Letters to the Editor
Intensive care unit treatment in
patients >65 yrs with a first-day
sequential organ failure assessment
score >15 is not futile
To the Editor:
With great interest, we read the study by
Kaarlola and colleagues (1), concerning
long-term survival, quality of life, and qual-
ity-adjusted life-years among critically ill
elderly patients. In their study, outcome
and quality aspects were investigated in 882
patients older than 65 yrs. We were in-
trigued by their sentence under the Discus-
sion that all patients in their study with a
day-1 Sequential Organ Failure Assessment
(SOFA) score ⬎15 died in the intensive
care unit (ICU). This seemed to differ from
our experience. After a explorative database
analysis of prospectively collected data, we
found that in 13,989 consecutive patients
admitted to our ICU, 7,984 patients were
⬎65 yrs of age. Of these elderly patients,
131 had a day-1 SOFA score ⬎15. The hos-
pital mortality of these patients was 65 of
131. A hospital survival rate of 50% in those
⬎65 yrs with a day-1 SOFA of ⬎15 con-
trasts with the 100% mortality reported by
Kaarlola et al.
Under the Discussion, it is stated that a
systematic bias toward overestimated qual-
ity-adjusted life years may exist if intensive
care is withheld from elderly patients or
selection in admission occurs and not all
elderly patients are included in the analysis.
It is possible, therefore, that the reported
100% mortality rate with day-1 SOFA score
in patients ⬎65 yrs could have been per-
ceived as futile therapy, resulting in
overestimated quality-adjusted life
years. We agree with the authors that
older age alone is not a valid reason to
withhold intensive care; we disagree
with their implicit statement that ICU
treatment in patients ⬎65 yrs with a
first-day SOFA score ⬎15 is futile.
The authors have not disclosed any
potential conflicts of interest.
Durk F. Zandstra, MD, Rob J. Bosman,
MD, Department of Intensive Care
Medicin, Onze Lieve Vrouwe Gasthuis,
Amsterdam, The Netherlands
Copyright © 2007 by the Society of Critical Care
Medicine and Lippincott Williams & Wilkins
Crit Care Med 2007 Vol. 35, No. 3
REFERENCE
1. Kaarlola A, Tallgren M, Petillä V: Long-term
survival, quality of life, and quality-adjusted
life-years among critically ill elderly patients.
Crit Care Med 2006; 34:2120 –2126
DOI: 10.1097/01.CCM.0000257233.52136.3B
The authors reply:
We are grateful for the opportunity to
respond to the letter by Drs. Zandstra and
Bosman concerning our study published in
Critical Care Medicine (1). They raise an
important issue, the outcome of elderly pa-
tients with five or more organ failures the
first day in the intensive care unit (ICU;
day-1 Sequential Organ Failure Assessment
[SOFA] score ⬎15). Patients with such a
severe multi-organ failure are usually a mi-
nority in any ICU population. In our con-
secutive material from 1995 to 2000, the
number of patients with day-1 SOFA scores
⬎15 and ICU mortality of 100% [95% con-
fidence interval, 0% to 100%] was ex-
tremely small (0.6%). Because of the small
number, five of 882, it is not possible to
make definitive conclusions about whether
intensive care is futile in this subpopula-
tion.
Drs. Zandstra and Bosman reported
results in treating patients with this se-
vere multi-organ failure in their ICU. In a
retrospective analysis from a large pro-
spectively collected ICU database, they
found 131 of 7,984 (1.6%) patients ⬎65
yrs of age with a day-1 SOFA score ⱖ15,
with hospital mortality as low as 65 of
131 (50%). These figures are good, and
we are looking forward to more details
from their future article. However, our
own data (2) and the data by Ferreira et
al. (3) disagree with the good survival
rates of elderly patients with high SOFA
scores ⬎15 presented by Zandstra and
Bosman.
In interpreting the results of outcome
studies, it is crucial to establish whether
the population studied was similar to the
population served by one’s own ICU. One
factor that may affect the results is the
case-mix of the patients (for example, sur-
gical/medical, emergency/elective). Elective
cardiac surgery is a good example of a sub-
population with good outcome, despite rel-
atively high day-1 SOFA scores. Second, the
treatment options before ICU admission af-
fect the outcome. Organ dysfunction may
be significantly improved by early therapy
in the emergency room (4), leading to
lower day-1 SOFA scores in the ICU. This
may be pronounced in ICUs with a small
number of beds serving a large population.
Third, the instructions on how the SOFA
and Acute Physiology and Chronic Health
Evaluation scores are to be calculated leave
some room for interpretation. For instance,
no instructions exist on how the neurologic
evaluation is to be performed in patients
receiving sedative medication. In our unit,
the Glasgow Coma Scale score is assumed
to be normal, if it was so before sedation
and if it is not feasible to stop sedation
totally to facilitate reevaluation.
We agree with Drs. Zandstra and Bos-
man in that neither older age alone nor
any severity of illness score number per
se, without taking into consideration the
full information concerning each case
and the response to treatment over time,
is a valid reason to withhold intensive
care. Because of the small proportion of
elderly patients with day-1 SOFA scores
⬎15, in general, we consider our estima-
tion of quality-adjusted life years to be
reliable and not prominently affected by
any selection bias.
Anne Kaarlola, RN MSc, Minna Tallgren,
MD, Ville Pettilä, MD, Department of
Anaesthesia and Intensive Care Medi-
cine, Helsinki University Hospital,
Helsinki, Finland
REFERENCES
1. Kaarlola A, Tallgren M, Pettilä V: Long-term
survival, quality of life, and quality-adjusted
life-years among critically ill elderly patients.
Crit Care Med 2006; 34:2120 –2126
2. Pettilä V, Pettilä M, Sarna S, et al: Comparison
of multiple organ dysfunction scores in the
prediction of hospital mortality in the criti-
cally ill. Crit Care Med 2002; 30:1705–1711
3. Ferreira FL, Bota DP, Bross A, et al: Serial
evaluation of the SOFA score to predict out-
come in critically ill patients. JAMA 2001; 286:
1754 –1758
4. Demetriades D, Karaiskakis M, Velmahos G, et
al: Effect of early intensive management of
geriatric trauma patients. Br J Surg 2002;
89:1319 –1322
DOI: 10.1097/01.CCM.0000257476.65629.B3
Anti-inflammatory activity of albumin
In addition to its role in maintaining
colloid oncotic pressure, albumin dis-
981
plays an array of non-oncotic properties,
including antioxidant and anti-inflamma-
tory activity (1–3). Such properties might
benefit patients adversely affected by in-
flammatory processes, such as those un-
dergoing cardiopulmonary bypass or
those developing sepsis or the systemic
inflammatory response syndrome. In a
rat endotoxemia model (1), for instance,
albumin decreased myocardial nitric ox-
ide synthase II messenger RNA and pro-
tein expression (p ⬍ .05 for both compar-
isons). Accompanying these effects with
regard to the capacity to produce nitric
oxide, an established modulator of in-
flammation, was a greater improvement
in myocardial function, as measured by
fractional shortening of isolated cardiac
myocytes, in animals receiving albumin
as compared with saline or hydroxyethyl
starch 200/0.5 (p ⬍ .01 for both compar-
isons).
In a new study, Dr. Bar-Or and col-
leagues (4) demonstrate that each of six
commercial albumin solutions markedly
inhibits production of the pro-inflamma-
tory cytokines tumor necrosis factor-␣
and interferon-␥ from human peripheral
blood mononuclear cells in vitro (p ⬍ .05
for all comparisons). They also provide
evidence that these anti-inflammatory ef-
fects may be partially attributable to
amino acids at the N-terminus of the
albumin polypeptide chain. A high-
affinity binding site for Cu2⫹ ions is
known to reside at the N terminus, and
the binding and sequestration of these
ions by albumin prevents their participa-
tion in oxidation reactions, thus illustrat-
ing one of the mechanisms underlying
the antioxidant/anti-inflammatory activ-
ity of albumin. The thiol moiety at cys-
teine 34 of albumin can also exert direct
antioxidant actions.
Incongruously, despite these encour-
aging results, Dr. Bar-Or and colleagues
(4) elected to interpret their data as in-
dicative of a potentially deleterious im-
munosuppressive effect. They also call at-
tention to prior in vitro evidence (5) that
a larger fraction of the albumin in com-
mercial than in freshly prepared solu-
tions is oxidized at cysteine 34 and might
possibly exacerbate, rather than amelio-
rate, oxidative stress. However, clinical
data do not support this proposition. In a
randomized trial of patients with acute
lung injury, albumin infusion increased
both plasma thiols (p ⬍ .0001) and total
antioxidant capacity (p ⫽ .0015). It, thus,
appears that augmentation of the redox
982
buffering capacity may be more impor-
tant than the redox state of the albumin
solution at the time of administration.
Furthermore, albumin has been shown to
exhibit antioxidant/anti-inflammatory ac-
tivity independent of thiol status. For ex-
ample, treatment of bovine aortic endo-
thelial cells with commercial human
albumin solution in vitro (2) protected
against HOCl-induced oxidative damage
in a dose-dependent manner both with
and without previous reduction of thiols
by sodium borohydride (p ⬍ .05 for both
comparisons). Additionally, albumin de-
creased the in vitro binding of activated
polymorphonuclear leukocytes to aortic
endothelial cells (2), and the magnitude
of the effect was closely similar for native
albumin, sodium borohydride-reduced
albumin, and albumin alkylated with N-
ethylmaleimide to block thiol groups
(p ⬍ .05 for all comparisons).
Based on their data, Dr. Bar-Or et al.
(4) advise caution in the administration
of albumin to critically ill patients. How-
ever, also requiring caution is the specu-
lation about the implications of in vitro
experiments for clinical practice. Dr.
Bar-Or and colleagues (4) are affiliated
with DMI BioSciences, a company en-
gaged in the development of a synthetic
tetrapeptide mimetic composed of the
same amino acid sequence as the N-
terminus of intact human albumin for
the prevention of myocardial ischemia-
reperfusion injury (www.dmibio.com/
misc/pipeline.html). This mimetic would
directly compete with commercial solu-
tions of albumin protein.
Indeed, these investigators provide
data in their article to show that a portion
of the albumin molecules in commercial
solutions may have undergone cleavage
of the N-terminal aspartyl-alanyl (DA)
dipeptide to generate albumin DA and
measurable concentrations of cyclized
cleavage product (DA-DKP). These re-
sults might suggest advantages of a
small-molecular mimetic over the intact
protein. However, the representation of
albumin DA in commercial solutions may
have been overestimated. On the basis of
18 determinations using six commercial
solutions, Dr. Bar-Or et al. (4) report that
the percentage of albumin DA averaged
15.3%. This value is nearly three times
the 5.6% mean of 87 determinations with
the same six commercial solutions they
observed in another recent study using
the same methods, namely, high-perfor-
mance liquid chromatography coupled
with mass spectrometry (5). Moreover,
the mean DA-DKP concentration for the
six commercial solutions (62.6 ␮M) mea-
sured in the new study as compared with
that of albumin protein in the 25% solu-
tions (3763 ␮M) suggests that the per-
centage of albumin DA might be as low
1.7% (62.6/3763). These disparities would
need to be reconciled before an albumin
DA estimate as high a 15.3% could be ac-
cepted. In any case, whatever the actual
percentage of albumin DA, the commercial
solutions all diminished production of tu-
mor necrosis factor-␣ and interferon-␥.
The intriguing non-oncotic properties
of albumin continue to be the focus of
active investigation. Their clinical rele-
vance will need to be determined in fur-
ther investigations. The in vitro study of
Dr. Bar-Or et al. (4) is of great interest,
although their interpretation of the clin-
ical implications is likely to be received
with justifiable skepticism.
The author has not disclosed any po-
tential conflicts of interest.
Christian J. Wiedermann, MD, Division
of Internal Medicine 2, Department of
Medicine, Central Hospital of Bolzano,
Bolzano, Italy
REFERENCES
1. Walley KR, McDonald TE, Wang Y, et al: Al-
bumin resuscitation increases cardiomyocyte
contractility and decreases nitric oxide syn-
thase II expression in rat endotoxemia. Crit
Care Med 2003; 31:187–194
2. Lang JD Jr, Figueroa M, Chumley P, et al:
Albumin and hydroxyethyl starch modulate
oxidative inflammatory injury to vascular en-
dothelium. Anesthesiology 2004; 100:51–58
3. Quinlan GJ, Mumby S, Martin GS, et al: Albu-
min influences total plasma antioxidant ca-
pacity favorably in patients with acute lung
injury. Crit Care Med 2004; 32:755–759
4. Bar-Or D, Thomas GW, Bar-Or R, et al: Com-
mercial human albumin preparations for clin-
ical use are immunosuppressive in vitro. Crit
Care Med 2006; 34:1707–1712
5. Bar-Or D, Bar-Or R, Rael LT, et al: Heteroge-
neity and oxidation status of commercial hu-
man albumin preparations in clinical use. Crit
Care Med 2005; 33:1638 –1641
DOI: 10.1097/01.CCM.0000257234.87784.91
The author replies:
We are a basic research laboratory com-
ponent of a level I trauma program com-
mitted to the clinical implications of our
work. The basic premise of our manuscript
“Commercial human albumin preparations
for clinical use are immunosuppressive in
Crit Care Med 2007 Vol. 35, No. 3
vitro” (1) is to alert clinicians and pharma-
cists that “albumin preparations” contain a
significant amount of a chemical (aspartyl-
alanyl diketopiperazine; DA-DKP), which is
the result of processing (heating) and stor-
age of albumin. Diketopiperazines have
been shown to have significant biological
activities (2, 3). We would hope that Dr.
Wiedermann agrees that clinicians should
be aware of the ingredients and impurities
present in a medication that they prescribe
to be administered intravenously to their
patients (indeed, there is no mention on
the label of albumin preparations of the
presence of a diketopiperazine).
We certainly did not imply that the
administration of commercial albumin
should be halted. In view of our “in vitro”
findings, we believe and stand by our con-
clusion that “. . . administering HSA to
immunocompromized, critically ill pa-
tients might need to be reevaluated.” In-
flammation is a natural biological re-
sponse to injury. It has its benefits and
perils. There are instances in which sup-
pressing the immune response could be
deleterious and other indications when it
is beneficial. A hypoalbuminemic cancer
patient suffering from chemotherapy-
induced immunosuppression, for example,
could be harmed if further immunosup-
pression is added by the administration of
an albumin preparation. A patient with se-
vere systemic immune response syndrome,
on the other hand, might benefit from this
intervention.
We believe that we have clearly dem-
onstrated an immunosuppressive (“anti-
inflammatory”) effect of the commercial
albumin products. This effect was abol-
ished following the removal by dialysis of
small molecular weight compounds (in-
cluding DA-DKP). We demonstrated that
a synthetic DA-DKP could reconstitute
the identical in vitro immunosuppressive
effect as the commercial human albumin
products. These effects are not “. . . at-
tributable to the amino acids at the N-
terminus of (the intact) albumin . . .” as
Dr. Wiedermann suggests, but to the
cleaved cyclic product derived from the
N-terminal dipeptide DA separated from
albumin. Isolated human plasma albu-
min alone did not have any anti-inflam-
matory activities in our investigations.
The proportion of albumin minus DA
was not overestimated. The apparent dis-
crepancy that Dr. Wiedermann suggests is
easily explained. In the first manuscript (4)
the proportion for albumin minus DA re-
ported is only for native albumin that lost
its N-terminal DA. In this recent manu-
Crit Care Med 2007 Vol. 35, No. 3
script (1), the proportion is for the sum of
all species that lost their N-terminal DA. If
we just estimate the proportion of species
that represent native albumin minus DA in
this latest manuscript, it is also 5.6% (av-
erage); however, because there are other
species of albumin minus DA with several
posttranslational modifications (such as
cysteinylation), it is more accurate to sum
all species that have this modification as it
is a true representation of the level of trun-
cation.
Dr. Wiedermann also points out that
the concentration of DA-DKP seems in-
consistent with the level of albumin that
lost its N-terminal DA. Again, this is not
inconsistent and is explained by the fact
that some of the albumin derived from
pooled plasma is already truncated (-DA)
before the heating step in the final con-
tainer, and the corresponding DA-DKP
generated before that step has already
been eliminated. Furthermore, some of
the DA-DKP in solution will hydrolyze
into a straight dipeptide chain, DA, which
has no known biological activity.
We agree that the N-terminus of hu-
man plasma albumin is a high-affinity
binding site for cupric ions and of its role
as an antioxidant. We also concur with
the role of cysteine 34 free thiol group as
a major extracellular-reducing agent. We
have reasons to believe (supported by our
unpublished data) that commercial (pro-
cessed) albumin products have a greatly
reduced ability to chelate transition met-
als, not only because of a truncated N-
terminus. Commercial albumin has a de-
monstrably higher percentage of oxidized
(cysteinylated, sulfonated) cysteine 34
than normal human plasma albumin. We
simply stated that a systematic review of
the composition of HSA commercial prep-
arations and correlation to morbidity/
mortality rates should be accounted for
in clinical trials—not all commercial al-
bumin products are the same!
Although we have disclosed our finan-
cial affiliations and conflicts of interest in
our publication (1), Dr. Wiedermann ne-
glects to mention that he has been spon-
sored and remunerated by companies di-
rectly involved in the manufacture and
marketing of albumin. A Google search
(“Wiedermann CJ”) reveals numerous au-
thorships with employees of these com-
panies and sponsorship activities. We
ourselves benefit from industrial funding
that can promote the translation of basic
research to clinical care. We would hope
that our article might allow insight into
the molecular content and clinical utility
of commercial albumin products, which
our results demonstrate could be im-
proved to the benefit of the patient. Skep-
ticism should be reserved to the unbiased
scientist whose patients’ well-being
stands first.
The author is an independent contrac-
tor with Swedish Medical Center. He
holds ⬎65 patents, is employed by DMI
BioSciences, and owns stock and stock
options in the company. DMI BioSciences
is currently developing DA-DKP for the
treatment of multiple sclerosis.
David Bar-Or, MD, FACEP, Trauma
Research Department, Swedish Med-
ical Center, Englewood, CO
REFERENCES
1. Bar-Or D, Thomas GW, Bar-Or R, et al: Com-
mercial human albumin preparations for clin-
ical use are immunosuppressive in vitro. Crit
Care Med 2006; 34:1707–1712
2. Borthwick AD, Davies DE, Exall AM, et al:
2,5-Diketopiperazines as potent, selective, and
orally bioavailable oxytocin antagonists: Syn-
thesis, pharmacokinetics, and in vivo potency.
J Med Chem 2006; 49:4159 – 4170
3. Lucietto FR, Milne PJ, Kilian G, et al: The
biological activity of the histidine-containing
diketopiperazines cyclo(His-Ala) and cyclo-
(His-Gly). Peptides 2006; 27:2706 –2714
4. Bar-Or D, Bar-Or R, Rael LT, et al: Heteroge-
neity and oxidation status of commercial hu-
man albumin preparations in clinical use. Crit
Care Med 2005; 33:1638 –1641
DOI: 10.1097/01.CCM.0000257246.40096.BA
Endotracheal intubation in the intensive
care unit: Non-anesthesiologists know
rapid sequence intubation, but is it
accurate in all cases?
To the Editor:
We were very surprised when reading
the article by Dr. Jaber and colleagues (1)
with regard to endotracheal intubation in
the intensive care unit (ICU). First, the ref-
erence that supported the use of a rapid
sequence induction (RSI) with Sellick’s
technique is relevant in the operating room
(2). These guidelines may be used in other
clinical contexts, but to the best of our
knowledge, none has been specially pub-
lished to be used in the ICU. Second, and of
most importance, the use of RSI in the ICU,
essentially because of adrenal dysfunction
induced by etomidate, is extremely contro-
versial (3, 4). We do not believe, as demon-
strated by the study of Dr. Jaber and col-
leagues (1), when RSI is used in only 36%
983
of the patients, that this technique must be
used in all the cases in the ICU. Being
familiar with a range of induction drugs is
important because the specific clinical cir-
cumstances dictate the appropriate induc-
tion method (5). Third, we do not agree
with Dr. Jaber and colleagues (1), who em-
phasize that RSI with Sellick’s technique is
“probably unknown among non-anesthesi-
ologists” (1). In France, many intensivists
are non-anesthesiologists, usually called
medical intensivists. They first acquired a
specialty by studying for 4 or 5 yrs and
completed it by an additional formation for
4 yrs, including 200 hrs of interactive sem-
inars and 18 months of clinical practice in
intensive care medicine. For the year 2005–
2006, 254 students were enrolled. Only
50.8% were anesthesiologists, but 13.8%
were cardiologists, 11.8% pneumologists,
10.6% internists, and 5.5% nephrologists.
Some of them specialized in pediatrics,
neurology, gastroenterology, or any other
medical specialties. All of them learned RSI
with Sellick’s technique, but as there is no
consensus, they use it only when they think
that it is appropriate. The conclusions
about the use of this technique drawn by
Dr. Jaber and colleagues (1) do not seem
accurate to us and would require further
investigations.
François Vincent, MD, Frédéric Gonzalez,
MD, Yves Cohen, MD, Medico Surgical
Intensive Care Unit, Assistance Pub-
lique-Hôpitaux de Paris, Avicenne
University Hospital, Bobigny, France
REFERENCES
1. Jaber S, Amraoui J, Lefrant J-Y, et al: Clinical
practice and risk factors for immediate com-
plications of endotracheal intubation in the
intensive care unit: A prospective, multiple-
center study. Crit Care Med 2006; 34:2355–
2361
2. Practice Guidelines for Management of the
Difficult Airway: An updated report by the
American Society of Anesthesiologits Task
Force on Management of the Difficult Airway.
Anesthesiology 2003; 98:1269 –1277
3. Jackson WL: Should we use etomidate as an
induction agent for endotracheal intubation
in patients with septic shock? A critical ap-
praisal. Chest 2005; 127:1031–1038
4. Annane D: ICU physicians should abandon the
use of etomidate! Intensive Care Med 2005;
31:325–326
5. Reynolds SF, Heffner J: Airway management
of the critically ill patient: Rapid sequence
intubation. Chest 2005; 127:1397–1412
DOI: 10.1097/01.CCM.0000257470.40571.92
984
The authors reply:
We were somewhat perplexed by the
comments from Dr. Vincent and col-
leagues to our observational study that
described the current practice of physi-
cians and reported complications associ-
ated with endotracheal intubation (ETI)
performed in intensive care unit (ICU)
(1). Their comments give us the oppor-
tunity to refer to some data not reported
in our study and at least to correct vari-
ous misrepresentations. First, rapid se-
quence intubation (RSI) for ETI is the
combined administration of a sedative
and neuromuscular blocking agent to fa-
cilitate rapid endotracheal intubation.
This technique was originally described
in the anesthesia literature nearly 40 yrs
ago for the prevention of gastric content
aspiration (2). RSI can be used with other
hypnotic agents with rapid action (pento-
thal, propofol), not only with etomidate.
Moreover, to our knowledge, there are no
prospective, randomized, controlled stud-
ies providing strict statistical evidence of
an increased risk of immediate complica-
tions in ICU patients when RSI was used
with and/or without etomidate. As we fo-
cused on in our study, no significant dif-
ference was observed between the com-
plicated and noncomplicated ETI patients
for RSI use. Contrary to anesthesia, emer-
gency departments, and pre-hospital condi-
tions in which RSI showed beneficial effects
to intubate critically ill patients or to empty
gastric contents, to date there are no ran-
domized, controlled studies that evaluate
RSI use when intubating the trachea in ICU
patients. However, RSI is recommended in
ICUs by several medical societies, especially
by two French critical care societies: the
Société Française d’Anesthésie-Réanima-
tion (3) and the Société de Réanimation de
Langue Française.
Second, in our observational study per-
formed in seven ICUs (1), RSI using the
Sellick’s technique was applied in 36% of
ETIs with a significant difference between
anesthesiologists and non-anesthesiolo-
gists (70/171 ⫽ 41% vs. 22/82 ⫽ 27%;
p ⬍ .05). As we focused on in our study,
although 67% of physicians and residents
were anesthesiologists, there was no dif-
ference in difficult intubations between
anesthesiologists and non-anesthesiolo-
gists. Therefore, it can be suggested that
most of the operators were experienced in
this procedure. The lack of statistically
significant difference in complication
rates between anesthesiologists and non-
anesthesiologists shows that appropri-
ately trained and experienced non-
anesthetist physicians in the ICU have a
similarly high level of airway manage-
ment for patient safety compared with
anesthesiologists. We think that all inten-
sivists, whatever their initial formation
(anesthesiologist or not), in France and
other countries, do the same job. Further
investigations should be undertaken to
define what is the best way to perform
ETI in ICU patients, such as anesthesia
drugs, the best pre-oxygenation tech-
nique (4), and fluid management as em-
phasized in the editorial by Andrew B.
Leibowitz (5), because “there is a dearth
of literature concerning airway manage-
ment techniques in the ICU.”
The authors have not disclosed any
potential conflicts of interest.
Samir Jaber, MD, PhD, Intensive Care
Unit, Department of Anesthesiology B,
DAR B, CHU de Montpellier, Hôpital
Saint Eloi, Montpellier, cedex France;
Jean-Yves Lefrant, MD, Fédération Anes-
thésie-Douleur-Urgences-Réanimation,
Groupe Hospitalo-Universitaire Care-
meau, Centre Hospitalier Universitaire
Nîmes, Nîmes cedex, France
REFERENCES
1. Jaber S, Amraoui J, Lefrant J-Y, et al: Clinical
practice and risk factors for immediate com-
plications of endotracheal intubation in the
intensive care unit: A prospective, multiple-
center study. Crit Care Med 2006; 34:2355–
2361
2. Stept W, Safar P: Rapid induction-intubation
for prevention of gastric content aspiration.
Anesth Analg 1970; 49:633– 636
3. Molliex S, Berset JC, Billard V, et al: Airway
management in adult anesthesia except with
the exception of difficult intubation: Recom-
mendations. Ann Fr Anesth Reanim 2003; 22:
745–749
4. Baillard C, Fosse JP, Sebbane M, et al: Nonin-
vasive ventilation improves preoxygenation
before intubation of hypoxic patients. Am J
Respir Crit Care Med 2006; 174:171–177
5. Leibowitz A: Tracheal intubation in the inten-
sive care unit: Extremely hazardous even in
the best of hands. Crit Care Med 2006;
34:2497–2498
DOI: 10.1097/01.CCM.0000257247.44531.09
The future of surgical critical care: A
European perspective
To the Editor:
We read with great interest the arti-
cle by Dr. Tisherman and colleagues (1)
and the accompanying editorial by Dr.
Crit Care Med 2007 Vol. 35, No. 3
Shapiro (2) regarding the future of sur-
gical critical care (SCC). The lack of in-
terest among young surgical residents to
become involved in the care of critically
ill patients is worrisome. As addressed by
Dr. Tisherman et al. and Dr. Shapiro,
another important factor contributing to
the decreased interest is the significant
impact of practicing SCC on private life.
SCC practitioners dedicate themselves to
a lifelong practice of long working hours
and time spent in the hospital during the
night. In addition, there is an increasing
demand from patients and their relatives
and increasing liability issues. All these
factors lead to a high rate of burnout in
critical care, and also SCC, physicians (3).
Expanding the role of the trauma and
SCC surgeon to an acute care surgeon,
which would also include emergency gen-
eral abdominal surgery, is proposed as a
solution to stimulate interest in a career in
SCC (4). Apparently, the decrease in time
spent in the operating room is experienced
by many fellows or fellows-to-be as an ob-
stacle for entering a SCC fellowship. Al-
though attractive from a surgical point of
view, we feel that expanding the role of the
acute care surgeon would not abolish the
grounds for the lack of interest in SCC.
When, apart from trauma surgery,
emergency abdominal surgical interven-
tions will also be performed by the acute
care surgeon, this is unlikely to reduce
working hours and the pressure on the
night and weekend shifts, as the majority of
emergency surgical interventions are per-
formed outside office hours. The problem
of liability may also increase when the
acute care surgeon is expected to cover
both emergency abdominal and trauma
surgery; beyond this, the acute care sur-
geon also is responsible for the critically ill
patient. It is difficult, if not impossible, to
stay up to date in all these rapidly evolving
specialties, and spending more time in the
operating room inevitably means less time
at the bed of the critically ill patient, in
whom conditions may rapidly deteriorate
and ad hoc medical decision making is of-
ten necessary.
In Belgium—and this is the same in
most European countries— critical care
medicine has evolved to become a sepa-
rate specialty, with full-time intensivists
taking care of the critically ill patient.
This was first observed in academic cen-
ters some 20 –30 yrs ago but is now also
becoming a reality in many larger com-
munity hospitals. One of the reasons is
the increased perception that continuous
Crit Care Med 2007 Vol. 35, No. 3
bedside medical care is necessary when
caring for the most severely ill patients in
the hospital. There is also ample scien-
tific data to support the notion that care
provided by full-time intensivists leads to
better outcomes (5).
As an example, in our hospital, the dif-
ferent adult intensive care units (surgical,
medical, burn, and cardiac surgery) are run
by a team of dedicated full-time intensiv-
ists, providing 24-hr/7-days a week on-site
care for our patients. “Multidisciplinarity”
has been essential in this team; the basic
specialty of the attending intensivists in-
cludes anesthesiology, nephrology, pul-
monology, gastroenterology, hematology,
and surgery. This has many advantages,
because surgical problems in the medical
intensive care unit can be dealt with in
most cases by the surgical intensivist; like-
wise, the advice regarding complicated re-
spiratory or hematologic conditions in pa-
tients in the surgical intensive care unit is
readily available from intensivists who can
put things in a proper perspective. Also, the
interaction with the surgical and medical
departments often happens through the li-
aison intensivist, which does not decrease
the surgical attention to the patient.
The disinterest of U.S. residents in
SCC is worrying, indeed, but the question
remains whether expanding the expertise
of the acute care surgeon will counter the
reasons for this decreased interest and
whether increasing time in the operat-
ing room will benefit the critically ill
patient and, in the end, the develop-
ment of critical care medicine in the
United States.
Jan J. De Waele, MD, Eric A. J. Hoste,
MD, PhD, Intensive Care Unit, Ghent
University Hospital, Ghent, Belgium
REFERENCES
1. Tisherman SA, Angood PB, Barie PS, et al:
Structure of surgical critical care and trauma
fellowships. Crit Care Med 2006; 34:2282–
2286
2. Shapiro MJ: Where have all the surgical inten-
sivists gone? Crit Care Med 2006; 34:2485–
2486
3. Guntupalli KK, Fromm RE Jr: Burnout in the
internist-intensivist. Intensive Care Med 1996;
22:625– 630
4. Cryer HM 3rd: The future of trauma care: At
the crossroads. J Trauma 2005; 58:425– 436
5. Pronovost PJ, Angus DC, Dorman T, et al:
Physician staffing patterns and clinical out-
comes in critically ill patients: A systematic
review. JAMA 2002; 288:2151–2162
DOI: 10.1097/01.CCM.0000257469.33018.67
The authors reply:
We appreciate the interest of Drs. De
Waele and Hoste in our recent article about
the current structure of surgical critical
care fellowships in the United States (1).
We agree with most of their observations.
Although many factors have contributed to
the decreased interest of surgical residents
in trauma and surgical critical care, the
development of the acute care surgery
model (combining surgical critical care,
trauma, and emergency general surgery)
has focused primarily on increasing the
quantity and diversity of surgical experi-
ences for residents and attending surgeons.
We agree that this model may not reduce
work hours, that broadening the scope of
care may actually increase the risks of lia-
bility, and that the acute care surgeon will
become a jack of all trades, but master of
none.
As surgical intensivists, we must sup-
port new training paradigms that promote
career satisfaction and discipline longevity,
as well as initiatives to foster the multipro-
fessional practice of critical care medicine.
These interests are not mutually exclusive.
It seems clear that we cannot maintain the
status quo and still recruit sufficient num-
bers of trainees. Consequently, many insti-
tutions are adopting the acute care surgery
model by establishing a separate service for
emergency general surgery, whereas others
have linked emergency general surgery
with trauma coverage, usually with an ad-
ditional attending surgeon assigned for
backup.
As we develop and implement these
models, there is much we can learn from
our European counterparts. We agree with
Drs. De Waele and Hoste that patients gain
from the care of full-time intensivists who
provide continuous bedside patient care.
However, surgical intensivists are essen-
tially nonexistent in Europe, and the
unique realities of surgical critical care
practice in North America must be ac-
knowledged and incorporated. The chal-
lenge for acute care surgery, with increased
operative responsibilities for the surgeon, is
to ensure that an intensivist is available for
the patient every day, around the clock.
Surgeons must maintain their commit-
ment to the intensive care unit, providing
equivalent value as our non-surgical, full-
time intensivist colleagues. Many groups
accomplish this by separating trauma/
emergency general surgery call from criti-
cal care coverage. We must strive to provide
first-rate surgical critical care coverage for
all surgical patients. It is of concern that
985
according to a survey by Nathens et al. (2),
only 61% of level I trauma centers and 22%
of level II centers provide an intensivist
model of care in the trauma intensive care
unit.
If trauma surgery, emergency general
surgery, and surgical critical care are to
move forward for the benefit of both pa-
tients and practitioners, we need to ad-
dress models of care, shared team respon-
sibilities, and clinical coverage schemes
in a creative way. We should not dismiss
the European model of separation of crit-
ical care medicine from primary special-
ties, just as we must recognize the value
of surgeons who are skilled critical care
practitioners. As critical care medicine
becomes increasingly sophisticated and
specialized, surgeons may need to dedi-
cate their time to the intensive care unit
and the operating room, but not simul-
taneously. Continued dialog with our col-
leagues, both surgical and non-surgical,
from around the world will be invaluable
in making these decisions.
The authors have not disclosed any
potential conflicts of interest.
Samuel A. Tisherman, MD, FACS, FCCM,
University of Pittsburgh, Pittsburgh, PA;
Peter B. Angood, MD, FACS, FCCM, Joint
Commission on Accreditation of Health-
care, Oakbrook Terrace, IL; Philip S.
Barie, MD, MBA, FACS, FCCM, New
York Hospital/Cornell Campus, De-
partment of Surgery, New York, NY;
Lena M. Napolitano, MD, FACS, FCCM,
University of Michigan Health System,
Ann Arbor, MI
REFERENCES
1. Tisherman SA, Angood PB, Barie PS, et al:
Structure of surgical critical care and trauma
fellowships. Crit Care Med 2006; 34:2282–
2286
2. Nathens AB, Maier RV, Jurkovich GJ, et al: The
delivery of critical care services in U.S. trauma
centers: Is the standard being met? J Trauma
2006; 60:773–784
DOI: 10.1097/01.CCM.0000257249.55518.6F
Silver-coated endotracheal tubes: Is
the bactericidal effect time limited?
To the Editor:
In the intubated patient, bacterial bio-
film within the lumen of endotracheal
tubes has been implicated as a reservoir
of bacteria that can lead to ventilator-
associated pneumonia (1). Although the
986
contribution of bacterial colonization of
the endotracheal tube (ETT) in the patho-
genesis of ventilator-associated pneumo-
nia is still debated, we and others have
continued to explore the benefits and
methods to reduce/prevent bacterial col-
onization on the inner surface of ETTs.
The recent study by Dr. Rello and col-
leagues (2) presented the results of a clin-
ical study to test the “respiratory infec-
tion control device,” a silver-coated ETT
developed to prevent bacterial growth
within the lumen of the ETT. The inves-
tigators found delayed bacterial coloniza-
tion on the inner surface of the ETT and
in tracheal aspirates. Overall, there was
lower quantitative bacterial colonization
of the ETT and tracheal aspirates. How-
ever, it is important to emphasize that
ultimately, all ETTs were colonized. A
previous study by Olson et al. (3) in dogs
evaluated the bacterial burden within the
ETT, following instillation of Pseudomo-
nas aeruginosa into the buccal pouch of
dogs. Similar to results described in pa-
tients, the silver coating only delayed
bacterial colonization of the inner surface
of the ETT and the lumen of the ETT was
again colonized after 3.2 ⫾ 0.8 days of
mechanical ventilation.
In a previous study in sheep intubated
for 24 hrs, we showed significant ab-
sence/reduction in bacterial colonization
in the ETT, the ventilator circuit, and
lower respiratory tract using silver-based
coated ETT (4). Our results in a more
recent clinical study were equally good
(5). However, when our studies in sheep
were extended beyond 24 hrs, the pro-
gressive build-up of colonized secretions
on the lumenal surface of the coated
ETTs greatly impaired its bactericidal
properties (6).
We had previously described a novel
device, the “Mucus Shaver,” a device de-
signed to totally remove all secretions
from within the lumen of the ETT (7).
Laboratory studies have shown that sil-
ver-based coated ETTs, regularly cleaned
with the Mucus Shaver, retained full bac-
tericidal activity for 168 hrs (and possibly
much, much longer) without impairment
in bactericidal properties, provided the
silver-based coated ETT was cleaned with
the Mucus Shaver once every 6 hrs (6).
The total absence of bacterial coloniza-
tion of the inner ETT surface for extended
periods of time demonstrated the efficacy
of silver-based coated ETTs only, when
combined with the regular use of the
Mucus Shaver.
It, hence, appears that coating the lu-
men of the ETT with bactericidal agents
is potentially a promising strategy to re-
duce bacterial translocation from the lu-
men of the ETT to the lower airways. The
goal of both laboratory and clinical stud-
ies should be the total prevention, not
just decrease, in bacterial colonization of
the lumen of the ETT during the course
of prolonged tracheal intubation. Coating
the lumen of a tracheal tube with bacte-
ricidal agents, alone, is of no long-term
benefit. Accumulated secretions within
the ETT must be removed meticulously
and regularly with the Mucus Shaver, or
a similar device, to preserve long-term
efficacy of the bactericidal coating.
Gianluigi Li Bassi, MD, Section on Pul-
monary and Cardiac Assist Devices,
Pulmonary and Critical Care Medicine
Branch, NHLBI, NIH, Bethesda, MD;
Lorenzo Berra, MD, Massachusetts
General Hospital, Anesthesia and Crit-
ical Care Department, Boston, MA;
Theodor Kolobow, MD, Section on Pul-
monary and Cardiac Assist Devices,
Pulmonary and Critical Care Medicine
Branch, NHLBI, NIH, Bethesda, MD
REFERENCES
1. Adair CG, Gorman SP, Feron BM, et al: Impli-
cations of endotracheal tube biofilm for ven-
tilator-associated pneumonia. Intensive Care
Med 1999; 25:1072–1076
2. Rello J, Kollef M, Diaz E, et al: Reduced bur-
den of bacterial airway colonization with a
novel silver-coated endotracheal tube in a ran-
domized multiple-center feasibility study. Crit
Care Med 2006; 34:2766 –2772
3. Olson ME, Harmon BG, Kollef MH: Silver-
coated endotracheal tubes associated with re-
duced bacterial burden in the lungs of me-
chanically ventilated dogs. Chest 2002; 121:
863– 870
4. Berra L, De Marchi L, Yu ZX, et al: Endotra-
cheal tubes coated with antiseptics decrease
bacterial colonization of the ventilator cir-
cuits, lungs, and endotracheal tube. Anesthe-
siology 2004; 100:1446 –1456
5. Panzeri M, Marelli C, Brambillasca P, et al:
Evaluation of bactericidal coated tracheal tube
on prevention of bacterial colonization. Inten-
sive Care Med 2005; 31:S78
6. Berra L, Curto F, Li Bassi G, et al: Antibacte-
rial-coated tracheal tubes cleaned with the
Mucus Shaver: A novel method to retain long-
term bactericidal activity of coated tracheal
tubes. Intensive Care Med 2006; 32:888 – 893
7. Kolobow T, Berra L, Li Bassi G, et al: Novel
system for complete removal of secretions
within the endotracheal tube: The Mucus
Shaver. Anesthesiology 2005; 102:1063–1065
DOI: 10.1097/01.CCM.0000257477.44926.90
Crit Care Med 2007 Vol. 35, No. 3
The authors reply:
The pathogenesis of ventilator-associ-
ated pneumonia is complex and depends
on the interaction of multiple risk fac-
tors. We agree that abrogating bacterial
colonization on the endotracheal tube
should be the ultimate goal, but using
the respiratory infection control device
(1) to delay colonization and the onset of
ventilator-associated pneumonia is note-
worthy because the risk increases with
the duration of intubation. For example,
the cumulative risk increased during the
first 5 days, peaked at 3.3% on day 5, and
subsequently decreased to 2.3% on day
10 and 1.3% on day 15 in a large study
(2). A more recent, large observational
study has confirmed that most patients are
experiencing shorter intubation times and
are no longer intubated after 10 days (3).
With delayed colonization, patients may be
extubated before infection can develop.
We applaud Dr. Li Bassi and col-
leagues for the promising results ob-
tained by cleaning antibacterial-coated
tracheal tubes with the “Mucus Shaver”
(4); however, their study had several lim-
itations (5). Although between-group dif-
ferences looked promising, the controlled
study included only 12 sheep. The strat-
egy was limited to the lumen of the tube,
with an internal coating of silver-sulfadi-
azine in polyurethane, thereby failing to
address the problems in the throat and
subglottic space, which are potential res-
ervoirs of pathogenic bacteria (5).
Multicentered, randomized, controlled
clinical trials are needed to determine
whether either strategy will prevent ven-
tilator-associated pneumonia. More than
1,500 patients have been enrolled in a
phase III study of the respiratory infec-
tion control device, and statistical analy-
sis is underway. Regardless of the out-
come, we predict that a bundle approach
will be required to block the multifacto-
rial processes that contribute to the de-
velopment of ventilator-associated pneu-
monia. We would welcome the addition
of other preventive strategies supported
by adequate clinical trials.
Dr. Rello has consulted for Wyeth and
Intrabiotics. He has also received grant
funding from BARD. Dr. Kollef has not dis-
closed any potential conflicts of interest.
Jordi Rello, MD, PhD, Joan XXIII Uni-
versity Hospital, Tarragona, Spain;
Marin Kollef, MD, Washington Univer-
sity School of Medicine, St. Louis, MO
Crit Care Med 2007 Vol. 35, No. 3
REFERENCES
1. Rello J, Kollef M, Diaz E, et al: Reduced bur-
den of bacterial airway colonization with a
novel silver-coated endotracheal tube in a ran-
domized multiple-center feasibility study. Crit
Care Med 2006; 34:2766 –2772
2. Cook DJ, Walter SD, Cook RJ, et al: Incidence
of and risk factors for ventilator-associated
pneumonia in critically ill patients. Ann In-
tern Med 1998; 129:433– 440
3. Freeman BD, Borecki IB, Coopersmith CM, et
al: Relationship between tracheostomy timing
and duration of mechanical ventilation in crit-
ically ill patients. Crit Care Med 2005; 33:
2513–2520
4. Berra L, Curto F, Li Bassi G, et al: Antibacte-
rial-coated tracheal tubes cleaned with the
Mucus Shaver: A novel method to retain long-
term bactericidal activity of coated tracheal
tubes. Intensive Care Med 2006; 32:888 – 893
5. Spronk PE, Rommes JH, Schultz MJ: Comment
on “Antibacterial-coated tracheal tubes cleaned
with a Mucus Shaver” by Berra et al. Intensive
Care Med 2006; 32:2080 –2081
DOI: 10.1097/01.CCM.0000257459.13130.07
Albumin supplementation and organ
function
To the Editor:
The recent article by Dr. Dubois and
colleagues (1) adds data to the long-
running debate about the usefulness of
albumin supplementation in critically
care. The accompanying editorial high-
lights some of the limitations of the
study, notably that it was unblinded and
the control group did not receive intra-
vascular volume expansion to equal that
of the albumin administered to the in-
tervention group. As a result, differ-
ences in intravascular volume may con-
found interpretation of any specific effect of
albumin.
An additional issue is that the claimed
effects may be an artifact of the outcome
measure used and unconventional re-
porting. The stated primary outcome
measure was a change in the Sequential
Organ Failure Assessment (SOFA) score
from baseline to day 7; this was reported
to be greater in the albumin group than the
control group (3.1 vs. 1.4; p ⫽ .03) because
of differences in the cardiovascular, respi-
ratory, and neurologic components.
There are a number of issues that re-
quire clarification. Specifically, the base-
line cardiovascular SOFA score in the
control group was zero and, therefore,
there is no potential for improvement.
Any observed difference would have to be
the result of a higher baseline SOFA score
in the albumin group. Furthermore, any
difference may represent only a difference
in intravascular volume resulting from
the study design. Last, the cardiovascular
component of the SOFA score is signifi-
cantly affected by clinical decisions to use
or not to use vasoactive agents, and in an
unblinded trial, this introduces signifi-
cant potential for bias.
The respiratory component of the
SOFA score is not reported; the PaO2/FIO2
ratio is reported instead. The increases
for the albumin and control groups were
from 215 to 257 and 238 to 248, respec-
tively. All these figures represent a SOFA
score of 2, and so, it appears that the
nominated outcome measure was un-
changed in both groups. The authors
present no data on the use of mechanical
ventilation or positive end-expiratory
pressure, which significantly affect the
PaO2/FIO2 ratio and represent another po-
tential source of bias.
The neurologic component of the
SOFA score is not reported; the authors
instead report the Glasgow Coma Score
(GCS). The GCS increased from 13 to 15
in the albumin group and 14 to 15 in the
control group; i.e., in both groups the
neurologic SOFA score decreased from 1
to 0. Again, there appears to be no differ-
ence. As the GCS in both groups in-
creased to the maximum possible, a dif-
ference can only result from a greater
potential for improvement in the albumin
group. It was not possible for the GCS in
the control group to increase to 16!
We welcome the conduct of high-
quality, randomized, controlled trials in
critical care and hope the data from this
pilot study will inform the design of a
large, definitive trial. The report high-
lights the importance of using robust pa-
tient-centered outcome measures, such
as mortality, of adhering to a predeter-
mined analysis plan, and of faithfully re-
porting a study’s stated outcome mea-
sures. We trust that any large phase III
trial will be designed in such a way that
claimed differences between groups are
not the subject of unnecessary uncer-
tainty.
Simon Finfer, MB BS, FRCA, FRCP,
FJFICM, Intensive Care Research,
Royal North Shore Hospital, Sydney;
John Myburgh, MBBCh, PhD, FANZCA,
FJFICM, Intensive Care Research, St.
George Hospital, Sydney; Rinaldo
Bellomo, FRACP, FJFICM, MD, Inten-
sive Care Research, The Austin Medi-
cal Centre, Melbourne, Australia
987
REFERENCE
1. Dubois M-J, Orellana-Jimenez C, Melot C, et
al: Albumin administration improves organ
function in critically ill hypoalbuminemic pa-
tients: A prospective, randomized, controlled,
pilot study. Crit Care Med 2006, 34:2536 –
2540
DOI: 10.1097/01.CCM.0000257235.05199.9A
High-quality enteral nutrition
essential for reducing morbidity and
mortality in acute care patients
To the Editor:
I appreciated the recent excellent article
by Dr. Pontes-Arruda and colleagues (1),
which reports that enteral feeding with en-
riched levels of eicopentaenoic acid, ␥-lin-
olenic acid, and antioxidant vitamins re-
duced mortality by 19.4% (p ⫽ .037) in
mechanically ventilated patients with sepsis
and septic shock, compared with patients
receiving standard enteral formula.
Recent additional research has indi-
cated that better nutritional status, early
enteral feeding, and the use of immu-
nonutrition enteral formulas (which con-
tain larger amounts of such nutrients as
omega-3 fats, RNA, arginine, glutamine,
zinc, and vitamins) can significantly re-
duce both morbidity and mortality in
acutely ill patients. A study of 630 hospi-
talized patients reported that that the
odds ratio risk of nosocomial infections
was 4.98 times as great (95% confidence
interval, 4.6 – 6.4) in severely malnour-
ished patients compared with adequately
nourished patients (2). A study of 4,049
critically ill, mechanically ventilated pa-
tients found that enteral feeding within
48 hrs of intubation reduced hospital
mortality by 27% (p ⫽ .001) compared
with patients not given enteral feeding in
the first 48 hrs (3). This significantly lower
mortality rate was seen, even though the
incidence of ventilator-associated pneumo-
nia was 34% higher in the patients who
received enteral nutrition in the first 48
hrs (3).
A prospective, randomized study of 181
intensive care unit (ICU) patients found
that mortality and the rate of nosocomial
infections were both significantly reduced
in patients given an enteral formula sup-
plemented with arginine, messenger RNA,
and omega-3 containing fish oil compared
with patients given a standard enteral for-
mula (4). A meta-analysis of 11 studies in-
volving ICU patients found that the use of
nutrient-enriched immunonutrition en-
988
teral nutrition formulas resulted in a 46%
lower risk of nosocomial pneumonia com-
pared with patients given a standard enteral
formula (p ⫽ .007) (5). A similar meta-
analysis of nine studies found that ICU pa-
tients given enteral immunonutrition for-
mulas had a 55% lower risk of bacteremia
compared with patients receiving standard
formula (p ⫽ .0002) (5).
Better nutrition plays a major role in
reducing mortality and morbidity among
acutely ill patients. I hope Critical Care
Medicine can publish more good studies
on acute care nutrition.
The author of this letter received no
outside financial support. The author has
not disclosed any financial interest in
food, food supplement, or pharmaceutical
companies.
Luke Curtis, MD, MS, CIH, Norwegian
American Hospital, Chicago, IL
REFERENCES
1. Pontes-Arruda A, Aragão AMA, Albuquerque
JD: Effects of enteral feeding with eicosapen-
taenoic acid, ␥-linolenic acid, and antixoidants
in mechanically ventilated patients with se-
vere sepsis and septic shock. Crit Care Med
2006; 34:2325–2333
2. Schneider SM, Veyres P, Pivot X, et al: Mal-
nutrition is an independent risk factor associ-
ated with nosocomial infections. Br J Nutr
2004; 92:105–111
3. Artinian V, Krayem H, DiGiovine B: Effects of
early enteral feeding on the outcome of criti-
cally ill mechanically ventilated patients.
Chest 2006; 129:960 –967
4. Galban C, Montejo JC, Mesejo A, et al: An
immune-enhancing diet reduces mortality
rate and episodes of bacteriemia in septic in-
vasive care unit patients. Crit Care Med 2000;
28:643– 648
5. Montejo JC, Zarazaga A, Lopez-Martinez J, et
al: Immunonutrition in the intensive care
unit: A systemic review and consensus state-
ment. Clin Nutr 2003; 22:221–233
DOI: 10.1097/01.CCM.0000257471.74561.7B
The author replies:
Indeed, nutritional support plays an
important role in improving outcomes
and reducing mortality in critical illness.
For instance, the use of an enteral diet
enriched with eicosapentaenoic acid,
␥-linolenic acid, and antioxidants proved
to be an effective therapy not only for
patients with severe sepsis and septic
shock requiring mechanical ventilation
(1), but also for patients with acute respi-
ratory distress syndrome (2) and acute
lung injury (3). However, there is still a
long journey for us to start the transla-
tion of published evidence into clinical
practice and to have critical care practi-
tioners recognize nutrition not only as a
way to deliver calories and nutrients, but
also as a powerful therapeutic tool.
International guidelines can play an
important role in this changing behavior
process. For instance, the Surviving Sep-
sis Campaign Guidelines for the Treat-
ment of Patients with Severe Sepsis and
Septic Shock (4) does not contain any
nutritional advice among its 44 recom-
mendations. This and other international
guidelines should consider reviewing the
literature and include nutrition advice in
their recommendations.
We appreciate Dr. Curtis’ comments,
and we hope to see new nutrition studies
published, debated, and eventually incor-
porated into clinical practice.
The author has consulted for Abbott
Laboratories; received honoraria from
Abbott Laboratories, Eli Lilly, and Baxter
Healthcare; and received grant support
from Abbott Laboratories and Baxter
Healthcare.
Alessandro Pontes-Arruda, MD, PhD,
Fernandes Távora Hospital, Ildefonso
Albano, Fortaleza, CE Brazil
REFERENCES
1. Pontes-Arruda A, Aragão AMA, Albuquerque
JD: Effects of enteral feeding with eicosapen-
taenoic acid, ␥-linolenic acid, and antioxidants
in mechanically ventilated patients with se-
vere sepsis and septic shock. Crit Care Med
2006; 34:2325–2333
2. Gadek JE, DeMichele SJ, Karlstad MD, et al:
Effect of enteral feeding with eicosapentaenoic
acid, gamma-linolenic acid and antioxidants
in patients with acute respiratory distress syn-
drome. Crit Care Med 1999; 27:1409 –1420
3. Singer P, Theilla M, Fisher H, et al: Benefit of
an enteral diet enriched with eicosapentaenoic
acid and gamma-linolenic acid in ventilated
patients with acute lung injury. Crit Care Med
2006; 34:1033–1038
4. Dellinger RP, Carlet JM, Mansur H, et al: Sur-
viving Sepsis Campaign Guidelines for man-
agement of severe sepsis and septic shock. Crit
Care Med 2004; 32:858 – 872
DOI: 10.1097/01.CCM.0000257722.50567.96
Saving lives in severe sepsis with the
help of enteral nutrition
To the Editor:
We read, with great interest, the article
by Dr. Pontes-Arruda and colleagues (1)
about the effects of an enteral diet enriched
with eicosapentaeonic acid, ␥-linolenic
Crit Care Med 2007 Vol. 35, No. 3
acid, and antioxidants in acute respiratory
distress syndrome (ARDS) patients with se-
vere sepsis and septic shock. As a group
long interested in the management of crit-
ically ill patients with sepsis, the conclu-
sions of this article seem amazing.
In a field in which different groups are
looking for the magic bullet in the treat-
ment of sepsis, with moderate to modest
results, these authors have found a 19.4%
absolute risk reduction for mortality and
a number needed to treat of 5 at day 28.
These results are better than those from
the early goal-directed therapy (reduction
for mortality, 16%; number needed to
treat, 6 – 8) (2).
Although these are the best published
results among the assorted weaponry for
sepsis, a lot of confounding factors, bias,
and omissions need to be solved before
accepting the results. It is well known
that the outcome of septic patients is
different in terms of focus, the etiological
agent, and the type of patient. However,
these first two variables have not been
considered in the methods. Moreover, the
number of medical and surgical sepsis
cases in each group is not exposed. Al-
though adequate antibiotic therapy has
been recognized as one of the interven-
tions associated with a lower mortality
rate in sepsis (3), there were no refer-
ences about this issue in the publication,
and there were no references about the
timing of administration.
The authors established that all patients
were treated according the Surviving Sepsis
Campaign Guidelines and early goal-directed
therapy, but we cannot know which of the
two groups received more fluids, more va-
sopressors, and inotropics. How can it be
concluded that the study group is associ-
ated with a lower development of cardio-
vascular dysfunction (p ⬍ .001) without
considering these factors in the hemody-
namic support? Similar concerns arise
about the results of ventilator-free and in-
tensive-free days. A recently published arti-
cle (4) shows that a conservative strategy of
fluid management for patients with acute
lung injury improved lung function and
shortened the duration of mechanical ven-
tilation and intensive care, but how much
fluid did each group receive?
Other aspects of the article appear con-
fusing. Because the totality of patients were
ARDS patients (PaO2/FIO2 ratio, ⬍200), the
development of new respiratory dysfunc-
tion in both groups was surprising.
With all these considerations, we are
less optimistic than Dr. Pacht in his edi-
torial on the article (5) because the flaws
Crit Care Med 2007 Vol. 35, No. 3
in the methodology of the article cannot
convince us that a single modification in
enteral diet in a short period of time and
on a scarce number of severe sepsis and
septic shock patients with ARDS could be
one of the cornerstones in the treatment
of these patients.
Carlos Ortiz-Leyba, MD, PhD, José
Garnacho-Montero, MD, PhD, Servi-
cio de Cuidados Críticos y Urgencias,
Hospital Universitario Virgen del
Rocío, Sevilla, Spain
REFERENCES
1. Pontes-Arruda A, Aragão AMA, Albuquerque
JD: Effects of enteral feeding with eicosapen-
taenoic acid, ␥-linolenic acid, and antioxidants
in mechanically ventilated patients with se-
vere sepsis and septic shock. Crit Care Med.
2006; 34:2325–2333
2. Rivers E, Nguyen B, Havstad S, et al: Early
goal-directed therapy in the treatment of se-
vere sepsis and septic shock. N Engl J Med
2001; 345:1368 –1377
3. Garnacho-Montero J, García-Garmendia JL,
Barrero-Almodovar A, et al: Impact of ade-
quate empirical antibiotic therapy on the out-
come of patients admitted to the intensive
care unit with sepsis. Crit Care Med 2003;
31:2742–2751
4. The National Heart, Lung, and Blood Institute
Acute Respiratory Distress Syndrome (ARDS)
Clinical Trials Network: Comparison of two
fluid-management strategies in acute lung in-
jury. N Engl J Med 2006; 354:2564 –2575
5. Pacht ER: Enteral therapy to decrease morbid-
ity and improve survival in acute respiratory
distress syndrome: Its time has come. Crit
Care Med 2006; 34:2492–2493
DOI: 10.1097/01.CCM.0000257472.00249.02
The author replies:
The use of nutrition intervention en-
riched in eicosapentaenoic acid, ␥-linolenic
acid, and antioxidants as a therapeutic
strategy to reduce both pulmonary and sys-
temic inflammation represents a new and
innovative approach, sustained not only by
one but for several “gold standard” clinical
trials, all of them based in solid scientific
background.
Regarding our article published in Crit-
ical Care Medicine (1), we would like to
restate that although many variables were
collected during clinical trials, the space
available for publication is restricted, as
well as the amount of tables and figures.
Because we or any other author were not
allowed to publish every single aspect of the
trial, this involuntary absence of informa-
tion in the published article occasioned by
the lack of space should not be considered
as a failure in the methodology.
In our trial, the patients in both groups
were well balanced in terms of source of in-
fection, number of medical/surgical patients
enrolled, and the amount or type of fluids
received. Moreover, many questions consid-
ered by Drs. Ortiz-Leyba and Garnacho-
Montero as omissions, were well defined in
the article itself. For instance, regarding
the adequacy and timing of the antibiotic
therapy, we mentioned that all patients
were treated in accordance with the Sur-
viving Sepsis Campaign recommendations
(2), which means that all patients included
received broad-spectrum antibiotics within
the first hour of recognition of severe sepsis.
The definition of a new respiratory
dysfunction was also stated in the article.
We consider a new respiratory failure as
the development of a new respiratory fail-
ure requiring new ventilator support
within the 28-day follow-up period. All
patients were submitted to the same ven-
tilator weaning protocol. We do not un-
derstand how this simple definition can
generate confusion and surprise.
Finally, we would like to restate that we
are not dealing with a single-trial result. In
fact, the study diet we used (Oxepa, Abbott
Laboratories, Abbott Park, IL) has been exten-
sively examined as a therapeutic tool for the
treatment of patients with pulmonary pathol-
ogies and undergoing mechanical ventilation
by different research groups, with highly con-
sistent findings. Two other trials showed sim-
ilar results regarding the improvement in ox-
ygenation status, ventilator-free days, and
intensive care unit (ICU)-free days, both in
acute respiratory distress syndrome (3) and
acute lung injury (4). In a recently performed
meta-analysis of these three trials, the use of
an enteral diet enriched with eicosapenta-
enoic acid, ␥-linolenic acid, and antioxidants
in mechanically ventilated patients is associ-
ated not only with a significant improvement
in the oxygenation status, but also with
more ventilator-free days (standardized
mean difference, 0.556; p ⬍ .0001), more
ICU-free days (SMD, 0.508; p ⬍ .0001) and
with a 60% reduction in the risk of mor-
tality (odds ratio, 0.404; p ⫽ .001) (5). For
this reason, we totally agree with Dr.
Pacht’s editorial. Although the adoption of
evidence-based medicine is not mandatory,
in our ICU, we choose not to ignore it. We
do believe that if the current evidence is
taken into consideration, the use of an en-
teral diet enriched in eicosapentaenoic
acid, ␥-linolenic acid, and antioxidants is
among the most important strategies to be
adopted in the treatment of mechanically
989
Figure 1. Levels of circulating soluble triggering receptors on myeloid cells (sTREM-1) in community-acquired pneumonia. Individual values are plotted
and the bars represent medians of the values. PSI, Pneumonia Severity Index.
ventilated, acutely ill patients; thus, not to
use this type of enteral support in recom-
mended patients should be considered bad
practice.
Alessandro Pontes-Arruda, MD, PhD,
Fernandes Távora Hospital, Ildefonso
Albano, Fortaleza, CE Brazil
REFERENCES
1. Pontes-Arruda A, Aragão AMA, Albuquerque
JD: Effects of enteral feeding with eicosapen-
taenoic acid, ␥-linolenic acid, and antioxidants
in mechanically ventilated patients with se-
vere sepsis and septic shock. Crit Care Med
2006; 34:2325–2333
2. Dellinger RP, Carlet JM, Mansur H, et al: Sur-
viving Sepsis Campaign Guidelines for the
Management of Severe Sepsis and Septic
Shock. Crit Care Med 2004; 32:858 – 872
3. Gadek JE, DeMichele SJ, Karlstad MD, et al:
Effect of enteral feeding with eicosapentaenoic
acid, gamma-linolenic acid and antioxidants
in patients with acute respiratory distress syn-
drome. Crit Care Med 1999; 27:1409 –1420
4. Singer P, Theilla M, Fisher H, et al: Benefit of
an enteral diet enriched with eicosapentaenoic
acid and gamma-linolenic acid in ventilated
patients with acute lung injury. Crit Care Med
2006; 34:1033–1038
5. Pontes-Arruda A, DeMichele SJ, Anand S, et al:
Enteral nutrition with eicosapentaenoic acid
(EPA), gamma-linolenic acid (GLA) and anti-
oxidants in critical illness: A meta-analysis
evaluation of outcome data. Crit Care Med
2006; 34(Suppl):A95
DOI: 10.1097/01.CCM.0000257478.43093.47
Circulating levels of soluble triggering
receptor expressed on myeloid cells
(sTREM)-1 in community-acquired
pneumonia
To the Editor:
Soluble triggering receptor expressed
on myeloid cells (sTREM)-1 has been put
990
forward for the diagnosis and outcome
prediction in patients with sepsis (1).
Measurement of sTREM-1 was advocated
in plasma and serum (1) and bronchoal-
veolar fluid (2). Importantly, more than
half of these patients had sepsis because
of respiratory tract infections. Indeed, a
prompt diagnosis of community-acquired
pneumonia has important therapeutic
and prognostic implications (3). Microbi-
ological culture results often remain neg-
ative and are only available after a delay of
24 – 48 hrs. A novel approach to rapidly
estimate the presence of an infection is
the use of biomarkers.
We measured sTREM-1 concentra-
tions by the immunoblot technique, as
well as by enzyme-linked immunosorbent
assay, using previously described anti-
bodies (1, 2) in plasma and serum of a
well-documented cohort of 302 consecu-
tive patients admitted to the emergency
department with community-acquired
pneumonia (CAP) (4). CAP was defined as
suggested (5), and the Pneumonia Sever-
ity Index (PSI) was calculated as previ-
ously described (6). All patients were fol-
lowed up after 6 wks. Cure was defined as
resolution of clinical, laboratory, and ra-
diographic signs and improvement as re-
duction of clinical, laboratory, and radio-
graphic findings. Treatment success
represented the sum of the rates for cure
and improvement. Treatment failure in-
cluded death and recurrence or persis-
tence of clinical, laboratory, and radio-
logic signs at follow-up.
In the 251 patients with a successful
outcome at follow-up, sTREM-1 levels at
admission were (median [interquartile
range]) 85.2 [44.3–156.8] and were un-
changed at follow-up (68.8 [42.9 –135.3];
p ⫽ .17) (Fig. 1). sTREM-1 concentra-
tions in mild CAP (defined as PSI I–III,
93.3 [44.1–165.2]) were similar compared
with patients with severe CAP (PSI IV–V,
79.1 [45.8 –154.1]; p ⫽ .31). sTREM-1
levels at admission in patients with a sub-
sequent failure were similar (79.1 [45.0 –
126.2]; p ⫽ .39) to patients with a subse-
quent successful outcome.
We found no significant correlation
between sTREM-1 levels, independent if
assessed with the use of immunoblot
technique or enzyme-linked immunosor-
bent assay using several antibodies (from
R&D Systems (2) and others), before and
after ultracentrifugation, in plasma or se-
rum, respectively. Similarly, sTREM-1
concentrations did not correlate with
other markers of infection, i.e., C-reactive
protein (r ⫽ .03; p ⫽ not significant
[NS]), procalcitonin (r ⫽ ⫺.03; p ⫽ NS),
and leukocyte count (r ⫽ .03; p ⫽ NS).
In conclusion, circulating sTREM-1
levels are not helpful for the assessment
of etiology and severity in patients with
CAP or in predicting outcome of the dis-
ease. Conversely, measurement of the lo-
cal production of sTREM-1 in bronchoal-
veolar fluid might provide more reliable
results (2). This, however, is not a cost-
efficient approach in the routine care of
patients with CAP.
Beat Müller, MD, Mikael M. Gencay,
PhD, Department of Internal Medi-
cine, University Hospital Basel, Swit-
zerland; Sebastien Gibot, MD, Depart-
ment of Intensive Care and Exper-
imental Physiology, Hopital Central,
Nancy Cedex, France; Daiana Stolz, MD,
Lukas Hunziker, MD, Michael Tamm,
MD, Mirjam Christ-Crain, MD, Depart-
ment of Internal Medicine, University
Hospital Basel, Switzerland
REFERENCES
1. Gibot S, Cravoisy A, Kolopp-Sarda M-N, et al:
Time-course of sTREM (soluble triggering re-
Crit Care Med 2007 Vol. 35, No. 3
 ceptor expressed on myeloid cells)-1, procal-
citonin, and C-reactive protein plasma con-
centrations during sepsis. Crit Care Med 2005;
33:792–796
2. Gibot S, Cravoisy A, Levy B, et al: Soluble
triggering receptor expressed on myeloid cells
and the diagnosis of pneumonia. N Engl J Med
2004; 350:451– 458
3. Meehan TP, Fine MJ, Krumholz HM, et al:
Quality of care, process, and outcomes in el-
derly patients with pneumonia. JAMA 1997;
278:2080 –2084
4. Christ-Crain M, Stolz D, Bingisser R, et al:
Procalcitonin-guidance of antibiotic therapy
in community-acquired pneumonia—A ran-
domized trial. Am J Respir Crit Care Med
2006; 174:84 –93
5. Niederman MS, Mandell LA, Anzueto A, et al:
Guidelines for the management of adults with
community-acquired pneumonia: Diagnosis,
assessment of severity, antimicrobial therapy,
and prevention. Am J Respir Crit Care Med
2001; 163:1730 –1754
6. Fine MJ, Auble TE, Yealy DM, et al: A predic-
tion rule to identify low-risk patients with
community-acquired pneumonia. N Engl
J Med 1997; 336:243–250
DOI: 10.1097/01.CCM.0000257480.45965.8C
What does it mean: Appropriate
therapy for methicillin-resistant
Staphylococcus aureus?
To the Editor:
We read with interest the article by Dr.
Shorr and colleagues (1), in which the
authors defined the negative impact that
methicillin-resistant Staphylococcus au-
reus (MRSA) may have on the outcome of
ventilator-associated pneumonia (VAP).
Nevertheless, we feel some concerns with
regard to the statement that protocols
finalized to improve initially appropriate
antibiotic administration are unlikely to
have much effect on containing the costs
associated with MRSA in the intensive
care unit. Although we share some of
their concerns and we join in advocating
new options for treating MRSA infec-
tions, we would like to argue briefly
about their definition of “appropriate an-
timicrobial therapy.”
The authors stated that all patients
initially received vancomycin at 15 mg/kg
twice daily and that a target trough se-
rum level (Cmin) of 15–20 mg/L was de-
fined as appropriate. In our opinion, it is
questionable that the conventionally rec-
ommended twice-daily regimen of vanco-
mycin may be appropriate for initial VAP
treatment. A recent retrospective study as-
sessing vancomycin serum levels 36 – 48
hrs after starting therapy according to no-
Crit Care Med 2007 Vol. 35, No. 3
mograms in 1,737 patients treated with two
to four separate doses or with continuous
infusion showed Cmin ⬍10 mg/L in as
much as 45.1% of patients receiving inter-
mittent infusion but in only 7.9% of those
receiving continuous infusion (2). Consid-
ering that only 5% to 25% of simultaneous
serum concentrations of vancomycin may
diffuse in epithelial lining fluid (3), it may
be supposed that several VAP patients
might experience underexposure when re-
ceiving this regimen, especially in the pres-
ence of normal renal function or of patho-
physiological conditions enhancing the
volume of distribution or renal clearance (4).
Conversely, continuous infusion, by
ensuring higher and more sustained se-
rum levels, should be considered more
appropriate with the intent of enhancing
clinical efficacy with vancomycin (2, 4).
Accordingly, a recent retrospective study
in patients treated with vancomycin for
MRSA VAP showed that continuous infu-
sion was independently associated with a
lower mortality rate (5).
In their article, Dr. Shorr and cowork-
ers (1) analyzed 107 cases of S. aureus
VAP. However, it was not stated how
many additional MRSA cases did not
reach the target Cmin in the first 24 hrs
and had to be excluded or how many of
the included MRSA patients had lower
than target Cmin subsequently, thereby
probably experiencing undertreatment.
It is often stressed that in controlled
clinical trials assessing new anti-MRSA
drugs, active comparators should be cho-
sen with care. Accordingly, when using
vancomycin, continuous infusion, proba-
bly the most efficacious dosing regimen,
should be chosen for optimal compari-
son. This means that the results of pre-
vious trials should be reassessed in the
light of potential underexposure.
Interestingly, ⬎60% of Italian inten-
sivists declare they use vancomycin in
continuous infusion (personal unpub-
lished data); so, it may be difficult for
them to participate in comparative stud-
ies in which the comparator schedule is
completely different from this. Indeed, in
the management of multi-drug resistant
Gram-positive infections optimization in
the usage of old drugs still remains a
clinical priority and a scientific chal-
lenge, whose dignity may be considered
of similar importance to that of the as-
sessment of the possible therapeutic role
of new compounds.
Dr. Pea is a consultant and on the
speakers’ bureaus for Pfizer and Sanofi-
Aventis. Dr. Viale is a consultant and on
the speakers’ bureaus for Pfizer and
Sanofi-Aventis and has received recent
research funding from Sanofi-Aventis.
Pierluigi Viale, MD, Clinic of Infectious
Diseases, Department of Medical and
Morphological Research, Medical
School, University of Udine, Italy;
Federico Pea, MD, Institute of Clinical
Pharmacology & Toxicology, Depart-
ment of Experimental and Clinical Pa-
thology and Medicine, Medical School,
University of Udine, Italy
REFERENCES
1. Shorr AF, Combes A, Kollef MH, et al: Methi-
cillin-resistant Staphylococcus aureus pro-
longs intensive care unit stay in ventilator-
associated pneumonia, despite initially
appropriate antibiotic therapy. Crit Care Med
2006; 34:700 –706
2. Kitzis MD, Goldstein FW: Monitoring of van-
comycin serum levels for the treatment of
staphylococcal infections. Clin Microbiol In-
fect 2006; 12:92–95
3. Lamer C, de Beco V, Soler P, et al: Analysis of
vancomycin entry into pulmonary lining fluid
by bronchoalveolar lavage in critically ill pa-
tients. Antimicrob Agents Chemother 1993;
37:281–286
4. Pea F, Viale P: The antimicrobial therapy puzzle:
Could pharmacokinetic-pharmacodynamic rela-
tionships be helpful in addressing the issue of
appropriate pneumonia treatment in critically
ill patients? Clin Infect Dis 2006; 42:1764 –
1771
5. Rello J, Sole-Violan J, Sa-Borges M, et al:
Pneumonia caused by oxacillin-resistant
Staphylococcus aureus treated with glycopep-
tides. Crit Care Med 2005; 33:1983–1987
DOI: 10.1097/01.CCM.0000257473.18308.64
The authors reply:
We appreciate the comments of Drs.
Viale and Pia on our recent article regard-
ing the differential impact of methicillin-
resistant Staphylococcus aureus (MRSA)
on outcomes in ventilator-associated
pneumonia (VAP). They raise a concern
regarding the definition of appropriate
therapy that we used for our analysis.
Specifically, we defined as appropriate
therapy for MRSA the administration of
vancomycin at a dose of 15 mg/kg to
target a trough level of 15–20 mg/L. As
we state in the article, this definition was
chosen because of the recent recommen-
dations for vancomycin therapy in the
joint American Thoracic Society/Infec-
tious Disease Society of America position
statement on various forms of health-
care-associated and nosocomial pneumo-
nia. We concur that this definition cer-
991
tainly has limitations (1, 2). The optimal
regimen for the dosing of vancomycin in
pneumonia is unknown. However, it does
seem clear that the conventional U.S.
practice of administering 1 gm every 12
hrs and not monitoring trough levels is
inadequate. We concur with Drs. Viale
and Pia that more study is needed to
determine how and if to use vancomycin
for MRSA pneumonia.
They suggest a role for continuous
infusion that has certain theoretical ben-
efit. No patient in our analysis received
continuous-infusion vancomycin. More
importantly, several recent studies sug-
gest that even driving up the trough level
with vancomycin does not improve out-
comes in VAP (3, 4). For example, Jeffres
et al. (3) found that mortality rates in
MRSA VAP were similar among those
with low, moderate, and high vancomy-
cin trough levels. More concerning, Hi-
dayat and colleagues (4) confirmed that
pushing the trough levels of vancomycin
through aggressive dosing schemes has
no impact on outcomes but came at the
expense of increased rates of nephrotox-
icity. Given these data coupled with our
findings, we share their concern that
many practicing intensivists seem hesi-
tant either to adjust their approach to the
use of vancomycin or to adopt novel ther-
apies for MRSA VAP.
Andrew F. Shorr, MD, MPH, Pulmonary
and Critical Care Medicine, WA Hospital
Center, Washington, DC; Alain Combes,
MD, PhD, Service Reanimation Medicale,
Pr Gilbert, Institut de Cardiologie, Groupe
Hospitalier Pitie-Salpetriere, Paris, France;
Marin H. Kollef, MD, Pulmonary and
Critical Care Medicine, Barnes-Jewish
Hospital, Washington University, St.
Louis, MO; Jean Chastre, MD, Service
Reanimation Medicale, Pr Gilbert, In-
stitut de Cardiologie, Groupe Hospi-
talier Pitie-Salpetriere, Paris, France
REFERENCES
1. Shorr AF, Combes A, Kollef MH, et al: Methicil-
lin-resistant Staphylococcus aureus prolongs
intensive care unit stay in ventilator-associated
pneumonia, despite initially appropriate antibi-
otic therapy. Crit Care Med 2006; 34:700 –706
2. American Thoracic Society, Infectious Dis-
eases Society of America: Guidelines for the
management of adults with hospital-acquired,
ventilator-associated, and healthcare-associ-
ated pneumonia. Am J Respir Crit Care Med
2005; 171:388 – 416
3. Jeffres MN, Isakow W, Doherty JA, et al: Predictors
of mortality for methicillin-resistant Staphylococ-
992
cus aureus health-care-associated pneumonia:
Specific evaluation of vancomycin pharmacoki-
netic indices. Chest 2006; 130:947–955
4. Hidayat LK, Hsu DI, Quist R, et al: High dose
vancomycin therapy for methicillin-resistant
Staphylococcus aureus infections: Efficacy and
toxicity. Arch Intern Med 2006; 166:2138 – 2144
DOI: 10.1097/01.CCM.0000257248.77811.55
The findings of the International
Conference on Medical Emergency
Teams are biased and misleading
To the Editor:
We read with interest the consensus
findings on medical emergency teams
(METs) (1). We congratulate the authors
for their considerable efforts in further-
ing debate in this area of practice. How-
ever, their appraisal of the evidence for
METs is biased and their summary of the
literature is misleading. We agree with
the more measured tones expressed in
the accompanying editorial (2).
The authors drew considerable atten-
tion to the problems in the MERIT study
(3). Although there are limitations of this
study, they were wrong not to give a
similar critique to the studies that they
cited in favor of METs. Most of these
studies had major flaws. Lack of a power
calculation was common to most. A short
implementation period was also a feature
in studies by Bellomo et al (4, 5) and
Sebat et al (6). Not all of the 12 studies
cited as demonstrating an outcome ben-
efit examined or demonstrated significant
differences in each of the endpoints to
which they were referenced. None of the
cited studies actually investigated cost,
only speculated on it. As a further exam-
ple, only six studies reported the inci-
dence of cardiac arrest as an endpoint. In
two studies (7, 8), cardiac arrest call was
the endpoint; this is clearly very different
from a cardiac arrest. Of the remaining
four studies, a significant reduction was
only found in two (4, 9). The total num-
ber of cardiac arrests from these two
studies is only 107. The positive results
may be attributed to the accompanying
education packages.
The authors failed to mention that some
of the cited studies only examined planned
review of discharged intensive care patients
(10, 11). These studies are not applicable to
a general hospital population. It was mis-
leading to cite these studies, and we rein-
force the point that authors should “help
the reader understand the patient popula-
tion being described” (1). Three studies
looked at specific, selected populations (4,
6, 12); thus, of the 12 cited studies, only
seven were in an unselected general hospi-
tal population. The authors also failed to
balance this section with a mention of stud-
ies that did not demonstrate a benefit of
METs (13) or outreach (14, 15).
The MERIT study is the only large
randomized, controlled study in this area.
It not only showed that METs failed to
reduce the primary (composite) outcome
but it also demonstrated that MET calling
systems failed to identify sick patients
(sensitivity, 30%; specificity, 50%). If the
fully powered study was undertaken and
it showed the same magnitude of differ-
ence between groups as the MERIT study,
then the number needed to treat to pre-
vent one event would be approximately
2,000. This would hardly be an effective
treatment.
Debate needs to consider that one ex-
planation for the negative result in the
MERIT study is that maybe rapid response
system do not work. Perhaps we should not
be pursuing a noneffective intervention on
the basis of misplaced enthusiasm.
Richard J. Price, FRCA, Anaesthetics,
Gartnavel Hospital; Brian H. Cuthbertson,
FRCA, Health Services Research Unit,
University of Aberdeen; Christopher J.
Cairns, FRCA, Intensive Care Unit,
Stirling Royal Infirmary
REFERENCES
1. DeVita MA, Bellomo R, Hillman K, et al:
Findings of the First Consensus Conference
on Medical Emergency Teams. Crit Care Med
2006; 34:2463–2478
2. Teplick R, Anderson AE: Rapid response sys-
tems: Move a bit more slowly. Crit Care Med
2006; 34:2507–2509
3. Merit Study Investigators: Introduction of
the medical emergency team (MET) system:
A cluster randomised controlled trial. Lancet
2005; 365:2091–2097
4. Bellomo R, Goldsmith D, Uchino S, et al: A pro-
spective before-and-after trial of a medical emer-
gency team. Med J Aust 2003; 179:283–287
5. Bellomo R, Goldsmith D, Uchino S, et al:
Prospective controlled trial of effect of med-
ical emergency team on postoperative mor-
bidity and mortality rates. Crit Care Med
2004; 32:916 –921
6. Sebat F, Johnson D, Musthafa AA, et al: A
multidisciplinary community hospital pro-
gram for early and rapid resuscitation of
shock in nontrauma patients. Chest 2005;
127:1729 –1743
7. Buist MD, Moore GE, Bernard SA, et al: Effects
of a medical emergency team on reduction of
incidence of and mortality from unexpected
Crit Care Med 2007 Vol. 35, No. 3
 cardiac arrest in hospital: Preliminary study.
BMJ 2002; 324:1– 6
8. DeVita MA, Braithwaite RS, Mahidhara R, et
al: Use of medical emergency team responses
to reduce hospital cardiopulmonary arrests.
Qual Safe Health Care 2004; 13:251–254
9. Goldhill DR, Worthington L, Mulcahy A, et
al: The patient-at-risk team: Identifying and
managing seriously ill ward patients. Anaes-
thesia 1999; 54:853– 860
10. Ball C, Kirkby M, Williams S: Effect of criti-
cal care outreach team on patient survival to
discharge from hospital and readmission to
critical care: Non-randomised population
based study. BMJ 2003; 327:1014
11. Garcea G, Thomasset S, McClelland L, et al:
Impact of a critical care outreach team on
critical care readmissions and mortality. Acta
Anaesthesiol Scand 2004; 48:1096 –1100
12. Pittard AJ: Out of our reach? Assessing the
impact of introducing a critical care out-
reach service. Anaesthesia 2003; 58:882– 885
13. Kenward G, Castle N, Hodgetts T, et al: Eval-
uation of a medical emergency team one year
after implementation. Resuscitation 2004;
61:257–263
14. Story DA, Shelton AC, Poustie SJ, et al: The
effect of critical care outreach on postopera-
tive serious adverse events. Anaesthesia
2004; 59:762–766
15. Leary T, Ridley S: Impact of an outreach
team on readmissions to a critical care unit.
Anaesthesia 2003; 58:328 –332
DOI: 10.1097/01.CCM.0000257474.01932.2F
Requirements of the afferent arm of
rapid response systems
To the Editor:
In their report on rapid response sys-
tems (RRS), Dr. DeVita and colleagues (1)
draw the elegant analogy between the re-
sponse to unexpected patient deteriora-
tion and organic systems with afferent
and efferent arms and feedback loops. In
the accompanying editorial, Dr. Teplick
and Ms. Anderson point out that the af-
ferent arm of the RRS has the most room
for improvement (2). It is axiomatic that
if clinicians do not know about a patient’s
deteriorating condition, they cannot do
anything about it. Many studies show
that the signs of patient deterioration are
present hours before cardiopulmonary
arrest (3).
Unfortunately, the present generation
of continuous monitoring systems often
generate false positives for RRS activa-
tion, leading to provider frustration and
unnecessary costs. This problem of over-
sensitivity is matched by a problem of
undersensitivity: many patients on gen-
eral medical-surgical floors have signs
Crit Care Med 2007 Vol. 35, No. 3
that, if known, would trigger the RRS (4,
5). To be effective, an afferent arm on a
general care floor environment must meet
the following criteria: a) it must be invisible
to the patient (thus removing any compli-
ance issues with probes, cuffs, or cannulas);
b) it must integrate into existing nurse
workflows and infrastructure, removing
the need for additional staffing; c) it must
be customizable to allow for individual vari-
ability; and d) it must filter out the noise of
clinically insignificant blips in vital signs
that so often trigger false alarms in most
traditional monitors. Examples of technical
solutions to address these points are now
becoming commercially available (e.g., www.
hoana.com). Advantages of modern systems
include the ability to noninvasively moni-
tor for RRS criteria, the capacity to set and
customize alarms, invisibility to the pa-
tient, and acceptable levels of false alarms.
The article by Dr. DeVita and colleagues (1)
is helpful in that it focuses attention not
simply on the response (i.e., the rapid re-
sponse team) but also on how the system
and its providers learn of impending pa-
tient deterioration.
Dr. Jacobs is the Director of Medical Af-
fairs for Hoana Medical, a manufacturer of
noninvasive continuous vigilance systems,
and has stock options with the company.
Joshua Jacobs, MD, University of Hawaii,
John A. Burns School of Medicine, De-
partment of Medicine, Division of Medical
Informatics, Honolulu, HI
REFERENCES
1. DeVita MA, Bellomo R, Hillman K, et al: Find-
ings of the First Consensus Conference on
Medical Emergency Teams. Crit Care Med
2006; 34:2463–2478
2. Teplick R, Anderson AE: Rapid response sys-
tems: Move a bit more slowly. Crit Care Med
2006; 34:2507–2509
3. Hillman KM, Bristow PJ, Chey T, et al: Ante-
cedents to hospital deaths. Intern Med J 2001;
31:343–348
4. Harrison GA, Jacques TC, Kilborn G, et al: The
prevalence of recordings of the signs of critical
conditions and emergency responses in hos-
pital wards—The SOCCER study. Resuscita-
tion 2005; 65:149 –157
5. Meyer G, Lavin MA: Vigilance: The essence of
nursing. Online J Iss Nurs June 23, 2005.
Available at: http://nursingworld.org/ojin/
topic22/tpc22_6.htm. Accessed September 19,
2006
DOI: 10.1097/01.CCM.0000257232.82866.7A
The authors reply:
We thank Dr. Jacobs for his comments.
We too have become concerned that the
current emphasis on the “team” has ob-
scured other important components of the
rapid response system (RRS). It is our opin-
ion that all four components of the system
are underdeveloped and understudied. We
hope that as rapid response systems ma-
ture, all four components will improve. We
agree that attention to crisis detection
needs to increase. There are two compo-
nents to monitoring (and neither replaces
the other): monitoring devices and bedside
caregivers. We hope our article will foster
an impetus for monitoring more (perhaps
all) patients more effectively. Investigations
are needed to generate data: 1) to demon-
strate the financial return on investment of
high-cost devices; 2) to identify the ideal
monitor for detecting patients developing a
crisis; 3) to choose appropriate alert levels;
and 4) to identify caregiver skill gaps. The
quality improvement impact of RRS is also
underrecognized. Each event is an oppor-
tunity to discover why crises occur. Finally,
there seem to be gaps in knowledge, judg-
ment, and skills of crisis responders. Many
organizations are improving crisis response
skills, often using simulation education.
We welcome the healthy scientific skep-
ticism expressed by Dr. Price and col-
leagues. We agree that historical control,
single-center interventions have obvious
limitations. We reported brief summaries of
all studies cited so that readers can rapidly
access and judge them for themselves. Ac-
cordingly, we disagree that our summary of
the literature is biased or misleading. Our
article reports the findings of an expert
panel and is not a scientific review of the
literature, per se. Although many of the
conclusions reached by the panel, which
included patient safety and human factors
engineering experts, were evidence-based,
some were consensus-based in the absence
of evidence. Significant considerations
were the well-documented risk (both the
number of patients at risk and the potential
harm), potential for large benefit, lack of
alternative strategies showing some evi-
dence of success, lack of any evidence of
harm, limited cost, and, of course, benefit
shown by the few reports to date (with all of
their imperfections) (1).
We want to put the debate into proper
context. Data supporting RRS exceed that
supporting hospital cardiac arrest teams,
trauma teams, and even intensive care
unit specialists. Complex medical inter-
ventions that involve system change and
the delivery of other bundles of care are
difficult, perhaps impossible, to study in a
randomized clinical trial because systems
of care may be too complex to adequately
993
control and measure. Our consensus panel
decided, accordingly, not to kill common
sense on the altar of pure scientific ortho-
doxy. The point is straightforward: provide
suddenly critically ill patients with critical
care resources systematically.
Dr. Price and colleagues draw conclu-
sions from MERIT (2) that we feel are un-
warranted, specifically because of MERIT’s
construction. First, MERIT was too short
an intervention. Single-center reports were
much longer. The study by Bellomo et al.,
which included all hospitalized patients,
used a preparation time before the intro-
duction of the RRS of 9 months (twice as
long as in MERIT) and an additional 2
months run-in period (3). A similar time
frame for changing culture was used for the
results of DeVita et al (4). Time is impor-
tant. In MERIT, staff in medical emergency
treatment hospitals did not activate the
RRS as instructed, despite the presence of
identifying criteria in most cases, high-
lighting the need for longer and more in-
tensive education for cultures and systems
to change behavior. Second, making as-
sumptions on the number needed to treat
from MERIT is fraught with danger be-
cause of the following: 1) it ignores the
marked degree of medical emergency treat-
ment-like activity in control hospitals and
wide confidence intervals for the outcome
measures; and 2) it ignores the change in
behavior and outcome compared with base-
line that both arms experienced. We note a
recent study of an established RRS that the
number needed to prevent a cardiac arrest
was calculated at 17 (5).
Finally, the purpose of the consensus
conference was to provide a roadmap for
the future with the following: 1) organiz-
ing nomenclature; 2) reviewing data; 3)
identifying areas in which research is
warranted; and 4) providing expert guid-
ance based on data and real world con-
siderations. Although the science of sys-
tems research in this sphere of health
care is still in its infancy, we assert there
is sufficient data with which to act.
Michael A. DeVita, MD, Department
of Critical Care Medicine, University
of Pittsburgh School of Medicine;
Rinaldo Bellomo, MD, Austin Hospital,
Heidelberg, Melbourne, Australia;
Kenneth Hillman, MBBS, FRCA, FANZCA,
FJFICM, Intensive Care, University of
New South Wales; John Kellum, MD,
Department of Critical Care Medicine,
University of Pittsburgh School of Med-
icine; Maurene Harvey, RN, MPH,
994
FCCM, Consultants in Critical Care,
Glenbrook, NV
REFERENCES
1. DeVita MA, Bellomo R, Hillman K, et al: Find-
ings of the First Consensus Conference on
Medical Emergency Teams. Crit Care Med
2006; 34:2463–2478
2. Hillman K, Chen J, Cretikos M, et al: Intro-
duction of the medical emergency team (MET)
system: A cluster randomised controlled trial.
Lancet 2005; 365:2091–2097
3. Bellomo R, Goldsmith D, Uchino S, et al: A
prospective controlled trial of the medical
emergency team. Med J Aust 2003; 179:
283–288
4. DeVita MA, Braithwaite RS, Mahidhara R, et
al: Use of medical emergency team (MET) re-
sponses to reduce hospital cardiac arrests.
Qual Safety Healthcare 2004; 13:251–254
5. Jones, Bellomo R, Bates S, et al: Long-term
effect of a medical emergency team on cardiac
arrests in a teaching hospital. Crit Care 2005;
9:R808 –R815
DOI: 10.1097/01.CCM.0000257250.35337.66
Early goal-directed therapy of septic
shock: We honestly remain skeptical
To the Editor:
We read with interest the recent arti-
cle by Dr. Micek and colleagues (1), sug-
gesting that early protocolized resuscita-
tion using goal-directed therapy (EGDT)
should be routine for all patients with
septic shock, and the accompanying edi-
torial by Dr. Carlet (2). We would like to
point out that we remain honestly skep-
tical of the results of this study and the
original trial which form the basis for
recommending EGDT (3). There are a
number of reasons why the results of
these studies may not be applicable in
other settings.
There are concerns about the external
validity of both the study by Dr. Micek
and colleagues (1) and the previously re-
ported study by Rivers and colleagues (3).
The evidence supporting the introduction
of goal-directed cardiovascular resuscita-
tion in the authors’ institution is primar-
ily based on the results of a single-center
study of severe sepsis patients presenting
to an urban emergency department. It is
unknown whether the results of such a
single-center study could be reproduced
in other settings. Despite similar reduc-
tions in absolute mortality in both the
trials by Micek et al. and Rivers et al., the
high control (or before) group mortality
observed in both studies (49.2 and 48.3%,
respectively, at 28 days) potentially limits
the widespread applicability of these re-
sults. Of note, overall control arm mor-
tality in multicenter, randomized, con-
trolled trials of treatments for sepsis is
generally reported to be approximately
30% to 35% (4, 5).
There are also concerns about the in-
ternal validity of both studies. In addition
to the obvious lack of randomization and
the potential for a “Hawthorne effect” in
the after (or intervention) group, a change
in the outcome of interest (i.e., mortality)
over time undoubtedly confounds interpre-
tation of the results of the study by Micek
and colleagues. Friedman et al. (6) demon-
strated a progressive decline in sepsis mor-
tality over time (between 1958 and 1997).
The EPISEPSIS study also reported a sig-
nificant improvement in survival from se-
vere sepsis during the past decade (7). This
apparent natural regression resulting from
medical progress is further compounded by
the effect of regression to the mean. There
are questions regarding the internal valid-
ity of the study by Rivers and colleagues,
such as the lack of blinding. There are also
questions about the components of EGDT,
such as the recommendation for liberal use
of blood transfusions that is contradictory
to other high-level evidence (8). These is-
sues give rise to the honest skepticism we
have regarding the widespread use of this
therapy.
Although EGDT offers great promise
for the treatment of patients with severe
sepsis, we believe it is premature to rec-
ommend the widespread application of
EGDT because of the limitations in the
evidence as it currently exists. Before rec-
ommending early goal-directed therapy
for all patients with severe sepsis, not just
those patients presenting to the emer-
gency department, a well-designed mul-
ticenter, randomized trial evaluating this
intervention should be conducted.
Sandra Peake, PhD, FJFICM, Intensive
Care, The Queen Elizabeth Hospital, Ad-
elaide, SA, Australia, School of Medicine,
University of Adelaide, Adelaide, SA, Aus-
tralia; Steve Webb, PhD, FJFICM, Inten-
sive Care, Royal Perth Hospital, Perth,
WA, Australia, University of Western
Australia, Perth, WA, Australia;
Anthony Delaney, MBBS, FJFICM, In-
tensive Care Unit, Royal North Shore
Hospital, St. Leonards, NSW, 2065,
Australia, Northern Clinical School,
University of Sydney, St. Leonards,
NSW, Australia
Crit Care Med 2007 Vol. 35, No. 3
REFERENCES
1. Micek ST, Roubinian N, Heuring T, et al: Be-
fore-after study of a standardized hospital or-
der set for the management of septic shock.
Crit Care Med 2006; 34:2707–2713
2. Carlet J: Early goal-directed therapy of septic
shock in the emergency room: Who could
honestly remain skeptical? Crit Care Med
2006; 34:2842–2843
3. Rivers E, Nguyen B, Havstad S, et al: Early
goal-directed therapy in the treatment of se-
vere sepsis and septic shock. N Engl J Med
2001; 345:1368 –1377
4. Abraham E, Reinhart K, Opal S, et al: Efficacy
and safety of tifacogin (recombinant tissue
factor pathway inhibitor) in severe sepsis: A
randomized controlled trial. JAMA 2003; 290:
238 –247
5. Bernard GR, Vincent J-L, Laterre P-F, et al:
Efficacy and safety of recombinant human ac-
tivated protein C for severe sepsis. N Engl
J Med 2001; 344:699 –709
6. Friedman G, Silva E, Vincent JL: Has the mor-
tality of septic shock changed with time. Crit
Care Med 1998; 26:2078 –2086
7. Brun-Buisson C, Meshaka P, Pinton P, et al:
EPISEPSIS: A reappraisal of the epidemiology
and outcome of severe sepsis in French inten-
sive care units. Intensive Care Med 2004; 30:
580 –588
8. Hebert PC, Wells G, Blajchman MA, et al: A
multicenter, randomized, controlled clinical
trial of transfusion requirements in critical
care. N Engl J Med 1999; 340:409 – 417
DOI: 10.1097/01.CCM.0000257481.37623.3B
The authors reply:
We appreciate the comments of Dr.
Peake and colleagues regarding our re-
cently published study. Their concerns
regarding the external and internal valid-
ity of our study, however, are defensible.
First, the objection about the high rate of
mortality in the before group in our study
compared with the control arm in recent
severe sepsis studies is an unfair compar-
ison. As pointed out in the editorial to
our article by Dr. Carlet (1), we included
only patients with septic shock, a popu-
lation that has a significantly higher mor-
tality rate at baseline compared with that
in the trials referenced by Dr. Peake and
colleagues. In fact, the mortality rate in a
recent study of patients with septic shock
is as high as 63% in the control arm (2).
Lost in translation appears to be the
underlying goals of our institution’s sur-
viving sepsis initiative, which were pro-
cess improvements related to fluid resus-
citation and antimicrobial therapy. Our
first goal was to improve the early, ag-
gressive fluid resuscitation, specifically
the initial amount of fluid in the patient’s
bolus. Additionally, we sought to improve
Crit Care Med 2007 Vol. 35, No. 3
the number of patients who had an ob-
jective measure of intravascular volume,
namely, central venous pressure. This ap-
proach to care, which was standard in
both the experimental and control arm in
the study by Rivers et al. has recently
been shown to be achievable in two other
real-life settings (3–5). Second, we tar-
geted improvement in the appropriate-
ness and timeliness of the initially admin-
istered antimicrobial therapy. Numerous
studies have demonstrated the impor-
tance of appropriate antimicrobial ther-
apy as it relates to hospital survival in
patients with severe sepsis (6, 7). The
duration of time from the onset of shock
to the administration of antimicrobial
therapy also appears to have a direct as-
sociation with patient outcome (8). Con-
sequently, one cannot discount the effect
our improvement had in the rapidity and
overall number of patients who received
appropriate antimicrobial therapies in
our study. We feel these simple perfor-
mance measures can be readily achieved
in settings outside of our own institution
and positively impact the outcome in pa-
tients with septic shock.
All performance improvement projects
are subject to enhanced outcomes di-
rectly after intensive education and train-
ing related to the intervention, and our
study is no exception. We clearly state
this as a limitation in our article. Addi-
tionally, we agree that the natural ten-
dency over time is to have regression to
the mean, particularly when dealing with
internal improvement projects. Nonethe-
less, the larger point to be made is that
institution of standardized order sets or
some other systematic approach for the
management of patients with septic
shock can consistently improve the deliv-
ery of recommended therapies and as a
result may improve patient outcomes.
Scott T. Micek, PharmD, Department
of Pharmacy, Barnes-Jewish Hospital,
St. Louis, MO; Marin H. Kollef, MD,
Division of Pulmonary and Critical
Care Medicine, Washington University
School of Medicine
REFERENCES
1. Carlet J: Early goal-directed therapy of septic
shock in the emergency room: Who could
honestly remain skeptical? Crit Care Med
2006; 34:2842–2843
2. Annane D, Sebille V, Charpentier C, et al:
Effect of treatment with low doses of hydro-
cortisone and fludrocortisone on mortality in
patients with septic shock. JAMA 2002; 288:
862– 871
3. Rivers E, Nguyen B, Havstad S, et al: Early
goal-directed therapy in the treatment of se-
vere sepsis and septic shock. N Engl J Med
2001; 345:1368 –1377
4. Trzeciak S, Dellinger RP, Abate NL, et al:
Translating research to clinical practice: A
1-year experience with implementing early
goal-directed therapy for septic shock in the
emergency department. Chest 2006; 129:
225–232
5. Shapiro NI, Howell MD, Talmor D, et al: Im-
plementation and outcomes of the multiple
urgent sepsis therapies (MUST) protocol. Crit
Care Med 2006; 34:1025–1032
6. Garnacho-Montero J, Garcia-Garmendia JL,
Barrero-Almodovar A, et al: Impact of ade-
quate empirical antibiotic therapy on the out-
come of patients admitted to the intensive
care unit with sepsis. Crit Care Med 2003;
31:2742–2751
7. Harbarth S, Garbino J, Pugin J, et al: Inappro-
priate initial antimicrobial therapy and its effect
on survival in a clinical trial of immunomodu-
lating therapy for severe sepsis. Am J Med 2003;
115:529 –535
8. Kumar A, Roberts D, Wood KE, et al: Duration
of hypotension before initiation of effective
antimicrobial therapy is the critical determi-
nant of survival in human septic shock. Crit
Care Med 2006; 34:1589 –1596
DOI: 10.1097/01.CCM.0000257482.38723.1E
Selenium in Intensive Care (SIC)
study: The XX files are still
unresolved
To the Editor:
First, I would like to congratulate Dr.
Angstwurm and colleagues on their thor-
ough study and the recent publication in
Critical Care Medicine (1). Their trial
represents another fundamental, clear,
and convincing piece of evidence that
emphasizes the importance of an ade-
quate selenium status for a positive out-
come of patients in the intensive care
unit. It is high time that such results are
taken serious and are translated into clin-
ical practice.
However, I cannot fully agree, at
present, with the generalized conclusion
drawn by the authors, i.e., “. . . high-dose
sodium-selenite reduces mortality rate in
patients with severe sepsis or septic
shock.” The data presented support this
claim only for males with low selenium
status, not for all septicemia patients. The
findings need to be discussed in view of
sex-specific peculiarities of selenium me-
tabolism and individual baseline sele-
nium status.
995
 The biological effects of selenium de-
ficiency or selenium supplementation dif-
fer considerably between the sexes. We
and others observed in transgenic mice
that males displayed stronger phenotypes
than females on inactivation of the sele-
nium transport protein selenoprotein P,
which is the major determinant of sele-
nium status (2). In human trials, the che-
mopreventive effects of selenium show a
clear bias for males, and data for effects of
selenium on female participants are usu-
ally limited or inconclusive (3). This may
be caused by sex-specific differences in
hepatic selenoprotein biosynthesis as de-
scribed recently in experimental animals
(4). If these findings hold true for hu-
mans and if hepatically derived seleno-
protein P does, indeed, translate supple-
mented selenium into biological effects
(as suggested by the authors), it is not
surprising that the effectiveness of selen-
ite supplementation was mainly observed
in males. Unfortunately, the number of
female patients in the Selenium in Inten-
sive Care study, as well as in cancer pre-
vention trials, are usually disproportion-
ately low. Therefore, it currently appears
to be difficult to unequivocally conclude a
potential benefit for the full patient pop-
ulation. The design of follow-up studies
should consider this need of additional
data.
Moreover, as shown in the Selenium
in Intensive Care study and cancer trials
alike, the available data point to a strong
correlation of selenium status with mor-
tality and tumor risk, respectively, if the
individual belongs to the lowest tertile or
quartile of study participants (5). In the
publication by Angstwurm et al., this
finding is well reflected by a direct corre-
lation between selenium concentration
and survival rate (Table 5). Remarkably,
the subgroup with the highest baseline
selenium levels had no further reduction
in mortality. Monitoring the selenium
status of patients before or during septi-
cemia could, thus, restrict selenium sup-
plementation to those patients in need.
Even though no adverse effect has been
observed in their study, the amount of
sodium-selenite given (i.e., 15 mg within
14 days) raises concern because it clearly
exceeds tolerable upper intake levels.
Therefore, it might be prudent to inter-
vene with selenium and to correct for
excessive loss, only in those cases in
which a deficiency has been asserted.
I am confident that the authors agree
on the need for conducting larger studies
that take the sexual dimorphism of sele-
996
nium metabolism into account. Because
these data are not at hand, a prophylactic
supplementation before and during hos-
pitalization within the recommended
daily range represents a globally applica-
ble strategy to both men and women to
avoid life-threatening deficiencies of sele-
nium in the clinic.
The author has received grant support
from the German Science Foundation
and the German Cancer Foundation.
Lutz Schomburg, PhD, Charité Berlin,
Insitute for Experimental Endocrinol-
ogy Charitéplatz, Berlin, Germany
REFERENCES
1. Angstwurm MW, Engelmann L, Zimmermann
T, et al: Selenium in Intensive Care (SIC):
Results of a prospective randomized, placebo-
controlled, multiple-center study in patients
with severe systemic inflammatory response
syndrome, sepsis, and septic shock. Crit Care
Med 2007; 35:118 –126
2. Burk RF, Hill KE, Selenoprotein P: an extra-
cellular protein with unique physical charac-
teristics and a role in selenium homeostasis.
Annu Rev Nutr 2005; 25:215–235
3. Knekt P, Aromaa A, Maatela J, et al: Serum
selenium and subsequent risk of cancer
among Finnish men and women. J Natl Can-
cer Inst 1990; 82:864 – 868
4. Riese C, Michaelis M, Mentrup B, et al: Se-
lenium-dependent pre- and posttranscrip-
tional mechanisms are responsible for sex-
ual dimorphic expression of selenoproteins
in murine tissues. Endocrinology 2006; 147:
5883–5892
5. Reid ME, Duffield-Lillico AJ, Garland L, et
al: Selenium supplementation and lung can-
cer incidence: An update of the nutritional
prevention of cancer trial. Cancer Epidemiol
Biomarkers Prev 2002; 11:1285–1291
DOI: 10.1097/01.CCM.0000257479.88792.A5
The authors reply:
We thank Dr. Schomburg for his impor-
tant comments on the results of the Sele-
nium in Intensive Care (SIC) study, the
first multicenter, randomized, placebo-
controlled, double-blind study on the adju-
vant treatment of patients with severe sep-
sis and septic shock with high doses of
selenium (1).
Indeed, our conclusion that adjuvant
selenium treatment reduces mortality is
only shown in males, not in females (Ta-
ble 4). However, these results have to be
interpreted with caution, as we did not
randomize the patients by gender; the
138 males and 51 females were distrib-
uted differently between groups. There
were different characteristics of males
and females regarding age (62 yrs, 69
yrs), comorbidities, Acute Physiology and
Chronic Health Evaluation III score (93
vs. 97), shock, or drop in platelet count
(44.4% vs. 36.8%). Death was attributable
to sepsis in 95% of males and only 76% of
females. Therefore, we cannot conclude
statistical differences in selenium effects
between males and females, and both
genders were put together in the final
analysis. During followup, there was no
difference in selenium whole blood levels
between genders after substitution (Se1:
male, 1.89 ⫾ 0.49 ␮mol/L, female, 2.04 ⫾
0.64 ␮mol/L). In addition, the 28-day
mortality rate was dependent on the max-
imum serum selenium levels in both fe-
males and males, as well as in both con-
trol and selenium substitution group.
Nevertheless, the sex-specific differences
in transgenic mice in hepatic selenopro-
tein biosynthesis are important and
should be kept in mind during the plan-
ning of the following next large multi-
center trial.
Selenium levels in serum are low in
septic patients already at admission (1)
associated with increasing severity of dis-
ease (2). The mortality in severe sepsis is
inversely related to selenium levels dur-
ing follow-up. In control patients, the
urinary selenium loss was low (0.13
␮mol/L). Therefore, not a selenium loss
but a redistribution of selenoproteins has
to be postulated. Low selenium levels in
septic patients at admission cannot be
used to define a total body selenium defi-
ciency (3). Despite the acute phase reac-
tion, selenium levels increase, even during
the acute phase reaction in the selenium-
treated patients (1). Selenoprotein P as the
major determinant of selenium in plasma
might be attached to the endothelium or
disappear in other organs but seems to be
regenerated after selenium supplementa-
tion. This clearly demonstrates a higher
demand of selenium in severely ill patients.
It is right that those patients with
higher selenium levels at admission had no
benefit from the selenium supplementa-
tion, but these patients were less ill. There-
fore, only the most ill patients should be
treated with selenium.
The selenium dosage is high and ex-
ceeds the long-term upper tolerable level,
but this level is defined for healthy people
with normal levels and demand of sele-
nium, but obviously severely septic pa-
tients have a higher demand of selenium.
In our study, no adverse effects were seen
in these patients, even in those without
septic shock syndrome. The short high-
Crit Care Med 2007 Vol. 35, No. 3
dose selenium supplementation, there-
fore, seems to be safe.
The measurement of selenium as a pre-
requisite for selenium substitution might
be a good parameter. The determinations of
selenium content, as well as selenoprotein
P, one possible actor of selenium at the
endothelial site, however, are not yet rap-
idly available. Further studies should deter-
mine more parameters of selenium metab-
olism and confirm the optimistic results of
the first prospective and double-blind con-
ducted SIC study (1).
Crit Care Med 2007 Vol. 35, No. 3
The authors have not disclosed any
potential conflicts of interest.
Matthias Angstwurm, MD, Roland
Gärtner, MD, Medizinische Klinik,
Ziemssenstr 1, Munich, Germany
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DOI: 10.1097/01.CCM.0000257253.49826.3A
997