Outcomes for Septic Shock Survivors: ADRENAL followup

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The Pre-brief

Sepsis and septic shock syndromes affect 49 million people each year, accounting for an annual $41.5 billion cost to the US healthcare system, and they are associated with about 1 in 3 inpatient deaths (1, 2). In 2018, the NEJM published the ADRENAL study, a multinational, double-blinded, placebo-controlled trial that randomized 3800 people in septic shock to receive hydrocortisone or placebo (3). While it showed no significant 90-day mortality benefit, it did demonstrate safety and also suggested faster resolution of shock in the treatment arm.

The ADRENAL group included in their secondary endpoints a 6 month follow-up interview with survivors regarding their Health Related Quality of Life (HRQoL) after their index hospitalization. This was meant to address whether steroids caused any previously unknown effects that persisted into the future.

THE ARTICLE: Hammond NE, Finfer SR, Li Q, et al. Health-related quality of life in survivors of septic shock: 6-month follow-up from the ADRENAL trial [published online ahead of print, 2020 Jul 16]. Intensive Care Med. 2020;10.1007/s00134-020-06169-1. doi:10.1007/s00134-020-06169-1

What did they do?

If a patient in the ADRENAL study survived hospitalization, a 6-month follow-up interview was arranged (dated 6 months from the time of randomization in the trial). A trained, intervention-blinded phone interviewer used a validated tool that scores quality of life for patients, the EQ-5D-5L (4). If a patient was incapacitated, then a family member, proxy, or healthcare aid could answer for them. The EQ-5D-5L tool segments out 5 domains of quality of life: mobility, self-care, usual activities, pain or discomfort, and anxiety or depression. Responses to these domains get mapped to 5 levels corresponding to the level of disability within those domains: no problems, slight problems, moderate problems, severe problems, or extreme problems.

Interviewers also asked patients to assign themselves a score on 2 separate general indices of health:

Visual Analogue Scale (VAS), 1 = worst and 100 = perfect health
Australian Mean Utility score, 0 = death, 1 = perfect health, and <0 = a fate “worse than death”

Finally, the investigators evaluated differences in scores within a pre-specified comparison groups:

Treatment vs. placebo
Male vs. female
Peak dose of norepinepherine equivalents (mcg/min)
Illness severity (APACHE II)
Incidence of renal replacement therapy (RRT) (ie. needed RRT at any point vs no RRT at all)
Time to shock resolution (≤2 days, 3-4 days, 5-7 days, >7 days)

What did they find?

Of the original 3600 patients enrolled in ADRENAL, 1265 patients in the hydrocortisone arm and 1256 in the placebo arm were alive at 6 months (mortality of 33.7%). Of these survivors, about 85% of participants in the HRQoL follow-up were the patients themselves, about 25% of responders were patient proxies or family.

Health quality indices were pretty terrible overall:
- Mean VAS = 70.8
- Mean Australian Mean Utility Score = 59.8
15-30% of survivors reported moderate to severe disability in any one domain.
No differences were found across treatment arms (i.e. hydrocortisone did not seem to contribute to long term disability), and no difference were found in pre-specified subgroups when it came to severity of illness , norepinephrine dose, or subsequent bacteremia incidence.
Differences were found among other pre-specific comparison groups:
- Men were less likely to report moderate to extreme pain disorders (OR 0.69; 95% CI 0.57-0.84)
- Patients requiring RRT were more at risk to have moderate to extreme mobility problems (adjusted OR 1.30; 95% CI 1.02-1.65) and issues with activities of daily living (ADLs) (OR 1.39; 95% CI 1.11-1.75)
- Patients with longer time to shock resolution (>7 days compared to ≤2 days) more often reported moderate to extreme difficulty with mobility (OR 2.11; 95% CI 1.51-2.96), self-care (OR 1.76; 95% CI 1.17-2.65), and performance of ADLs (OR 2.10; 95% CI 1.52-2.91). These patients also had worse mean VAS and Australian Mean Utility scores.

What should we take away from this?

Septic shock is a big deal. In this study it killed about 33% of people, but it also devastated about 20% of those who survived. What was the chance that a given survivor would be disability free 6 months after their septic shock episode? About the same as a coin flip.

A 2018 meta-analysis compiled functional outcomes for thousands of ICU survivors with a 1 year follow up period; finding 9-14% of patients had substantial disability when it came to ADLs and 20-40% of patients experienced physical disability(5). This quality of life data further supports efforts like the THRIVE initiative; as well as, the idea that Post Intensive Care Syndrome may be a huge obstacle for recovering patients. Septic shock is the fight of somebody’s life, and it’s crucial to understand that the job is not done just because someone survives the ICU. Insofar as ICU care is about “survivorship” and navigating the waters of a medical catastrophe, we may be underestimating just how long the storm of septic shock truly lasts.

The Debrief

Hydrocortisone does not affect quality of life for sepsis survivors.
Among septic shock survivors in the ADRENAL study, at 6 month follow up:
- 20% had moderate to severe disability
- Only about 50% felt they were disability free

References

Buchman TG, Simpson SQ, Sciarretta KL, et al. Sepsis Among Medicare Beneficiaries: 3. The Methods, Models, and Forecasts of Sepsis, 2012-2018. Crit Care Med. 2020;48(3):302-318. doi:10.1097/CCM.0000000000004225. PMID: 32058368.
Torio CM, Moore BJ. National Inpatient Hospital Costs: The Most Expensive Conditions by Payer, 2013: Statistical Brief #204. In: Healthcare Cost and Utilization Project (HCUP) Statistical Briefs. Rockville (MD): Agency for Healthcare Research and Quality (US); 2006. PMID: 27359025.
Venkatesh B, Finfer S, Cohen J, et al. Adjunctive Glucocorticoid Therapy in Patients with Septic Shock. N Engl J Med. 2018;378(9):797-808. doi:10.1056/NEJMoa1705835. PMID: 29347874.
Janssen MF, Pickard AS, Golicki D, et al. Measurement properties of the EQ-5D-5L compared to the EQ-5D-3L across eight patient groups: a multi-country study. Qual Life Res. 2013;22(7):1717-1727. doi:10.1007/s11136-012-0322-4. PMID: 23184421.
Ohtake PJ, Lee AC, Scott JC, et al. Physical Impairments Associated With Post-Intensive Care Syndrome: Systematic Review Based on the World Health Organization’s International Classification of Functioning, Disability and Health Framework. Phys Ther. 2018;98(8):631-645. doi:10.1093/ptj/pzy059. PMID: 29961847.