Page 78 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

46 PART 1: An Overview of the Approach to and Organization of Critical Care

for management at the ECMO center. By definition, the potential for Group Risk
confounding exists when factor A, in this case, care at a tertiary referral
center, may be associated with improved outcomes, and is also related Antibiotics 10/200 = 0.050
to Factor B, in this case, management using ECMO, but is not a result Placebo 15/200 = 0.075
of Factor A. Critics have argued, in fact, that the improved in outcomes
may have been related to overall improved care at the single referral
center rather than the ECMO intervention itself. 9 And the RR is

THE PROBLEM OF SURROGATE OUTCOMES Risk in Intervention Group 0.050 = 0.67
=
Risk in Control Group
MEASURES IN CRITICAL CARE RESEARCH 0.075
https://kat.cr/user/tahir99/
The RRR is 0.33 or 33% and the absolute risk reduction is 0.025 or
Before implementing a new treatment, clinicians would ideally like 2.5%. The statistical significance of RR is measured by the 95% confi-
to know what that treatment’s impact will be on important patient- dence interval which, as we will discuss further below, tells us the range
centered outcomes such as mortality and quality of life. Critical care of values that is most consistent with the true RR.
research, however, is often both complex and costly. The time and
resources needed to carry out studies that are adequately powered ■ NUMBER NEEDED TO TREAT
to detect a mortality difference sometimes make them infeasible.
Therefore, critical care research not infrequently relies on surrogate Knowing the relative risk and absolute risk reduction allows the cal-
18
end points that allow demonstration of treatment effect with fewer culation of the number needed to treat (NNT). NNT is the number
patients over less time. 1 of patients that must receive the intervention in order to avoid a single
Trials using surrogate end points should be interpreted with great occurrence of the outcome being studied. Using our example, the NNT
caution. Acceptable surrogate end points are those that have been would tell us how many patients would need to be treated with antibiot-
validated as a marker for the disease outcome of interest. Few surrogate ics in order to avoid one episode of VAP. NNT is calculated by dividing
markers meet this criterion. There have been important examples in the absolute risk difference into 1. In this small VAP study, the NNT =
critical care research in which a surrogate end point has suggested that a 1/(0.075 − 0.05) = 40.
therapy was beneficial when it was in fact harmful. 10 It is important to remember, however, that the risk ratio from a given
Investigations of partial liquid ventilation (PLV) for acute respiratory study can be misleading. In a much larger study that examines a less com-
distress syndrome (ARDS) in adults are an example of this problem. mon outcome, an equivalent risk ratio can be found even with a much
Early studies of PLV for ARDS demonstrated significant improvements different NNT. For example, if there were 20,000 patients in each group,
in oxygenation, and some interpreted these findings to mean that the rather than 200, and there were 100 cases of VAP in the antibiotic group
11
treatment was beneficial for patients. However, subsequent studies failed and 150 cases in the placebo group, the risk ratio would be the same.
to show any impact on mortality. 12,13
Combined end points have been used in some critical care research as
a means to identify clinically meaningful outcomes with fewer patients. Group Risk
14
A commonly used combined end point in critical care research is
ventilator-free days (VFDs), which measures the amount of time a Antibiotics 100/20,000 = 0.0050
patient is alive and not on a mechanical ventilator, usually over 28 days. Placebo 150/20,000 = 0.0075
10
There are a number of problems with an outcome measure like VFD. 15,16
Although a thorough examination of combined end points is beyond
the scope of this chapter, it is important to remember that studies have And the RR is
demonstrated improvements in mortality even without differences in Risk in intervention group 0.050
VFD and, further, VFD as an end point assumes that the end points Risk in control group = 0.075 = 0.67
17
of mortality and prolonged mechanical ventilation are of equal weight. 15
The RRR would thus still be 0.33 or 33%, but the absolute risk reduc-
MEASURES OF ASSOCIATION AND tion would be 0.0025 or .25%. In this study, then, despite an equivalent
QUANTIFYING EFFECT SIZE risk ratio, the NNT is 1/(.0075 − .005) = 400 or 10 times higher.
Judging Applicability: Once the clinician has assessed the validity of a
Appropriate interpretation of the results of treatment trials requires study and is satisfied with the meaning of the outcomes in that study, he
clear understanding of measures of association, including both relative or she must make an assessment of whether the study findings are gen-
risk and absolute and relative risk reduction (RRR). Making an educated eralizable and truly applicable to a given patient. Consideration must be
decision about the application of a study’s findings to one’s patients also given to three different applicability questions. First, the clinician must
necessitates assessing the number needed to treat to see a benefit to the decide if there are biological or pathophysiologic reasons why the study
population. may not apply: Is the patient’s disease truly equivalent to the one evalu-
■ RELATIVE RISK AND RRR ated in the study? Second, the social context in which the treatment is

The relative risk (RR), also called the risk ratio, for a given outcome in to be provided should be considered: Are there reasons why this patient
cannot adhere to the intervention or are there reasons why I, as a clini-
a study is calculated by dividing the risk in the treatment group by the cian, cannot monitor this intervention appropriately? Finally, epidemio-
risk in the placebo group. The RRR is calculated by subtracting the RR logic factors must be assessed: Is there reason to believe that the patient
from 1, and the absolute risk reduction is simply calculated by subtract- is at different risk than those in the original study for the outcome being
ing the risk in the control group from the risk in the intervention group. prevented or for a side effect from the intervention? 19
Consider the following hypothetical example:
An RCT enrolls 400 patients to receive antibiotics or placebo in an
effort to decrease the incidence of ventilator-associated pneumonia P VALUES, CONFIDENCE INTERVALS, AND POWER
(VAP). A total of 200 patients are assigned to receive antibiotics and 200 No discussion about evaluating clinical research evidence is complete
are assigned to receive placebo. Ten patients in the antibiotic group and without addressing the meaning of p values and confidence intervals
15 in the placebo group get VAP. Therefore (CIs). These statistical measures aid the assessment of whether observed

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