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journal of medicine
established in 1812 january 2 , 2003 vol. 348 no. 1
abstract
background
Some observational studies suggest that the use of pulmonary-artery catheters to guide From the Faculty of Medicine, University
therapy is associated with increased mortality. of Calgary, Calgary, Alta. (J.D.S., R.D.H.,
R.F.B., L.K., G.F.P., C.J.D., S.V., A.K.); the
Sir Mortimer B. Davis Jewish General Hos-
methods pital, Montreal (D.P.L.); the Faculty of
We performed a randomized trial comparing goal-directed therapy guided by a pulmo- Medicine, University of Montreal, Montreal
(L.P.); the Faculty of Medicine, Dalhousie
nary-artery catheter with standard care without the use of a pulmonary-artery catheter. University, Halifax, N.S. (H.D.); and the
The subjects were high-risk patients 60 years of age or older, with American Society of University of Alberta, Edmonton (M.J.)
Anesthesiologists (ASA) class III or IV risk, who were scheduled for urgent or elective all in Canada. Address reprint requests to
Dr. Sandham at the Department of Critical
major surgery, followed by a stay in an intensive care unit. Outcomes were adjudicated Care Medicine, EG23 Foothills St. NW, Cal-
by observers who were unaware of the treatment-group assignments. The primary out- gary, AB T2N 2T9, Canada, or at sandham@
come was in-hospital mortality from any cause. ucalgary.ca.
line characteristics of the two treatment groups were similar. A total of 77 of 997 patients N Engl J Med 2003;348:5-14.
who underwent surgery without the use of a pulmonary-artery catheter (7.7 percent) Copyright 2003 Massachusetts Medical Society.
conclusions
We found no benefit to therapy directed by pulmonary-artery catheter over standard
care in elderly, high-risk surgical patients requiring intensive care.
included, in order of priority, fluid loading, inotrop- fined by a serum bilirubin concentration higher than
ic therapy, vasodilator therapy, vasopressors for hy- 34 mmol per liter and an increase of four seconds
potension, and blood transfusion for a hematocrit in the prothrombin time without the use of antico-
of less than 27 percent. Thromboprophylaxis using agulant agents. Sepsis from the central venous or
low-dose subcutaneous heparin was recommended pulmonary-artery catheter was defined by inflam-
for all patients both before and after surgery. A min- mation at the insertion site and systemic sepsis plus
imal postoperative ICU stay of 24 hours was re- a positive culture of blood or of material swabbed
quired; the length of the ICU stay thereafter was at from the catheter tip that resolved with removal of
the discretion of the attending clinician. the catheter.
Clinical data, including New York Heart Associ-
ation38 (NYHA) functional class, Goldman Cardiac avoidance of bias
Risk Index,39 vital capacity, and forced expiratory To avoid selective enrollment and crossover of pa-
volume in one second, were recorded at enrollment. tients, participating surgeons, anesthesiologists,
Clinical and outcome data were obtained 24 hours and intensivists at 19 Canadian institutions agreed
after surgery and weekly during the ICU stay and to refer all their eligible patients. At each site, a
the hospital stay, until death or hospital discharge. principal investigator was actively involved in en-
Vital status was ascertained 6 and 12 months after rollment and in the conduct of the study; a log was
randomization by telephone contact with patients, maintained to record information about all eligible
family members, surgeons, or family physicians, or patients. Random assignment to treatment groups
through hospital or provincial records. Base-line and assessment of outcomes on the basis of a prio-
clinical and demographic data were collected on all ri definitions was performed in a blinded manner.
patients who were eligible but not enrolled. A data So that adjudicators of chest radiographs would
safety and monitoring committee conducted a safe- remain unaware of treatment-group assignments
ty analysis after the enrollment of 800 patients and when reading the radiographs, we placed opaque
another after the enrollment of 1600 patients. tape over the pulmonary-artery catheter in images
and dummy tape on images from patients in the
outcome standard-care group. All outcomes except death
The primary outcome was in-hospital mortality were adjudicated by two observers who were un-
from any cause. Secondary outcomes were 6-month aware of the treatment-group assignments. Blind-
mortality, 12-month mortality, and in-hospital mor- ing of patients and clinicians was not considered to
bidity, which was defined a priori according to ob- be feasible.
jective criteria as follows. Myocardial infarction was
defined by the presence of a new Q-wave myocar- statistical analysis
dial infarction on electrocardiography or the pres- The sample size of 1000 per group was chosen to
ence of compatible ST-T wave changes on electro- provide the study with power exceeding 90 percent
cardiography plus an increase in either the creatine for distinguishing between mortality rates of 10 per-
kinase MB fraction or troponin to abnormal levels. cent and 15 percent in the two groups, allowing a
Left ventricular failure was assessed on the basis of two-sided type I error rate of 5 percent. Additional
adjudicated chest radiography. Arrhythmia was de- calculations confirmed that there would be ade-
termined by electrocardiography or analysis of a quate power under varied assumptions for ex-
rhythm strip. Pneumonia was defined according to ample, 78 percent power to distinguish between
the criteria of the Centers for Disease Control and mortality rates of 5 percent and 8 percent.
Prevention.40 Pulmonary embolism was document- All analyses were conducted on an intention-to-
ed by autopsy, positive pulmonary angiography, pos- treat basis. Continuous variables such as age, vital
itive spiral computed tomography, high-probability capacity, and Goldman index39 were compared with
ventilationperfusion scanning, or positive nonin- the use of the unpaired t-test or the Wilcoxon rank-
vasive Doppler ultrasonography of the leg. Renal sum test, depending on their distributional proper-
insufficiency was defined by a 50 percent increase ties. Skewed variables were summarized as medians
in the creatinine concentration or the need for di- and interquartile ranges. Differences in proportions
alysis in a patient with preexisting nondialysis- (in-hospital mortality rates, rates of medical condi-
dependent renal failure. Liver insufficiency was de- tions and complications, rates of interventions, and
Table 1. (Continued.)
Goldman index
Median 8 8 8
Interquartile range 310 311 38
Vital capacity liters 2.780.94 2.800.99
Forced expiratory volume in one second liters 1.920.74 1.930.75
Hemoglobin concentration g/liter 13220.0 13020.8 13023.1
Serum bilirubin concentration mg/dl
Median 0.5 0.5
Interquartile range 0.40.8 0.40.8
Serum creatinine concentration mg/dl
Median 1.1 1.1 1.1
Interquartile range 0.91.4 0.91.4 0.91.4
* Plusminus values are means SD. Abdominal surgery included cholecystectomy, bowel resection, gastric surgery, radical hysterec-
tomy, radical cystectomy, nephrectomy, radical prostatectomy, and other types of abdominal surgery; thoracic surgery included
lobectomy, pneumonectomy, esophageal surgery, decortication, and other types of thoracic surgery; major vascular surgery includ-
ed repair of an abdominal aneurysm, aortofemoral bypass, and other types of major vascular surgery; and orthopedic surgery in-
cluded total hip replacement, fracture fixation, and other types of orthopedic surgery. Among the patients who were eligible but were
not enrolled, data on sex were missing for 40 patients, and data on type of surgery were missing for 9 patients with American Society
of Anesthesiologists (ASA) class III risk and 1 patient with ASA class IV risk. To convert values for bilirubin to micromoles per
liter, multiply by 17.1; to convert values for creatinine to micromoles per liter, multiply by 88.4. NYHA denotes New York Heart
Association.
P<0.05 for the comparison between the enrolled patients and the nonenrolled patients.
P<0.001 for the comparison between the enrolled patients and the nonenrolled patients.
The ASA risk classes range from I to V, with higher classes indicating greater risk; patients with class III risk have severe systemic
disease, and patients with class IV risk have severe systemic disease that is a constant threat to life.
The Goldman Cardiac Risk Index is a point system based on history, physical examination, electrocardiographic findings, general
status, and type of operation. Higher classes indicate a higher predicted risk of cardiac events or death from cardiac causes.
Class 1 is 0 to 5 points (risk of cardiac events, 0.7 percent; risk of death from cardiac causes, 0.2 percent); class 2 is 6 to 12 points
(risk of cardiac events, 5.0 percent; risk of death from cardiac causes, 2.0 percent); class 3 is 13 to 25 points (risk of cardiac
events, 15 percent; risk of death from cardiac causes, 2.0 percent); class 4 is more than 26 points (risk of cardiac events, 22 per-
cent; risk of death from cardiac causes, 56 percent).
P<0.05 for the comparison between the standard-care group and the catheter group.
the lack of an available operating room (in 9 cases), The base-line characteristics of the patients in
withdrawal of consent (in 7 cases), and other rea- the standard-care group and the catheter group
sons (in 3 cases). In addition, crossover to use of a were similar (Table 1). The screened patients who
pulmonary-artery catheter occurred in 24 of the pa- were not enrolled were marginally older, were less
tients in the standard-care group (2.4 percent). In likely to have ASA class IV risk, were more likely to
11 cases, these crossovers represented inadvertent be women, and had a lower incidence of angina and
protocol violations; 12 pulmonary-artery catheters previous myocardial infarction than the patients
were deliberately placed by the treating physician; who were enrolled.
and in 1 case, the reason for placement was un-
known. Twelve (50 percent) of the crossovers oc- mortality
curred on or after day 4. In the catheter group, 939 All subjects were followed until hospital discharge.
patients (94.2 percent) received the planned therapy, The median length of the hospital stay from the
and 58 did not; the reasons were the lack of an avail- time of enrollment was the same in the two groups
able ICU bed (in 5 cases), the lack of an available (10 days [interquartile range, 7 to 15]). Six-month
operating room (in 20 cases), withdrawal of con- follow-up was complete for 963 patients in the
sent (in 23 cases), failure of the pulmonary-artery standard-care group (96.6 percent) and 930 patients
catheter (in 5 cases), and other reasons (in 5 cases). in the group assigned to pulmonary-artery catheters
Proportion Surviving
0.8
cent, P=0.05). It was initiated within 24 hours after
surgery in 52.1 percent of the patients in the stand- 0.6 Standard care
Pulmonary-artery
ard-care group, as compared with 53.7 percent of catheter
0.4
those in the catheter group. Diagnostic testing for
clinically suspected venous thromboembolism was 0.2
performed in 69 patients in the standard-care group
0.0
(6.9 percent) and 57 patients in the catheter group 0 2 4 6 8 10 12
(5.7 percent, P=0.31). The types of testing used Months
(including venography, Doppler ultrasonography,
No. at Risk
ventilationperfusion lung scanning, and pulmo- Standard care 997 885 861 844 803 794 786
nary angiography) were similar in the two groups. Pulmonary-artery 997 842 826 808 773 761 747
catheter
The incidence of myocardial infarction, conges-
tive heart failure, supraventricular tachycardia, ven- Figure 1. KaplanMeier Survival Curves to One Year.
tricular tachycardia, hepatic insufficiency, sepsis Data for six patients in the standard-care group and seven patients in the cath-
from the central venous catheter or pulmonary- eter group for whom exact dates of death were unavailable are included in the
artery catheter, and pneumonia did not differ sig- number at risk up to the last follow-up contact when the patient was still alive.
nificantly between groups (Table 2). Fifteen patients
in the catheter group (1.5 percent) had one or more
adverse effects of the use of a pulmonary-artery preoperative, intraoperative, and postoperative pe-
catheter (two cases of hemothorax, three pulmo- riods were 6.5, 10.4, and 9.1 mm Hg, respectively,
nary hemorrhages, one pulmonary infarction, three in the standard-care group, as compared with 6.7,
inadvertent punctures of a major artery, and eight 10.1, and 9.3 mm Hg, respectively, in the catheter
cases of pneumothorax). Central venous catheters group.
were placed in 769 patients in the standard-care
group (77.1 percent). Five of these patients (0.7 per-
discussion
cent) had adverse effects of this catheter placement
(an inadvertent puncture of a major artery in one In this large, multicenter, randomized, single-blind
patient and pneumothorax in four patients). clinical trial, we observed no evidence of a benefit of
treatment guided by a pulmonary-artery catheter,
adherence to the protocol as compared with standard care. On the other hand,
More patients in the catheter group than in the the results of our study indicate that in this popula-
standard-care group received inotropic agents (48.9 tion of surgical patients, the insertion of a pulmo-
percent vs. 32.8 percent, P<0.001), vasodilators (8.5 nary-artery catheter is not linked to excess mortality,
percent vs. 3.9 percent, P<0.001), antihypertensive as has been reported previously. The confidence in-
medication (25.5 percent vs. 16.9 percent, P<0.001), terval for the difference in mortality excludes an ab-
packed red cells (56.6 percent vs. 47.0 percent, solute difference of more than 2.5 percent favoring
P<0.001), and colloid (54.8 percent vs. 47.7 per- either strategy, and no difference emerged at the
cent, P=0.002). one-year follow-up. The length of the hospital stay
In the catheter group, the goals for the cardiac in- was similar in the two groups.
dex (3.5 to 4.5 ml per minute per square meter) and In our study, treatment guided by a pulmonary-
the oxygen-delivery index (550 ml per minute per artery catheter was coupled with defined physiolog-
square meter) were met in 18.6 percent and 21.0 ical goals and treatment strategies designed to op-
percent of patients, respectively, at entry and in 79.0 timize treatment. Our findings and the findings of
percent and 62.9 percent of patients, respectively, af- others10,17,24 demonstrate that it is difficult to
ter surgery (Fig. 3). Central venous pressure did not achieve such physiological goals a practical real-
differ significantly between the patients in the cath- ity of therapy guided by a pulmonary-artery cathe-
eter group and the 769 patients in the standard-care ter. Nevertheless, such therapy was associated with
group in whom central venous catheters were a significantly different treatment effect from stand-
placed. The mean central venous pressure for the ard care. The a priori goals for the oxygen-delivery
1000
6.0
4.0
600
3.5 550
3.0
400
2.0
1.0 200
0
Base Line Preoperative Intraoperative Postoperative
Period Period Period
Figure 3. Box Plots of Maximal Attained Values for the Cardiac Index and the Oxygen-Delivery Index at Base Line and
during the Preoperative, Intraoperative, and Postoperative Periods in Patients Assigned to Pulmonary-Artery Catheters.
Lower and upper limits of boxes indicate the 25th and 75th percentiles; dots within boxes indicate the median values.
The lines extending from the boxes indicate the range of nonoutlying values. Outliers are plotted separately (open cir-
cles). The portion of the box plot above the broken line corresponds to the subgroup of patients in whom the defined
goals were met.
clinical trials of the use of pulmonary-artery cathe- to all the staff members of all the participating hospitals and ICUs
ters in other populations of patients are feasible. for their outstanding efforts; to the many research assistants and sec-
retaries who have been associated with the study; to Lucille Schave-
Supported by grants from the Canadian Institute for Health Re-
maker, Dongmei Wang, Judie Lasante, Dean Yergens, Reza Shahpori,
search and Abbott Laboratories of Canada.
and Darlene Williamson, Department of Critical Care Medicine,
Dr. Devitt has reported receiving lecture fees from Eli Lilly.
University of Calgary; and to Jeanne Sheldon, B.A., and the staff of
We are indebted to Allan Spanier, M.D., Sir Mortimer B. Davis
the Thrombosis Research Unit, University of Calgary.
Jewish General Hospital, Montreal, who was a site principal investi-
gator and coauthor until his death in May 1998. We are also indebted
ap p e n d i x
Participating members of the Canadian Critical Care Clinical Trials Group included the following centers and principal investigators: S. Vin-
er, T. Rosenal, Calgary GeneralPeter Lougheed Hospital, Calgary, Alta.; C.J. Doig, Foothills Hospital, Calgary, Alta.; H. Devitt, Sunnybrook
Health Sciences Centre, Toronto; D.P. Laporta, Jewish General Hospital, Montreal; L. Passerini, Hotel Dieu de Montreal, Montreal; P.J.E.
Boiteau, Mount Sinai Hospital, Toronto; A. Kirby, St. Josephs Hospital, London, Ont.; G. Rocker, R. Hall, Victoria General Hospital, Hali-
fax, N.S.; J. Hooper, Ottawa Civic Hospital, Ottawa, Ont.; P. Hebert, P. Cardinal, Ottawa General Hospital, Ottawa, Ont.; M. Jacka, A. Clark,
St. John General Hospital, St. John, N.B.; T. Houston, Toronto Western Hospital, Toronto; N. Mehta, Fredericton General Hospital, Frederic-
ton, N.B.; R. Johnston, Royal Alexandra Hospital, Edmonton, Alta.; R. Steinberg, Holy Cross Hospital, Calgary, Alta.; M. Jacka, Sudbury
General Hospital, Sudbury, Ont.; D. Roberts, Health Sciences Centre, Winnipeg, Man.; D. Evans, Montreal General Hospital, Montreal; M.
Tweedale, Vancouver General Hospital, Vancouver, B.C. Study Coordinator: L. Knox, University of Calgary, Calgary, Alta. Safety Monitoring Com-
mittee: G.F. Pineo (chair), University of Calgary, Calgary, Alta.; W. Sibbald, Sunnybrook Health Sciences Centre, Toronto; A. Laupacis, Uni-
versity of Toronto, Toronto.
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