EDITORIALS

Under Pressure: Reduced Cerebral Perfusion as a Risk Factor for

Postoperative Delirium in Lung Transplant Recipients
Brian J. Anderson1 and Joshua M. Diamond1,2
1

Division of Pulmonary, Allergy, and Critical Care Medicine, and 2Penn Lung Transplant Center, Perelman School of Medicine at the
University of Pennsylvania, Philadelphia, Pennsylvania

Delirium is common in the intensive care

unit (ICU) (1) and is particularly common
in patients recovering from lung
transplantation (2, 3). The emergence of
delirium is frightening to patients and
family members. Delirium complicates
patient care and is associated with
prolonged mechanical ventilation (4, 5),
longer hospital stays (36), and increased
mortality (57). In addition, delirium is
associated with signicant long-term
morbidity in ICU survivors, including
long-term cognitive impairment (1, 2, 8).
Importantly, growing evidence also
suggests delirium is associated with
potentially permanent brain injury.
Imaging studies comparing ICU survivors
with matched controls reveal signicant
volume loss in the frontal lobes and
hippocampus, the severity of which is
closely linked to the duration of delirium
and the degree of long-term cognitive
impairment (9, 10). The pathophysiology of
delirium and how it may lead to subsequent
cognitive impairment remains poorly
understood.
Few studies have investigated
hypoperfusion as a mechanism leading
delirium. One study by Wijdicks and
colleagues demonstrated that cardiovascular
failure was a risk factor for septic
encephalopathy in 84 postoperative patients
(11), but to our knowledge, the study in this
months issue of AnnalsATS by Smith and
colleagues (pp. 180187) is the only human
study linking hypoperfusion to delirium
(12).
Using a prospective cohort design, the
authors obtained detailed hemodynamic

measurements on 63 patients who

underwent lung transplantation. They
dened cerebral perfusion pressure (CPP) as
the difference between mean arterial
pressure (MAP), measured by a femoral or
radial arterial catheter, and central venous
pressure (CVP), measured by a pulmonary
artery catheter (CPP = MAP CVP).
Patients were assessed daily for delirium,
using the Confusion Assessment Method,
and were also assessed for delirium severity,
using the Delirium Rating Scale. Using
logistic regression adjusting for native lung
disease and primary graft dysfunction, the
authors demonstrated that every 10 mm Hg
decrease in CPP was associated with a
doubling of the odds of developing
postoperative delirium (odds ratio, 2.08;
95% condence interval, 1.084.24;
P = 0.043). Next, in a negative binomial
regression model adjusting for native lung
disease and primary graft dysfunction, they
showed that lower CPP was associated with
longer duration of delirium (b = 20.54;
95% condence interval, 21.00 to 20.08;
P = 0.22), such that every 10 mm Hg decrease
in CPP was associated with a 1.7-day
increase in delirium duration. Finally, they
identied an association of lower CPP with
higher delirium severity, as well as
associations of primary graft dysfunction
with both odds of delirium and delirium
duration.
The study by Smith and colleagues
has several strengths. First, the authors
rigorously investigated an important topic
that continues to challenge the critical care
community. Second, the authors employed
sound methodology, including a well-

dened exposure variable and use of a wellvalidated screening tool for delirium. Third,
the statistical techniques were appropriately
chosen and the authors assessed their
models for overtting, given the small
number of outcomes relative to the potential
numbers of covariates.
Several potential limitations of the
study should be noted. The study was
performed at a single center and thus may
not be generalizable. This remains the
primary limitation to the majority of studies
evaluating delirium and neurocognition in
lung transplant recipients. Although the
authors adjusted for native lung disease and
subsequent development of primary graft
dysfunction, the association of CPP with
delirium may be subject to residual
confounding by additional covariates such
as pretransplant cognitive function, severity
of illness (e.g., mechanical ventilation and/
or extracorporeal membrane oxygenation as
a bridge to transplant), age, chronic history
of hypertension, and benzodiazepine or
opiate use (3, 13). One prior study identied
graft ischemic time as an independent risk
factor of worse posttransplant cognitive
function (14); thus, it would be interesting
to investigate graft ischemic time as a
potential confounder.
A particular challenge in investigating
mechanisms of delirium in patients with
end-stage lung disease who undergo lung
transplantation is accounting for the effects
of hypoxemia on cognitive function. The
authors note that reduced cerebral
oxygenation has been associated with
postoperative neurocognitive dysfunction
(12), and additional studies have shown

(Received in original form December 3, 2015; accepted in final form December 4, 2015 )
Supported in part by National Institutes of Health grant K23-HL121406.
Correspondence and requests for reprints should be addressed to Brian J. Anderson, M.D., M.S., Pulmonary, Allergy, and Critical Care Division, Perelman
School of Medicine, University of Pennsylvania, 3400 Spruce Street, 5048 Gates Building, Philadelphia, PA 19104. E-mail: brian.anderson@uphs.upenn.edu
Ann Am Thorac Soc Vol 13, No 2, pp 156157, Feb 2016
Copyright 2016 by the American Thoracic Society
DOI: 10.1513/AnnalsATS.201512-796ED
Internet address: www.atsjournals.org

156

AnnalsATS Volume 13 Number 2 | February 2016

EDITORIALS
that low arterial partial pressure of oxygen
and low peripheral oxygen saturation
measurements are associated with poor
cognitive outcomes in survivors of Acute
Respiratory Distress Syndrome (15, 16).
Because decreased cerebral perfusion and
decreased arterial oxygen saturation both
ultimately result in reduced cerebral
oxygen delivery, it is likely that both
mechanisms can lead to brain injury and
manifest as delirium and/or cognitive
impairment. Although Smith and
colleagues did not investigate hypoxemia
in the present study, their well-phenotyped
cohort presents a unique opportunity to
explore the individual and combined
effects of poor cerebral perfusion and
reduced arterial oxygen saturation on

postoperative delirium and cognitive

function.
Despite potential limitations, the
present study by Smith and colleagues
suggests reduced cerebral perfusion is a
potentially modiable risk factor associated
with risk, duration, and severity of
postoperative delirium. A major question
moving forward is whether reduced cerebral
perfusion is associated with longer-term
outcomes, such as long-term cognitive
impairment and diminished executive
function, and whether reduced cerebral
perfusion pressure results in delirium
simply through neuronal dysfunction or by
causing more permanent brain injury.
Studies employing systemic biomarkers
of brain injury may be useful as a

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Editorials

quantitative trait for assessing the degree

of brain injury in critically ill patients.
Biomarkers may also serve as surrogates
when formal delirium testing is not possible
in the setting of prolonged mechanical
ventilation and signicant sedation
requirements. Detailed serial neuroimaging
and longer-term follow-up of transplant
recipient cognitive function may ultimately
lead to a better understanding of the lasting
effects of early posttransplant brain injury
and give insight into how we can intervene
to improve both short- and long-term
neurocognitive outcomes after lung
transplantation. n
Author disclosures are available with the text
of this article at www.atsjournals.org.

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