“Understanding how to prevent (or at least minimize) post–intensive care syndrome thus represents a new frontier in critical care.”

Image: J. P. Rathmell.

Image: J. P. Rathmell.

Historically, success in the intensive care unit (ICU) has been measured in easily quantifiable metrics such as mortality and length of stay. While these metrics have significant value, they do not take into account what a patient’s life is like after ICU discharge. By understanding that success is not simply measured by leaving the ICU, the recent identification of post–intensive care syndrome has revolutionized the manner in which we think of successful outcomes after critical illness.1  Unfortunately, a significant proportion of patients suffer from post–intensive care syndrome, in which they have long-term cognitive, physical, and emotional issues for extended periods of time—or permanently—after discharge from the ICU. Understanding how to prevent (or at least minimize) post–intensive care syndrome thus represents a new frontier in critical care.

Neurocognitive dysfunction occurs in 70% of sepsis survivors with chronic critical illness.2  A critical driver of sepsis-associated encephalopathy is uncontrolled neuroinflammation, which is precipitated by loss of blood–brain barrier function, as well as dysregulated peripheral-to-central signaling through vagal pathways.3  Key cellular mediators of this neuroinflammation include monocytes, macrophages, and microglial cells, and their activation is associated with the development and persistence of inflammatory products in the central nervous system.

Cognition alterations often occur early in the course of an ICU stay necessitating pharmacologic sedation to either assure that a patient can synchronize with a ventilator or to prevent a patient from self-harm. Multiple different sedating agents are available targeting different neural pathways. One commonly used sedation agent is dexmedetomidine, an α2 agonist that also has activity for the imidazoline receptor, as well as the α1 receptor. Dexmedetomidine has numerous clinical benefits including a short half-life and minimal effects on respiratory drive, allowing patients to interact while on mechanical ventilation in a manner that is often not possible with other sedating agents. Preclinical work has demonstrated that dexmedetomidine decreases cognitive decline in mice in the postoperative setting via resolution of systemic and neuroinflammation. In a complementary set of studies presented in this issue of Anesthesiology, Li et al. sought to determine the impact of dexmedetomidine on cognitive decline in a rodent model, and more similar to medical than surgical illness.4  The authors examined a variety of endpoints in young (12 week) mice subjected to a sterile inflammatory insult with lipopolysaccharide, a component of the cell wall in Gram-negative bacteria. Mice were then treated with dexmedetomidine in combination with blockers. At 3 days, the authors demonstrated that dexmedetomidine reversed cognitive dysfunction measured by decreased “freezing time” behavior. Mechanistically, this was mediated through α2 receptors as the reversal in cognitive decline was abrogated by α2 antagonists yohimbine and atipamezole, but was unaffected by the α1 antagonist prazosin. At 6 h, the authors also demonstrated that dexmedetomidine attenuated systemic and hippocampal release of macrophage-derived interleukin-1β through a α2-dependent mechanism. Similar findings were noted in the blood–brain barrier, where lipopolysaccharide-induced increased leakage was reversed by dexmedetomidine, a finding that was prevented by administering α2 inhibitors.

A common critique of preclinical studies of critical illness is that young mice are typically used despite the fact that the majority of patients in the ICU are aged. There are clear data that the host response changes significantly with age (so-called “inflam-aging”), which is a limitation in the utility of young mice to model older patients.5  Cognizant of this disconnect, Li et al. took the unusual step of repeating many of their experiments in 12-month-old mice, which are middle aged based on murine life tables. Importantly, they found similar findings in freezing time and systemic and hippocampal inflammation in 12-month-old mice. This represents a notable (and unusual) experimental design that strengthens the data presented.

However, above and beyond the noble pursuit of mechanistic insights for the sake of scientific understanding alone, a key goal of translational research is that these insights ultimately play a role in improving human health. In this context, there are a few key experimental decisions that must be taken into account when determining the potential relevance of the study of Li et al. to the bedside of critically ill patients. First, while lipopolysaccharide is a model of a short-term proinflammatory state that rapidly returns to baseline (or results in a similarly rapid death in more severe models), it does not closely mimic any disease seen in the ICU. While historically lipopolysaccharide was used as a model of sepsis since it is an integral part of Gram-negative bacteria, there is expansive literature demonstrating the differences between lipopolysaccharide and more authentic models of sepsis,6  which has resulted in international consensus guidelines explicitly recommending against using lipopolysaccharide to model sepsis.7  Next, the cognitive issues seen with post–intensive care syndrome are long-term complications of critical illness. Short-term cognitive dysfunction in the ICU is often due to underlying metabolic issues. While this can be problematic in the acute setting, it is unclear whether reversal of murine cognitive dysfunction shortly after the onset of an inflammatory insult in mice bears any relation to the cognitive deficits patients have weeks or months after their ICU stay. It is also difficult to mechanistically understand how two doses of dexmedetomidine—a drug that is used as a continuous drip, often for days in critically ill patients—can lead to long-term changes in cognition, especially considering that the adrenergic nervous system is often altered and pharmacologically targeted in critical illness.

This begs the larger question, however, of how useful animal models of critical illness are. A long-standing debate regarding how well rodent models of critical illness mimic human illness has led to conflicting results even when analyzing the identical data set.8,9  What is unfortunately unquestionable is that the overwhelming number of randomized controlled trials in the ICU fail to show benefit.10  This lack of efficacy is especially glaring in sepsis, a disease responsible for nearly 20% of all deaths worldwide, which costs more than $60 billion annually in the United States alone.11,12  Historically, much (if not most) sepsis research has utilized mouse models of sepsis. While this has resulted in a massive amount of mechanistic data, this approach has not yet been successfully translated into changes of treatment at the bedside, and multiple clinical trials based on successful therapies in mice have proven to be unsuccessful in the ICU. The causes of these failures are multiple. For instance, it is easy to see conceptually how translating findings in young, healthy, genetically homogenous mice to aged genetically diverse human patients with multiple comorbidities might be difficult.

Since sepsis impacts multiple organs, funding for research in this syndrome comes from multiple institutes at the National Institutes of Health (NIH). Of these, the National Institute of General Medical Sciences (NIGMS) provides the most funding for the field. Driven by a desire to translate discoveries to the bedside, NIGMS recently released “Priorities for Sepsis Research” for researchers submitting applications related to sepsis.13  The purpose of the notice was to explicitly notify applicants of NIGMS’s focus on areas that would “provide new knowledge of the mechanistic complexity of sepsis in humans and… [to] test strategies for translating this knowledge into improved diagnostics and therapies for sepsis patients.” This official guidance lists 12 topics of interest to NIGMS that cover a remarkably wide range of potential research directions. In contrast, it only lists two areas of low priority: rodent models, “unless uniquely well justified in terms of potential for providing novel insights into human sepsis,” and clinical trials. While the low priority of clinical trials is not a surprise given NIGMS’s overall mission, the direction to de-emphasize rodent research represents a fundamental shift in NIGMS’s approach toward sepsis. This approach also goes further than the advisory council to the NIGMS, which recommended broadly expanding approaches toward sepsis research (as in the final NIGMS priorities), but also recommended that NIGMS “support the standardization of animal models and the development of models that more closely mimic (1) non-immunological aspects of sepsis and (2) important co-morbidities in human sepsis” while additionally highlighting the strengths and weaknesses of existing rodent models.14 

It is important to note that NIGMS priorities are unique to a specific NIH institute and are not common to the other institutes with significant sepsis portfolios, such as the National Institute of Allergy and Infectious Disease and the National Heart, Lung, and Blood Institute. However, there are multiple sepsis projects that are not part of the missions of these other institutes and instead fit more naturally into the broader mission of NIGMS. We believe that in light of the inability to translate preclinical findings to the bedside to improve outcomes of septic patients, a rebalancing of priorities was a tremendous step forward that allows for a wider range of approaches to sepsis. At the same time, where this leaves excellent work like that of Li et al.—and multiple other investigators with sepsis-related questions that are best mechanistically approached via rodent studies—is unclear.

This work was supported by funding from the National Institutes of Health (Bethesda, Maryland; grant No. GM095442) and the United States Navy.

Dr. Coopersmith served on the National Advisory General Medical Sciences Council Working Group on Sepsis.

1.
Elliott
D
,
Davidson
JE
,
Harvey
MA
,
Bemis-Dougherty
A
,
Hopkins
RO
,
Iwashyna
TJ
,
Wagner
J
,
Weinert
C
,
Wunsch
H
,
Bienvenu
OJ
,
Black
G
,
Brady
S
,
Brodsky
MB
,
Deutschman
C
,
Doepp
D
,
Flatley
C
,
Fosnight
S
,
Gittler
M
,
Gomez
BT
,
Hyzy
R
,
Louis
D
,
Mandel
R
,
Maxwell
C
,
Muldoon
SR
,
Perme
CS
,
Reilly
C
,
Robinson
MR
,
Rubin
E
,
Schmidt
DM
,
Schuller
J
,
Scruth
E
,
Siegal
E
,
Spill
GR
,
Sprenger
S
,
Straumanis
JP
,
Sutton
P
,
Swoboda
SM
,
Twaddle
ML
,
Needham
DM
.
Exploring the scope of post-intensive care syndrome therapy and care: Engagement of non-critical care providers and survivors in a second stakeholders meeting.
Crit Care Med
.
2014
;
42
:
2518
26
2.
Gardner
AK
,
Ghita
GL
,
Wang
Z
,
Ozrazgat-Baslanti
T
,
Raymond
SL
,
Mankowski
RT
,
Brumback
BA
,
Efron
PA
,
Bihorac
A
,
Moore
FA
,
Anton
SD
,
Brakenridge
SC
.
The development of chronic critical illness determines physical function, quality of life, and long-term survival among early survivors of sepsis in surgical ICUs.
Crit Care Med
.
2019
;
47
:
566
73
3.
Ren
C
,
Yao
RQ
,
Zhang
H
,
Feng
YW
,
Yao
YM
.
Sepsis-associated encephalopathy: A vicious cycle of immunosuppression.
J Neuroinflammation
.
2020
;
17
:
14
4.
Li
R
,
Lai
IK
,
Pan
JZ
,
Zhang
P
,
Maze
M
.
Dexmedetomidine exerts an anti-inflammatory effect via α2 adrenoceptors to prevent lipopolysaccharide-induced cognitive decline in mice.
Anesthesiology
.
2020
;
133
:
393
407
5.
Bonafè
M
,
Sabbatinelli
J
,
Olivieri
F
.
Exploiting the telomere machinery to put the brakes on inflamm-aging.
Ageing Res Rev
.
2020
;
59
:
101027
6.
Remick
DG
,
Newcomb
DE
,
Bolgos
GL
,
Call
DR
.
Comparison of the mortality and inflammatory response of two models of sepsis: Lipopolysaccharide vs. cecal ligation and puncture.
Shock
.
2000
;
13
:
110
6
7.
Osuchowski
MF
,
Ayala
A
,
Bahrami
S
,
Bauer
M
,
Boros
M
,
Cavaillon
JM
,
Chaudry
IH
,
Coopersmith
CM
,
Deutschman
CS
,
Drechsler
S
,
Efron
P
,
Frostell
C
,
Fritsch
G
,
Gozdzik
W
,
Hellman
J
,
Huber-Lang
M
,
Inoue
S
,
Knapp
S
,
Kozlov
AV
,
Libert
C
,
Marshall
JC
,
Moldawer
LL
,
Radermacher
P
,
Redl
H
,
Remick
DG
,
Singer
M
,
Thiemermann
C
,
Wang
P
,
Wiersinga
WJ
,
Xiao
X
,
Zingarelli
B
.
Minimum quality threshold in pre-clinical sepsis studies (MQTiPSS): An international expert consensus initiative for improvement of animal modeling in sepsis.
Shock
.
2018
;
50
:
377
80
8.
Seok
J
,
Warren
HS
,
Cuenca
AG
,
Mindrinos
MN
,
Baker
HV
,
Xu
W
,
Richards
DR
,
McDonald-Smith
GP
,
Gao
H
,
Hennessy
L
,
Finnerty
CC
,
López
CM
,
Honari
S
,
Moore
EE
,
Minei
JP
,
Cuschieri
J
,
Bankey
PE
,
Johnson
JL
,
Sperry
J
,
Nathens
AB
,
Billiar
TR
,
West
MA
,
Jeschke
MG
,
Klein
MB
,
Gamelli
RL
,
Gibran
NS
,
Brownstein
BH
,
Miller-Graziano
C
,
Calvano
SE
,
Mason
PH
,
Cobb
JP
,
Rahme
LG
,
Lowry
SF
,
Maier
RV
,
Moldawer
LL
,
Herndon
DN
,
Davis
RW
,
Xiao
W
,
Tompkins
RG
;
Inflammation and Host Response to Injury, Large Scale Collaborative Research Program
.
Genomic responses in mouse models poorly mimic human inflammatory diseases.
Proc Natl Acad Sci USA
.
2013
;
110
:
3507
12
9.
Takao
K
,
Miyakawa
T
.
Genomic responses in mouse models greatly mimic human inflammatory diseases.
Proc Natl Acad Sci USA
.
2015
;
112
:
1167
72
10.
Santacruz
CA
,
Pereira
AJ
,
Celis
E
,
Vincent
JL
.
Which multicenter randomized controlled trials in critical care medicine have shown reduced mortality? A systematic review.
Crit Care Med
.
2019
;
47
:
1680
91
11.
Buchman
TG
,
Simpson
SQ
,
Sciarretta
KL
,
Finne
KP
,
Sowers
N
,
Collier
M
,
Chavan
S
,
Oke
I
,
Pennini
ME
,
Santhosh
A
,
Wax
M
,
Woodbury
R
,
Chu
S
,
Merkeley
TG
,
Disbrow
GL
,
Bright
RA
,
MaCurdy
TE
,
Kelman
JA
.
Sepsis among Medicare beneficiaries: 1. The burdens of sepsis, 2012-2018.
Crit Care Med
.
2020
;
48
:
276
88
12.
Rudd
KE
,
Johnson
SC
,
Agesa
KM
,
Shackelford
KA
,
Tsoi
D
,
Kievlan
DR
,
Colombara
DV
,
Ikuta
KS
,
Kissoon
N
,
Finfer
S
,
Fleischmann-Struzek
C
,
Machado
FR
,
Reinhart
KK
,
Rowan
K
,
Seymour
CW
,
Watson
RS
,
West
TE
,
Marinho
F
,
Hay
SI
,
Lozano
R
,
Lopez
AD
,
Angus
DC
,
Murray
CJL
,
Naghavi
M
.
Global, regional, and national sepsis incidence and mortality, 1990-2017: Analysis for the Global Burden of Disease Study.
Lancet
.
2020
;
395
:
200
11
13.
National Institute of General Medical Sciences (NIGMS)
.
Notice of information: NIGMS priorities for sepsis research. Notice number: NOT-GM-19-054. Released July 29, 2019.
14.
Ayala
A
,
Coopersmith
CM
,
Kraft
M
,
Liu
V
,
Meyer
NJ
,
Padbury
G
,
Parsons
PE
,
Przygodzki
RM
,
Younger
JG
.
NAGMSC Working Group on sepsis final report.
National Advisory General Medical Sciences (NAGMSC)
.
Published May 17, 2019. Available at: https://www.nigms.nih.gov/News/reports/Documents/nagmsc-working-group-on-sepsis-final-report.pdf. Accessed April 13, 2020.
The views expressed in this article reflect the results of research conducted by the author and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, nor the United States Government. Dr. Paterson is a military service member or federal/contracted employee of the United States Government. This work was prepared as part of his official duties. Title 17 U.S.C. 105 provides that “copyright protection under this title is not available for any work of the United States Government.” Title 17 U.S.C. 101 defines U.S. Government work as work prepared by a military service member or employee of the U.S. Government as part of that person’s official duties.