Criteria abstracted from The Users' Guide to Medical Literature, from the Health Information Research Unit and Clinical Epidemiology and Biostatistics, McMaster University

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Early Use of the Pulmonary Artery Catheter and Outcomes in Patients With Shock and Acute Respiratory Distress Syndrome: A Randomized Controlled Trial.

Richard C, Warszawski J, Angurl N, et al.

JAMA 2003;290 2713-2720. [abstract]

Reviewed by Satid Thammasitboon MD, MHPE, Jose Cortes MD, Pediatric Critical Care Medicine, Baylor College Medicine, Houston, TX

Review posted March 5, 2004

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I. What is being studied?:

The study objective:

To determine the effects on outcome of the early use of a Pulmonary artery catheter (PAC) in patients with shock of septic origin and/or respiratory distress syndrome (ARDS).

The study design:

A multicenter randomized controlled study

The patients included:

Inclusion criteria for shock - the presence of less than 12 hours of 4 criteria:

• Heart rate of at least 90/min
• Respiratory rate of at least 20/min or a PaCO2 of 32 mm Hg or lower or the use of mechanical ventilation
• The use of vasopressors to maintain a systolic blood pressure of at least 90 mm Hg despite fluid resuscitation, low dose of dopamine (≤ 5 mcg/kg/min), or dobutamine
• 1 of 3 signs of hypoperfusion (urine output < 0.5 ml/kg/hr); neurologic dysfunction defined by confusion, psychosis, or Glasgow coma scale score of ≤ 6; plasma lactate higher than upper limit of the normal value).

Inclusion criteria for ARDS - The presence of more than 24 hours of 4 criteria:

• Acute decrease in PaO2/FiO2 to 200 mmHg or lower
• Bilateral pulmonary infiltrate
• No clinical evidence of left atrial hypertension
• Requirement of positive pressure ventilation

The patients excluded:

• Younger than 18 years of age
• Hemorrhagic shock, myocardial infarction, thrombocytopenia,
• The patients who participated in other trials within the last 30 days, were moribund, or if the physicians refused to agree with the use of full life support.
• The patients with shock were excluded if the presence the 4 criteria were present more than 12 hours or if the last 2 criteria were present more than 12 hours.
• The patients with ARDS were excluded if the 4 criteria were present less than 24 hours.

The interventions compared:

The intervention group: The use of PAC to guide treatment within 2 hours following randomization

The control group: The conventional treatment without PAC.

No standard protocols for managing patients were used in either group. Patients in both groups were treated at the discretion of their physician.

The outcomes evaluated:

The primary outcome was mortality rate at 28 days. The secondary endpoints were mortality at 14 and 90 days, duration of ICU and hospital stay, ICU and hospital free days; ventilator free days; renal support, organ system, and vasoactive free days.

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes. The randomization and stratification for each center was conducted centrally using a permuted-block algorithm.

2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?

Was followup complete?

Yes. Only three patients were lost to follow-up between day 28 and day 90 (1 patient in the PAC group and 2 in the control group).

Were patients analyzed in the groups to which they were randomized?

Yes. The patients who did not receive the allocated treatment (10 patients in PAC group that didn't receive the PAC, and 15 patients in the control group received PAC) were included in the intention-to-treat analysis.

Secondary questions:

3. Were patients, health workers, and study personnel "blind" to treatment?

No. The blinding of the use of PAC is not possible. However, the potential biases on morbidity evaluation were minimized by an extensive on-site monitoring procedure. The severity scores were all calculated centrally by the statisticians, not the onsite investigators.

4. Were the groups similar at the start of the trial?

Yes. Patients' baseline characteristics did not differ between 2 groups (age, diagnosis, organ failure, SAPS II, SOFA, Odin, and Brussels scores) except for patient classification. There were more patients with medical conditions in PAC group (87 vs. 82%, p=0.02). Thirty three out of 42 surgical patients in PAC group were patients that underwent unscheduled surgery compared to 37/62 in the control group. The patients in PAC group might be slightly sicker than those in control group.

5. Aside from the experimental intervention, were the groups treated equally?

Treatments other than the experimental intervention were not standardized or explicitly described. Since there was no standardized protocol for patient management, each patient was treated on his/her physician's discretion. The general principles of treatment were set for all the participating centers as followings: optimization of circulating volume; use vasopressors to maintain MAP ≥ 60 mm Hg; no objective goal for O2 transport; free access to echocardiography; keep a maximum plateau pressure of 35 cm H2O and SpO2 > 90%, prevention of thromboembolism with low-molecular weight heparin. The type and site of PAC were decided at the discretion of the physician.

The information on patient management, such as, the amount of fluid resuscitation, number of blood transfusion, the use of activated protein C, cortisol therapy and ventilatory strategies, would be very helpful in determining the degree of heterogeneity of the treatment aside from the experimental intervention. All these therapies are potential confounders proved to have some impact on mortality in patients with sepsis and/or ARDS (1,2).

III. What were the results?

1. How large was the treatment effect?

The 28-day mortality rates were 59 vs. 61% in PAC and control group respectively. The mortality relative risk (RR) was 0.97 (95% CI 0.86, 1.10).

There was no significant difference in 14, 28 and 90-day mortality, length of ICU and hospital stays. There was also no significant difference between groups in day-14 organ system failure, renal support, vasoactive agents and mechanical ventilation free days.

2. How precise was the estimate of the treatment effect?

The 95% confident interval ranges from 0.86, a minimal beneficial effect, to 1.1, a very minimal harmful effect. There is a 95% probability that the true effect of PAC is in this range. This is a precise finding to conclude that the use of PAC does not affect 28-day mortality.

3. Did the treatment effect differ in subgroups of patients?

Subgroups analyzed included patients with shock exclusively, ARDS exclusively, shock and ARDS, and all septic shock patients. There were no significant differences on treatment effect in any subgroups of the patients.

IV. Will the results help me in caring for my patients?

1. Can the results be applied to my patient care?

Maybe. A similar study in children is not methodologically feasible. Since the mortality rates of sepsis is much lower in children (9% compared with 28% mortality), a considerably larger number of the patients would be required to have sufficient power to detect a meaningful effect. Although the subjects of the study were mainly adults, the results of the study could be applied to pediatric population with caution. Septic shock pathophysiology and response to therapies is age specific (3). It is unknown if technical complications of PACs are more common in children than adults.

2. Were all clinically important outcomes considered?

Yes. Since a single intervention, using PAC, may not decrease all-cause mortality in patients with septic shock and ARDS, other measures of morbidity were considered as secondary end points as described earlier.

3. Are the likely treatment benefits worth the potential harms and costs?

The study shows that the use of PAC does not increase morbidity or mortality. Whether or not it is efficacious when used with a goal directed therapy protocol is unknown and will require further investigation. Several factors that can influence the benefits of PAC include (1) the effectiveness of specific PAC data in discriminating between right and wrong therapeutic strategies, (2) the effectiveness of the right strategy in resolving the circulatory disorder, (3) the risk of deleterious effects with the wrong strategies, (4) the tightness of the relationship between the circulatory disorder and mortality. To conduct a well-designed study, it is critical to ensure quality of PAC data collection and interpretation, as well as, a careful selection of patients (4,5). Due to strong evidence on efficacy of goal-directed therapy on mortality in patients with septic shock, the future randomized controlled studies must include the goal-directed therapy with the use of PAC.

In regard to the safety issue, the author concluded the study demonstrated the use of PAC was a safe procedure in patients with shock and ARDS. The findings should be interpreted cautiously. In subgroup analysis, the mortality RR in patients with only ARDS was 0.98 (95% CI 0.69, 1.39). That means there is 95% probability that the true effect of PAC lies in the range of RR 0.69 to RR 1.39. Though it is not statistically significant, the RR of 1.39 brings up some clinical concerns. The problem of this subgroup analysis is that the sample size of 143 in ARDS subgroup was underpowered. There is probably too much uncertainty to conclude that PAC is safe for patients with ARDS.

References:

1. Patel GP, Gurka DP, Balk RA. New treatment strategies for severe sepsis and septic shock. Curr Opin Crit Care. 2003 Oct;9(5):390-6. [abstract]
2. Dellinger, RP. Cardiovascular management of septic shock. Crit Care Med. 2003 Mar;31(3):946-55. [abstract]
3. Carcillo JA, Fields AI; American College of Critical Care Medicine Task Force Committee Members. Clinical practice parameters for hemodynamic support of pediatric and neonatal patients in septic shock. Crit Care Med. 2002 Jun;30(6):1365-78. [abstract]
4. Squara P, Fourquet E, Jacquet L, Broccard A, Uhlig T, Rhodes A, Bakker J, Perret C A computer program for interpreting pulmonary artery catheterization data: results of the European HEMODYN Resident Study. Intensive Care Med. 2003 May;29(5):735-41. Epub 2003 Mar 25. [abstract]
5. Zarich S, Pust-Marcone J, Amoateng-Adjepong Y, Manthous CA. Failure of a brief educational program to improve interpretation of pulmonary artery occlusion pressure tracings. Intensive Care Med. 2000 Jun;26(6):698-703. [abstract]

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