FLINDERS CENTRE FOR EPIDEMIOLOGY AND BIOSTATISTICS (FCEB)

JOURNAL CLUB – 17TH MAY 2012

Dr Wayne Clapton, Public Health Physician, Lecturer, Critical Care Medicine, Flinders Uni.

1. “Spurious Inferences about Long-Term Outcomes: The Case of Severe Sepsis and Geriatric Conditions”, Theodore J. Iwashyna, Giora Netzer, Kenneth M. Langa, and Christine Cigolle, Am J Respir Crit Care Med Vol 185, Iss. 8, pp 835–841, Apr 15, 2012. 2. “Does the Hospital Make You Older Faster?”, Gordon D. Rubenfeld, Am J Respir Crit Care Med Vol 185, Iss. 8, pp 835–841, Apr 15, 2012. (Editorial)

DISCLAIMER

• PLEASE NOTE THAT MOST OF THE MATERIALS ON THE FOLLOWING SLIDES ARE SUMMARISED QUOTES FROM THE PAPER(S).

• SO YOU CAN ASSUME QUOTATION MARKS IN MULTIPLE PLACES.

• THERE IS NOTHING ORIGINAL FROM ME HERE.

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject (Study Rationale) • Survivors of critical illness in general, and severe sepsis in

particular, have a substantial burden of symptoms after their acute illness.

What This Study Adds to the Field • Many common problems of aging—the so-called geriatric

conditions—have a very high prevalence among survivors of severe sepsis, but they are not caused by severe sepsis.

• However, common study designs that did not fully control

for pre-sepsis levels and trajectories of illness might have reported a false-positive association.

OBJECTIVES

1. Test the hypothesis that severe sepsis leads to an increase in the prevalence of geriatric conditions (injurious falls, low body mass index [BMI], incontinence, vision loss, hearing loss, and chronic pain) among survivors.

2. To examine the concordance between different study designs evaluating the impact of critical illness on survivors.

METHODS – Data Source • Patients with severe sepsis were identified in the Health and Retirement

Study (HRS), • USA nationally representative cohort (27,000 people aged > 50 years) • Started 1992 • Interviewed every 2 years (reinterview rates > 90-95%)

• Linked Medicare claims (16,772 > age 65 agreed).

• Studied here: – all respondents with at least one HRS interview during 1998 to 2004 and – for whom there were subsequent claims-based data on a hospitalization for

severe sepsis during 1998 to 2005.

• All patients were followed through death or the 2006 HRS survey.

• Analyses focused on: – hospitalizations that respondents survived until at least one follow-up

interview—the “survivors” cohort.

METHODS - Ascertainment of Severe Sepsis • They relied on a claims-based definition of severe

sepsis, which has been widely used and clinically validated.

• Consistent with an international consensus conference

definition of severe sepsis. • This claims-based definition requires evidence of both

an infection and new-onset organ dysfunction during a single hospitalization.

• If a patient had more than one distinct septic

hospitalization, each hospitalization was included.

METHODS – Ascertainment of Outcomes: Geriatric Conditions

• Geriatric conditions were ascertained based on interviews with respondents or their proxies.

• Active or severe forms examined: – Falls: any fall resulting in injury, or three or more falls in

the previous 2 years. – Incontinence: incontinence requiring an undergarment, or

incontinence 15 or more days each month. – Low body mass index (BMI): below 18.5 kg/m2 (based on

self-report height and weight). – Poor vision: poor eyesight or blindness despite use of

corrective lenses. – Poor hearing: poor hearing despite use of hearing aids. – Severe pain: “often” troubled with severe pain.

ANALYSES - Overview

• Three comparators were used to assess an association of severe sepsis with geriatric conditions in survivors:

1. Prevalence in the United States population aged 65

years and older,

2. Survivors’ own pre-sepsis levels assessed before hospitalization, or

3. Survivors’ own pre-sepsis trajectory.

ANALYSIS 1: Compare with National Cohort • Replicated a cohort of patients, empanelled on the day of hospital

admission for severe sepsis. • Followed forward in time to their first post-sepsis HRS interview. • Prevalence of each geriatric condition in this survivors cohort

compared with the corresponding age-group–matched national population estimate of prevalence.

• Chi-square test. • These national prevalence estimates were assessed using the same

survey instrument at a similar point in time .

ANALYSIS 2: Patients’ pre-sepsis measurement • Pre-/post- design in the same cohort. • Respondents with severe sepsis were compared with their own pre-sepsis

measurement of the outcome variables. • Pre-sepsis assessments were collected prospectively, thus limiting the potential

bias of retrospective assessment of the geriatric conditions before the sepsis episode.

• Unadjusted and adjusted models. • Only eventual survivors were included in pre-sepsis measurements, not all pre-

sepsis patients. • In the adjusted models, respondents were matched to their own pre-sepsis

measurement, and only within-person variance was examined. • Respondents served as their own controls.

ANALYSIS 3: Pre-sepsis longitudinal data • In the same cohort, multiple years of pre-sepsis longitudinal data through the first

post-sepsis assessment were analyzed. • A within-person fixed effect model was used (also called a latent growth curve

model) . • “Fixed effect” is used here in its econometric/panel data sense, not the somewhat

distinct sense in which the term is used in biostatistics. • Respondents again served as their own controls, and only within-person variance

was assessed. • Each respondent provided full control for all characteristics of that respondent that

did not change over time. • These models are estimated for a dichotomous outcome, using clogit in Stata v.12. • The independent variable, time from the interview to severe sepsis - continuous

variable. • The effect of severe sepsis - dichotomous indicator variable, representing the

extent to which the probability of the geriatric condition was greater than expected based on the pre-sepsis linear time trend.

• Similar models estimated the effects of severe sepsis on the total number of geriatric conditions, using xtpoisson, fe in Stata.

MEASUREMENTS AND MAIN RESULTS • 623 severe sepsis hospitalizations were followed a median of 0.92 years.

• When compared with the 65 years and older population, surviving severe sepsis

was associated with increased rates of: – low BMI, – injurious falls, – incontinence, – vision loss.

• Results were similar when comparing survivors to their own pre-sepsis levels.

• The association of low BMI and severe sepsis persisted when controlling for

patients’ pre-sepsis trajectories, but after such controls, there was NO association of severe sepsis with:

– injurious falls, – incontinence, – vision loss, – hearing loss, – chronic pain

RESULTS - 1

RESULTS - 2

RESULTS - 3

RESULTS - 4

RESULTS - 5

DISCUSSION • Investigation of a nationwide, prospectively assessed cohort of older Americans found

that many geriatric conditions were very common after hospitalization for severe sepsis.

• This reinforces previous findings that cognitive impairment and limitations in activities of daily living are more common after severe sepsis.

• These results demonstrate an increase in low BMI among survivors, and in post hoc analyses, decreases in the ability to walk across a room and lift 10 pounds.

• However, the prevalence of five other major geriatric conditions—injurious falls, incontinence, chronic pain, and vision and hearing impairment—were not increased after severe sepsis when patients’ pre-sepsis trajectories of illness were considered.

• Failure to measure and control for these pre-sepsis trajectories might lead to the spurious inference of a clinically and statistically significant association with severe sepsis.

• These findings have both clinical and methodological implications.

DISCUSSION – Clinical Implications 1. A large burden of consequential conditions is carried by survivors.

– suggests that interventions to improve quality of life for survivors might benefit from an increased geriatric focus.

2. Suggest that the negative long-term effects of severe sepsis may be focused in sarcopenia and brain dysfunction (cognitive impairment), in contrast to other facets of aging. – Suggests that severe sepsis produces frailty in survivors.

– “biologic syndrome” model - Fried et al – “burden” model – Rockwood et al

3. Emphasize that some of the burdens of survivorship may not be caused

by severe sepsis or ICU care. – From a prevention perspective, this suggests:

• that some of the burdens of survivorship cannot be avoided by actions in the ICU, as they predate ICU admission.

– From a discharge and remediation perspective, the issue of causality is less important than the magnitude of the unmet need.

• For sepsis survivors, that magnitude seems substantial for geriatric conditions.

DISCUSSION – Methodological Implications - 1

• These results serve as a caution against the over-interpretation of studies based on inception cohorts that lack adequate measures of pre-diagnosis trajectory of outcomes of interest.

• Substantial anecdotal experience suggests that

analyses of the type presented in Tables 2 and 3 may be interpreted causally, even as they are formally acknowledged to be “only associations.”

• The present results demonstrate that this leap to a

causal interpretation can be hazardous.

DISCUSSION – Methodological Implications - 2

• At least four mechanisms that may generate this problem of spurious inference from the prospective cohort design. (Not mutually exclusive.):

1. Non-constant probability of developing the outcome.

2. Reciprocal causation.

3. Outcome of interest does not fully manifest the risk

status.

4. Outcome of interest is an absorbing state.

DISCUSSION – Methodological Implications – 3 (e.g.: Severe sepsis Incontinence ↑Risk for urinary tract infection and severe sepsis)

LIMITATIONS 1. The HRS is a biennial survey

it is useful for studying medium- to long-term adaptation after critical illness, not the acute phase of recovery.

2. A claims-based definition of severe sepsis was used, rather than detailed clinical

case ascertainment.

3. The negative conclusions about the associations of severe sepsis and most geriatric conditions may have been influenced by truncation by death, in which the extreme phenotype of loss of function cannot be observed because it is lethal.

• This potential bias can also be considered as informative censoring. • “We note, however, that such truncation by death did not preclude our ability to

detect associations between severe sepsis and disability, cognitive decline, and low BMI, suggesting it should be less of a problem for incontinence or hearing and vision loss.”

4. It has been demonstrated that potential spurious inferences can be a problem

for a range of outcomes of interest after acute illness, but it cannot be determined which such inferences are actually false without more data.

CONCLUSIONS • Geriatric conditions are common after severe sepsis substantial burden for patients in

addition to their other medical conditions.

• However, severe sepsis is associated with increased rates of only a subset of geriatric conditions, not all.

• Seems to rule out a direct causal link from severe sepsis to these geriatric conditions?

• Evidence of the complexity and heterogeneity of these multi-factorial conditions over time.

• In studying outcomes after acute illness, failing to measure and control for both pre-illness levels and trajectories may result in erroneous conclusions.

• Such spurious inferences may be present in the medical literature when baseline trajectories are not adequately controlled.

• In striving to meet patients’ many needs, we must carefully assess the causal evidence for the etiology of those needs, while also looking skeptically at when such causal evidence is truly necessary to motivate changes in clinical practice.

Does the Hospital Make You Older Faster? Editorial: Gordon D. Rubenfeld

“Although there is evidence that the ICU is a dangerous and harmful place, we can take some solace in the fact that it appears to be no more injurious to long term outcomes than the rest of the hospital.” (p798)