />
Percent of<br />
responders<br />
30<br />
Normal<br />
Recommended<br />
20<br />
10<br />
0<br />
< 5 5-9 10-13 14-17<br />
Tidal volume mL/kg measured body weight<br />
Carmichael L. J Crit Care 1996; 11: 9
Trials of lower tidal ventilation<br />
Mortality (%) Pressure<br />
Traditional “Protective” Limits<br />
Stewart 1 (n = 120) 47 50 PIP=50<br />
Brochard 2 (n = 116) 38 47 PIP=60<br />
Brower 3 (n = 52) 46 50 Pplat 45-55<br />
Amato 4 (n = 53) 71 38<br />
1. NEJM 338:355-361, 1998 2. AJRCCM 158: 1831, 1998<br />
3. CCM 27:1492, 1999 4. NEJM 339: 347, 1998
normal<br />
Hypothesis:<br />
In patients with <strong>ALI</strong>, ventilation with smaller tidal volumes<br />
(6 mL/kg) will result in better clinical outcomes than<br />
traditional tidal volumes (12 mL/kg) ventilation.<br />
ARDS Network N Engl J Med 2000; 342:1301
Ventilator procedures<br />
12 ml/kg Group<br />
•Initial Vt = 12 ml/kg PBW<br />
•If Pplat > 50 cmH 2 0, reduce Vt<br />
•Minimum Vt = 4 ml/kg<br />
6 ml/kg Group<br />
•Initial Vt = 6 ml/kg PBW.<br />
•If Pplat > 30 cmH 2 0, reduce Vt.<br />
•Minimum Vt = 4 ml/kg<br />
24<br />
20<br />
PEEP<br />
16<br />
12<br />
8<br />
4<br />
0<br />
0.3 0.4 0.4 0.5 0.5 0.6 0.7 0.7 0.8 0.9 0.9 0.9 1.0 1.0 1.0<br />
FIO2<br />
PaO 2 = 55 - 80 mmHg or SpO 2 = 88 - 95%<br />
St<strong>and</strong>ardized weaning protocol
Macro-barotrauma is not the<br />
mechanism of <strong>injury</strong><br />
6ml/kg 12 ml/kg<br />
p<br />
Requiring<br />
thoracostomy 13% 12% 0.932<br />
Not requiring<br />
thoracostomy 7% 9% 0.359<br />
ARDS Network N Engl J Med 2000; 342:1301
Effects of lower tidal volume<br />
14<br />
Tidal volume<br />
30<br />
Total <strong>respiratory</strong> rate<br />
Vt<br />
(ml/kg<br />
PBW)<br />
12<br />
10<br />
8<br />
6<br />
6 ml/kg<br />
12 ml/kg<br />
Breaths per<br />
minute<br />
26<br />
22<br />
18<br />
4<br />
0 1 2 3 4<br />
Study Day<br />
14<br />
0 1 2 3 4<br />
Study Day<br />
35<br />
Plateau pressure<br />
45<br />
Arterial PaCO2<br />
30<br />
cm water<br />
25<br />
20<br />
PaCO2 40<br />
(mm Hg)<br />
35<br />
15<br />
0 1 2 3 4<br />
Study Day<br />
ARDS Network N Engl J Med 2000; 342:1301<br />
30<br />
0 1 2 3 4<br />
Study Day
PaO 2 / FiO 2<br />
180<br />
160<br />
*<br />
*<br />
P/F<br />
140<br />
120<br />
ARDS Network N Engl J Med 2000; 342:1301<br />
6 ml/kg<br />
12 ml/kg<br />
0 1 2 3 4<br />
Study Day
Median ventilator<br />
free days<br />
7 days p=0.005<br />
Hospital mortality<br />
9 % ARR p=0.0054<br />
ARDS Network N Engl J Med 2000; 342:1301
Median organ failure free days<br />
CNS<br />
Hepatic<br />
*<br />
Cardiovascular<br />
*<br />
Coagulation<br />
*<br />
= 6 ml/kg<br />
= 12 ml/kg<br />
Renal<br />
ARDS Network N Engl J Med 2000; 342:1301<br />
0 7 14 21 28<br />
Days<br />
*
0<br />
6 mL/kg 12 mL/kg<br />
-20<br />
Percent change<br />
Day 0 to 3<br />
-40<br />
-60<br />
-80<br />
IL-6 IL-8 IL-10<br />
-100<br />
Crit Care Med. 2005;33:1<br />
P=0.001 between groups
Tidal volume as a risk factor for <strong>ALI</strong><br />
Baseline Vt 2001 Risk of developing <strong>ALI</strong><br />
♂=10.4 mL/kg<br />
♀=11.4 mL/kg<br />
Gajic O. Crit Care Med 2004, 32:1817<br />
OR 1.29 /mL Vt >6 PBW<br />
(1.12-1.51)
“Lung protective” ventilation<br />
V<br />
Add PEEP<br />
o<br />
l<br />
u<br />
m<br />
e<br />
<br />
12 ml/kg PBW<br />
Pressure<br />
Limit Distending<br />
Pressure
Hypothesis:<br />
In patients with <strong>ALI</strong> ventilated with 6 mL/kg, higher<br />
levels of PEEP will result in better clinical outcomes<br />
than lower levels of PEEP.<br />
N Engl J Med 2004; 351:327
Ventilation strategy<br />
PEEP<br />
•All given 6 mL/kg PBW tidal volume<br />
•Oxygenation: SpO 2 = 88 - 95% or PaO 2 = 55 - 80 mm Hg<br />
•St<strong>and</strong>ardized weaning<br />
24<br />
20<br />
16<br />
12<br />
8<br />
4<br />
0<br />
0.3 0.3 0.4 0.4 0.5 0.5 0.6 0.7 0.7 0.7 0.8 0.8 0.9 0.9 0.9 1.0 1.0 1.0 1.0<br />
N Engl J Med 2004; 351:327<br />
FIO2
Barotrauma<br />
20<br />
15<br />
Low PEEP<br />
High PEEP<br />
P=0.51<br />
Percent<br />
10<br />
5<br />
267 270<br />
0<br />
New Barotrauma<br />
N Engl J Med 2004; 351:327
Vt (ml/kg)<br />
9<br />
8<br />
7<br />
6<br />
Physiology of higher / lower PEEP<br />
Tidal volume<br />
Low PEEP<br />
High PEEP<br />
Pplat (mm Hg)<br />
28<br />
27<br />
26<br />
25<br />
24<br />
Pplat<br />
5<br />
16<br />
0 1 2 3 4 7<br />
PEEP<br />
23<br />
0.65<br />
0 1 2 3 4 7<br />
FIO2<br />
Low PEEP<br />
PEEP<br />
14<br />
12<br />
10<br />
FIO2<br />
0.60<br />
0.55<br />
0.50<br />
0.45<br />
High PEEP<br />
8<br />
0.40<br />
6<br />
0 1 2 3 4 7<br />
0 1 2 3 4 7<br />
Study day<br />
0.35<br />
N Engl J Med 2004; 351:327<br />
Study day
Physiology of higher / lower PEEP<br />
PaO2 / FIO2 ratio<br />
PaCO2<br />
210<br />
50<br />
190<br />
45<br />
P/F Ratio<br />
170<br />
PaCO2<br />
40<br />
150<br />
35<br />
Low PEEP<br />
High PEEP<br />
130<br />
0 1 2 3 4 7<br />
Study day<br />
30<br />
1 2 3 4 7<br />
Study day<br />
N Engl J Med 2004; 351:327
Hospital mortality<br />
25% low vs 28% high p=0.48<br />
Higher PEEP<br />
Lower PEEP<br />
Median ventilator free days<br />
14.5 low vs 13.8 high p=0.51<br />
N Engl J Med 2004; 351:327
Median organ failure free days<br />
Renal<br />
P=0.74<br />
Coagulation<br />
P=0.90<br />
Hepatic<br />
P=0.72<br />
Cardiovascular<br />
P=0.68<br />
CNS<br />
P=0.25<br />
0 7 14 21 28<br />
Low PEEP<br />
High PEEP<br />
N Engl J Med 2004; 351:327
“Lower tidal volume with 6 cc per kilo decreased mortality<br />
from 40% to 31%. You twirl a knob, you’re ‘gonna save a<br />
life..OK…”
Summary<br />
• Lower tidal volumes reduce death rates compared to<br />
“traditional” tidal volumes.<br />
• Patients on higher tidal volumes look more comfortable<br />
(until they die).<br />
• In the range tested higher PEEP is not “better” or<br />
“worse” than lower PEEP.<br />
• Lower tidal volumes may prevent <strong>ALI</strong> development.
Treating inflammation
Ketoconazole for Early Treatment of <strong>Acute</strong> Lung Injury <strong>and</strong> <strong>Acute</strong><br />
Respiratory Distress Syndrome: A R<strong>and</strong>omized Controlled Trial<br />
The NIH NHLBI ARDS Network<br />
JAMA 2000;283:1995-2002.
Crit Care Med. 2002;30:1-6.
RCT of Steroids for persistent ARDS<br />
• ARDS x 7 d with LIS > 2.5<br />
• R<strong>and</strong>omized (2:1) to<br />
steroids vs. placebo<br />
– MPS 2 mg/kg load then<br />
– 2 mg/kg/d x 14 d then<br />
– 1 mg/kg/d x 7 d then<br />
– 0.5 mg/kg/d x 7 d etc to 32 d<br />
• Improvement = LIS by 1<br />
• If no improvement at 10d,<br />
crossed over<br />
Placebo 8<br />
2 died<br />
2 improved<br />
4 cross-overs<br />
24 r<strong>and</strong>omized<br />
MPS 16<br />
16<br />
Meduri U. JAMA 1998; 280:159
Mortality outcomes<br />
Placebo MPS p value<br />
• Intention to Rx 5/8 (62%) 2/16 (12%) 0.03<br />
• As treated 2/4 (50%) 5/20 (25%) NS<br />
Meduri U. JAMA 1998; 280:159
• R<strong>and</strong>omized, blinded controlled trial of<br />
methylprednisilone vs. placebo for <strong>ALI</strong><br />
persisting > 7 days<br />
– 2 mg/kg/day x 14 days; then 1 mg/kg/day x 7<br />
days then tapered over 4 days.<br />
N Engl J Med. 2006 20;354:1671-84
Methylprednisilone vs. placebo results<br />
N Engl J Med. 2006 20;354:1671
Summary<br />
• With the exception of human recombinant<br />
activated protein C for severe sepsis, no antiinflammatory<br />
strategy has improved mortality<br />
in <strong>ALI</strong>.
Fluid therapy <strong>and</strong><br />
monitoring catheters
Is a PA catheter harmful or helpful <br />
• Prospective cohort study of the association<br />
between PAC (inserted ICU day 1) <strong>and</strong> survival,<br />
LOS, cost.<br />
• “Propensity score” to adjust for covariates.<br />
• PAC recipients matched with patients with same<br />
disease category <strong>and</strong> propensity score who did<br />
not get PAC.<br />
Connors A, JAMA 1996; 276:889-897
Evidence the PAC may be harmful<br />
Relative Hazard of Death:<br />
Patients (n)<br />
All (5735)<br />
ARF (1789)<br />
MOF (2480)<br />
CHF (456)<br />
Others* (1010)<br />
Odds Ratio (95% CI)<br />
1.21 (1.09-1.25)<br />
1.30 (1.05-1.61)<br />
1.32 (1.11-1.57)<br />
1.02 (0.55-1.89)<br />
1.06 (0.80-1.41)<br />
p<br />
< 0.001<br />
< 0.001<br />
< 0.001<br />
ns<br />
ns<br />
* (severe COPD, cirrhosis, nontraumatic coma, etc)<br />
Connors A. JAMA 1996; 276:889-897
Effectiveness of PAC in the initial care<br />
of the critically ill<br />
Mortality (30-day)<br />
ICU LOS (days)<br />
Total Costs<br />
PAC (n=1008)<br />
37.5%<br />
14.8<br />
$49,300<br />
No PAC (n=1008)<br />
32.8% p = 0.003<br />
13.0 p < 0.001<br />
$35,700 p < 0.001<br />
Connors A. JAMA 1996; 276: 889-897
FACTT trial objectives<br />
To evaluate the mortality <strong>and</strong> morbidity<br />
effects of:<br />
• PAC versus CVC management<br />
<strong>and</strong><br />
• “Fluid conservative” vs. “fluid liberal”<br />
management
FACTT: Factorial trial design<br />
C<br />
A<br />
T<br />
H<br />
E<br />
T<br />
E<br />
R<br />
PAC<br />
(n = 500)<br />
CVC<br />
(n = 500)<br />
Fluid Management<br />
“Conservative”<br />
(n = 500)<br />
“Liberal”<br />
(n = 500)<br />
250 patients 250 patients<br />
250 patients 250 patients
FACTT: Treatment principles<br />
• Evaluate MAP, UOP, CI, exam <strong>and</strong> CVP or PAOP <<br />
every 4 hours<br />
• Hypotension: correct as fast as possible using any<br />
combination of any fluid <strong>and</strong> vasopressor.<br />
• Oliguria treatment:<br />
– Fluid - if CVP or PAOP low or low-normal<br />
– Furosemide - if CVP or PAOP high/high-normal<br />
• Ineffective circulation (low cardiac output) treatment:<br />
– Fluid - if CVP or PAOP low or low-normal<br />
– Dobutamine - if CVP or PAOP high/high-normal
FACTT: Treatment principles<br />
• If hypotension, oliguria <strong>and</strong> ineffective circulation<br />
are absent or resolved:<br />
– <strong>and</strong> CVP or PAOP is abnormally high give<br />
incremental furosemide.<br />
– <strong>and</strong> CVP or PAOP is within the “normal range”<br />
give fluid or diuretics to separate patients into<br />
two “normal” pressure ranges (liberal <strong>and</strong><br />
conservative).
Intravascular<br />
Pressure<br />
(PAOP/CVP)<br />
>> Normal<br />
Low MAP<br />
Acceptable MAP off vasopressors<br />
Low UOP<br />
low flow nl flow<br />
Dobutamine<br />
Lasix<br />
Lasix<br />
Acceptable UOP<br />
low flow nl flow<br />
Dobutamine<br />
Lasix<br />
Lasix<br />
> Normal<br />
High normal<br />
Vasopressor<br />
Fluids<br />
Dobutamine<br />
Fluid<br />
Lasix<br />
Fluid<br />
Dobutamine<br />
Fluid<br />
Lasix<br />
Cons.<br />
Lasix<br />
Low normal<br />
Fluid<br />
Fluid<br />
Fluid<br />
Liberal<br />
Fluid
Conservative fluid strategy<br />
Furosemide<br />
UOP < 0.5 ml/kg/h &<br />
CVP or PAOP low<br />
MAP < 60 mmHg<br />
Low flow by exam or CI
Liberal fluid strategy<br />
Fluids<br />
FiO2 > 0.7<br />
CI > 4.5<br />
LUNG<br />
CVP 10-14<br />
14<br />
PAOP 14-18<br />
18<br />
Favors<br />
Perfused<br />
KIDNEY<br />
(organs)
FACTT: outcome variables<br />
Primary<br />
Mortality prior to hospital discharge to day 60<br />
Secondary (major)<br />
Ventilator - free days to day 28<br />
Organ - failure - free days to day 28
11,512 Met <strong>ALI</strong> Criteria<br />
1,001 R<strong>and</strong>omized<br />
1 Lost f/u<br />
Exclusions:<br />
•21% PAC<br />
•16% MD refusal<br />
•14% Chronic Lung Disease<br />
•11% Lethal underlying Disease<br />
•9% Dialysis<br />
•8% Time window<br />
•8% Severe liver Disease<br />
1,000 Entered Trial<br />
PAC Lib CVC Lib PAC Cons CVC Cons
N Engl J Med 2006; 354: 2213
Enrollment <strong>and</strong> outcomes<br />
1001 R<strong>and</strong>omized<br />
513 assigned to PAC<br />
501 received PAC<br />
12 not inserted<br />
5 withdrew consent<br />
5 exclusions discovered<br />
1 died before placement<br />
1 heart<br />
0 Lost<br />
block<br />
to follow<br />
during<br />
up<br />
insertion<br />
488 assigned to CVC<br />
487 received CVC<br />
7 crossovers 1 day 0<br />
2 day 1<br />
1 day 2<br />
1 withdrew 2 day consent 3<br />
1 day 6<br />
513 analyzed<br />
487 analyzed
Baseline demographics<br />
Characteristic<br />
Age<br />
Female (%)<br />
Primary <strong>lung</strong> <strong>injury</strong> (%)<br />
– Pneumonia<br />
– Severe sepsis<br />
– Aspiration<br />
– Trauma<br />
– Other<br />
Medical ICU (%)<br />
N Engl J Med 2006; 354: 2213<br />
PAC<br />
CVC p value<br />
50+1 50+1 0.81<br />
46 47 0.89<br />
0.81<br />
48 46<br />
23 24<br />
15 15<br />
8 7<br />
7 8<br />
66 66 0.91
Baseline severity of illness<br />
Characteristic<br />
APACHE III<br />
Shock (%)<br />
Pre-study fluid intake (L/24 h)<br />
PAC<br />
CVC p value<br />
95+1 94+1 0.55<br />
37 32 0.06<br />
4.9+0.2 4.9+0.2 0.99<br />
Tidal volume (ml/kg PBW)<br />
PEEP (cm H 2 O)<br />
PaO 2 /FIO 2<br />
Plateau pressure (cm H 2 0)<br />
7.4+0.1 7.4+0.1 0.88<br />
9.3+0.2 9.7+0.2 0.09<br />
159+3 151+3 0.10<br />
26.2+0.4 26.2+0.4 0.93<br />
N Engl J Med 2006; 354: 2213
Timing of protocol initiation<br />
Time to first protocol<br />
instruction (hours)<br />
ICU admission<br />
<strong>ALI</strong> qualification<br />
R<strong>and</strong>omization<br />
PAC CVC p value<br />
44.4+2 40.8+3 0.23<br />
25.2+0.7 23.0+0.6 0.02<br />
3.5+0.1 2.2+0.1
Instructions <strong>and</strong> compliance<br />
PAC<br />
CVC p value<br />
Instructions per day<br />
Instructions followed (%)<br />
4.8+0.1 4.4+0.1 0.03<br />
91+1 88+1 0.12<br />
N Engl J Med 2006; 354: 2213
Catheter use <strong>and</strong> complications<br />
Complications per catheter<br />
0.1<br />
0.05<br />
0<br />
3<br />
2<br />
1<br />
0.08<br />
P=0.35<br />
0.06<br />
PAC<br />
CVC<br />
Total catheters per patient<br />
2.47<br />
P
42 7
Positive blood cultures<br />
20<br />
15<br />
p=0.43<br />
Percent of<br />
patients<br />
10<br />
5<br />
PAC<br />
CVC<br />
0<br />
Any 1 2 >2<br />
Number of positive cultures<br />
N Engl J Med 2006; 354: 2213
No differences between PAC <strong>and</strong> CVC in:<br />
• Blood pressure<br />
• Heart rate<br />
• CVP<br />
• Net fluid balance<br />
• Vasopressor use<br />
• Tidal volume<br />
• PEEP<br />
• Plateau pressure<br />
• Oxygenation measures<br />
N Engl J Med 2006; 354: 2213
Proportion of assessments in shock after<br />
0.50<br />
entry<br />
0.40<br />
0.30<br />
PAC<br />
CVC<br />
0.20<br />
0.10<br />
0.00<br />
Shock Free<br />
Shock<br />
Engl J Med 2006; 354: 2213-2224<br />
Baseline shock status
1.6<br />
Creatinine<br />
(mg/dL)<br />
1.2<br />
0.8<br />
0.4<br />
Renal replacement therapy<br />
PAC 14 % vs. CVC 11% p=0.15<br />
Blood urea<br />
nitrogen<br />
(mg/dL)<br />
35<br />
30<br />
25<br />
PAC<br />
CVC<br />
N Engl J Med 2006; 354: 2213<br />
20<br />
0 1 2 3 4 5 6 7<br />
Study Day
11.0<br />
Hemoglobin<br />
(gm/dL)<br />
10.5<br />
10.0<br />
9.5<br />
PAC<br />
CVC<br />
9.0<br />
0 1 2 3 4 5 6 7<br />
Study Day<br />
Patients<br />
transfused to day 7<br />
(percent)<br />
Percent<br />
40<br />
30<br />
20<br />
38<br />
P
Kaplan Meier estimates of survival<br />
<strong>and</strong> unassisted breathing<br />
Mortality to day 60<br />
PAC 27.4% vs. CVC 26.3%<br />
P=0.69 CI -4.4 to 6.6%<br />
Ventilator-free days to day 28<br />
PAC 13.2+0.5 vs. CVC 13.5+0.5<br />
P=0.58
Organ failure free days to day 28<br />
Renal<br />
Hepatic<br />
Coagulation<br />
CNS<br />
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28<br />
PAC CVC N Engl J Med 2006; 354: 2213
Summary<br />
• Using the data from a PAC compared to that<br />
from a CVC in an explicit protocol:<br />
– Did not alter survival.<br />
– Did not improve organ function.<br />
– Did not change outcomes for patients entering in<br />
shock compared to those without shock.<br />
• PAC use resulted in more non-fatal<br />
complications, mostly arrhythmias.<br />
N Engl J Med 2006; 354: 2213
SICU mortality <strong>and</strong> PAC use<br />
40<br />
1<br />
Percent PAC use<br />
35<br />
30<br />
25<br />
20<br />
15<br />
10<br />
5<br />
0.9<br />
0.8<br />
0.7<br />
0.6<br />
0.5<br />
0.4<br />
0.3<br />
0.2<br />
0.1<br />
PAC Use<br />
O/E mortality<br />
0<br />
0<br />
'98 '99 '00 '01 '02 '03 '04 '05 '06<br />
Brunswold M Crit Care Med 2007;34:A55
N Engl J Med. 2006;354:2564
Frequency of diuretic <strong>and</strong> fluid bolus<br />
therapies<br />
0.5<br />
P
Cumulative furosemide dose<br />
1200<br />
1000<br />
Liberal<br />
Conservative<br />
800<br />
mg<br />
600<br />
400<br />
200<br />
0<br />
0 1 2 3 4 5 6 7<br />
N Engl J Med. 2006;354:2564<br />
Study Day
8000<br />
Net fluid balance<br />
ml of fluid<br />
6000<br />
4000<br />
2000<br />
0<br />
-2000<br />
40<br />
0 1 2 3 4 5 6 7<br />
Vasopressor use<br />
N Engl J Med. 2006;354:2564<br />
P=0.25<br />
Percent<br />
30<br />
20<br />
10<br />
0<br />
Prer<strong>and</strong><br />
Prefluid<br />
1 2 3 4 5 6 7<br />
Study Day<br />
Liberal<br />
Conservative
Cumulative fluid balance<br />
ml of fluid<br />
8000<br />
6000<br />
4000<br />
2000<br />
Liberal<br />
Conservative<br />
6 ml TV (1996-1999)<br />
PEEP (1999-2002)<br />
0<br />
0 1 2 3 4 5 6 7<br />
-2000<br />
N Engl J Med. 2006;354:2564<br />
Study Day
Cumulative fluid balance at day 7:<br />
Baseline shock vs. no shock<br />
12000<br />
ml of fluid<br />
9000<br />
6000<br />
3000<br />
Liberal<br />
Conservative<br />
6863 ml<br />
7234 ml<br />
0<br />
-3000<br />
N Engl J Med. 2006;354:2564<br />
Shock free<br />
Baseline<br />
Shock
CVP separation<br />
13<br />
12<br />
11<br />
10<br />
9<br />
8<br />
Liberal<br />
Conservative<br />
Prer<strong>and</strong><br />
Prefluid<br />
1 2 3 4 5 6 7<br />
Study Day<br />
N Engl J Med. 2006;354:2564
PAOP separation<br />
17<br />
16<br />
PAC Liberal<br />
PAC Conservative<br />
PAOP<br />
15<br />
14<br />
13<br />
12<br />
Prefluid<br />
N Engl J Med. 2006;354:2564.<br />
1 2 3 4 5 6 7<br />
Study Day
Proportion of assessments in shock after<br />
entry<br />
0.50<br />
0.40<br />
Liberal<br />
Conservative<br />
0.30<br />
0.20<br />
0.10<br />
0.00<br />
Shock Free<br />
Shock<br />
N Engl J Med. 2006;354:2564<br />
Baseline shock status
Tidal volume<br />
(mL/kg PBW)<br />
8.00<br />
7.00<br />
6.00<br />
5.00<br />
Conservative<br />
Liberal<br />
PEEP<br />
(cm H 2 O)<br />
N Engl J Med. 2006;354:2564<br />
4.00<br />
10.0<br />
9.0<br />
8.0<br />
7.0<br />
6.0<br />
0 1 2 3 4 7<br />
p=0.008<br />
0 1 2 3 4 7<br />
Study Day
200<br />
190<br />
Conservative<br />
Liberal<br />
PaO 2 / FiO 2<br />
14<br />
12<br />
Oxygenation index<br />
180<br />
170<br />
10<br />
160<br />
150<br />
P=0.07<br />
0 1 2 3 4 7<br />
8<br />
6<br />
P=0.003<br />
1 2 3 4 7<br />
On study plateau pressure<br />
Murray <strong>lung</strong> <strong>injury</strong> score<br />
27<br />
26<br />
P=0.002<br />
2.75<br />
2.50<br />
P < 0.001<br />
25<br />
2.25<br />
24<br />
2.00<br />
23<br />
0 1 2 3 4 7<br />
1.75<br />
0 1 2 3 4 7<br />
Study Day<br />
Study Day
Respiratory rate<br />
PaCO2<br />
30<br />
48<br />
46<br />
28<br />
44<br />
26<br />
42<br />
24<br />
Liberal<br />
Conservative<br />
1 2 3 4 7<br />
40<br />
38<br />
0 1 2 3 4 7<br />
13<br />
Minute ventilation<br />
7.43<br />
pH<br />
12<br />
7.41<br />
11<br />
7.39<br />
7.37<br />
10<br />
1 2 3 4 7<br />
Study Day<br />
7.35<br />
0 1 2 3 4 7<br />
Study Day
Survival to hospital discharge <strong>and</strong> breathing<br />
without assistance to day 60<br />
Mortality: Liberal 28.4% vs.<br />
Conservative 25.5% p = 0.30<br />
Median ventilator free days<br />
Liberal 14.6 vs. Conservative 12.1<br />
p = 0.002
ICU free days to day 28<br />
Conservative<br />
13.4<br />
P
Organ failure free days to day 28<br />
Renal<br />
Hepatic<br />
Coagulation<br />
CNS<br />
P=0.025<br />
0 4 8 12 16 20 24 28<br />
Conservative<br />
Liberal<br />
N Engl J Med. 2006;354:2564
Dialysis to Day 60<br />
Renal support<br />
Conservative Liberal P value<br />
Patients (%) 10 14 0.06<br />
Days 11.0 + 1.7 10.9 + 1.4 0.96<br />
N Engl J Med. 2006;354:2564
Hemoglobin<br />
(gm/dL)<br />
11.0<br />
10.5<br />
10.0<br />
9.5<br />
9.0<br />
Liberal<br />
Conservative<br />
0 1 2 3 4 5 6 7<br />
Study Day<br />
P
Frequency of metabolic abnormalities<br />
Abnormality<br />
K < 3.0<br />
K < 2.5<br />
Na > 150<br />
Na increase > 10<br />
HCO 3 > 40<br />
Conservative Liberal p value<br />
(Percent of patients)<br />
26 22 < 0.001<br />
4 3 0.23<br />
25 18 0.0088<br />
28 23 0.0810<br />
6 2 0.0005
Summary<br />
• Conservative patients had better <strong>lung</strong> <strong>injury</strong> scores,<br />
oxygenation index <strong>and</strong> lower PEEP <strong>and</strong> plateau pressures.<br />
• Conservative patients had lower MAP, SV, <strong>and</strong> CI.<br />
• No difference in heart rate, SvO 2 , proportion of protocol<br />
reassessments in shock, percentage receiving<br />
vasopressors.<br />
• The conservative strategy had higher BUN, but there was<br />
no difference in creatinine, renal failure free days, dialysis<br />
use or duration.<br />
N Engl J Med. 2006;354:2564
Conclusions<br />
• Use a normal tidal volume.<br />
• Use a level of PEEP you like.<br />
• Corticosteroids improve oxygenation not survival.<br />
• Routine use of a PAC should be avoided.<br />
• Application of a fluid conservative protocol after<br />
shock resolution improves physiology <strong>and</strong><br />
shortens time on ventilator.
ARDSnet<br />
FACTT: Acknowledgements