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Letters to the Editor

Intensive care unit treatment in REFERENCE in the emergency room (4), leading to
patients >65 yrs with a first-day lower day-1 SOFA scores in the ICU. This
1. Kaarlola A, Tallgren M, Petillä V: Long-term may be pronounced in ICUs with a small
sequential organ failure assessment survival, quality of life, and quality-adjusted
score >15 is not futile number of beds serving a large population.
life-years among critically ill elderly patients.
Crit Care Med 2006; 34:2120 –2126
Third, the instructions on how the SOFA
and Acute Physiology and Chronic Health
To the Editor: DOI: 10.1097/01.CCM.0000257233.52136.3B Evaluation scores are to be calculated leave
With great interest, we read the study by
some room for interpretation. For instance,
Kaarlola and colleagues (1), concerning The authors reply: no instructions exist on how the neurologic
long-term survival, quality of life, and qual- We are grateful for the opportunity to evaluation is to be performed in patients
ity-adjusted life-years among critically ill respond to the letter by Drs. Zandstra and receiving sedative medication. In our unit,
elderly patients. In their study, outcome Bosman concerning our study published in the Glasgow Coma Scale score is assumed
and quality aspects were investigated in 882 Critical Care Medicine (1). They raise an to be normal, if it was so before sedation
patients older than 65 yrs. We were in- important issue, the outcome of elderly pa- and if it is not feasible to stop sedation
trigued by their sentence under the Discus- tients with five or more organ failures the totally to facilitate reevaluation.
sion that all patients in their study with a first day in the intensive care unit (ICU; We agree with Drs. Zandstra and Bos-
day-1 Sequential Organ Failure Assessment day-1 Sequential Organ Failure Assessment man in that neither older age alone nor
(SOFA) score ⬎15 died in the intensive [SOFA] score ⬎15). Patients with such a any severity of illness score number per
care unit (ICU). This seemed to differ from severe multi-organ failure are usually a mi- se, without taking into consideration the
our experience. After a explorative database nority in any ICU population. In our con- full information concerning each case
analysis of prospectively collected data, we secutive material from 1995 to 2000, the and the response to treatment over time,
found that in 13,989 consecutive patients number of patients with day-1 SOFA scores is a valid reason to withhold intensive
admitted to our ICU, 7,984 patients were ⬎15 and ICU mortality of 100% [95% con- care. Because of the small proportion of
⬎65 yrs of age. Of these elderly patients, fidence interval, 0% to 100%] was ex- elderly patients with day-1 SOFA scores
131 had a day-1 SOFA score ⬎15. The hos- tremely small (0.6%). Because of the small ⬎15, in general, we consider our estima-
pital mortality of these patients was 65 of number, five of 882, it is not possible to tion of quality-adjusted life years to be
131. A hospital survival rate of 50% in those make definitive conclusions about whether reliable and not prominently affected by
⬎65 yrs with a day-1 SOFA of ⬎15 con- intensive care is futile in this subpopula- any selection bias.
trasts with the 100% mortality reported by tion.
Kaarlola et al. Drs. Zandstra and Bosman reported Anne Kaarlola, RN MSc, Minna Tallgren,
Under the Discussion, it is stated that a results in treating patients with this se- MD, Ville Pettilä, MD, Department of
systematic bias toward overestimated qual- vere multi-organ failure in their ICU. In a Anaesthesia and Intensive Care Medi-
ity-adjusted life years may exist if intensive retrospective analysis from a large pro- cine, Helsinki University Hospital,
care is withheld from elderly patients or spectively collected ICU database, they Helsinki, Finland
selection in admission occurs and not all found 131 of 7,984 (1.6%) patients ⬎65
elderly patients are included in the analysis. yrs of age with a day-1 SOFA score ⱖ15, REFERENCES
It is possible, therefore, that the reported with hospital mortality as low as 65 of
100% mortality rate with day-1 SOFA score 131 (50%). These figures are good, and 1. Kaarlola A, Tallgren M, Pettilä V: Long-term
in patients ⬎65 yrs could have been per- we are looking forward to more details
survival, quality of life, and quality-adjusted
ceived as futile therapy, resulting in life-years among critically ill elderly patients.
from their future article. However, our Crit Care Med 2006; 34:2120 –2126
overestimated quality-adjusted life own data (2) and the data by Ferreira et 2. Pettilä V, Pettilä M, Sarna S, et al: Comparison
years. We agree with the authors that al. (3) disagree with the good survival of multiple organ dysfunction scores in the
older age alone is not a valid reason to rates of elderly patients with high SOFA prediction of hospital mortality in the criti-
withhold intensive care; we disagree scores ⬎15 presented by Zandstra and cally ill. Crit Care Med 2002; 30:1705–1711
with their implicit statement that ICU Bosman. 3. Ferreira FL, Bota DP, Bross A, et al: Serial
treatment in patients ⬎65 yrs with a In interpreting the results of outcome evaluation of the SOFA score to predict out-
first-day SOFA score ⬎15 is futile. studies, it is crucial to establish whether come in critically ill patients. JAMA 2001; 286:
The authors have not disclosed any the population studied was similar to the 1754 –1758
potential conflicts of interest. 4. Demetriades D, Karaiskakis M, Velmahos G, et
population served by one’s own ICU. One al: Effect of early intensive management of
factor that may affect the results is the geriatric trauma patients. Br J Surg 2002;
Durk F. Zandstra, MD, Rob J. Bosman, case-mix of the patients (for example, sur- 89:1319 –1322
MD, Department of Intensive Care gical/medical, emergency/elective). Elective
Medicin, Onze Lieve Vrouwe Gasthuis, DOI: 10.1097/01.CCM.0000257476.65629.B3
cardiac surgery is a good example of a sub-
Amsterdam, The Netherlands population with good outcome, despite rel-
atively high day-1 SOFA scores. Second, the Anti-inflammatory activity of albumin
treatment options before ICU admission af-
Copyright © 2007 by the Society of Critical Care fect the outcome. Organ dysfunction may In addition to its role in maintaining
Medicine and Lippincott Williams & Wilkins be significantly improved by early therapy colloid oncotic pressure, albumin dis-

Crit Care Med 2007 Vol. 35, No. 3 981


plays an array of non-oncotic properties, buffering capacity may be more impor- with mass spectrometry (5). Moreover,
including antioxidant and anti-inflamma- tant than the redox state of the albumin the mean DA-DKP concentration for the
tory activity (1–3). Such properties might solution at the time of administration. six commercial solutions (62.6 ␮M) mea-
benefit patients adversely affected by in- Furthermore, albumin has been shown to sured in the new study as compared with
flammatory processes, such as those un- exhibit antioxidant/anti-inflammatory ac- that of albumin protein in the 25% solu-
dergoing cardiopulmonary bypass or tivity independent of thiol status. For ex- tions (3763 ␮M) suggests that the per-
those developing sepsis or the systemic ample, treatment of bovine aortic endo- centage of albumin DA might be as low
inflammatory response syndrome. In a thelial cells with commercial human 1.7% (62.6/3763). These disparities would
rat endotoxemia model (1), for instance, albumin solution in vitro (2) protected need to be reconciled before an albumin
albumin decreased myocardial nitric ox- against HOCl-induced oxidative damage DA estimate as high a 15.3% could be ac-
ide synthase II messenger RNA and pro- in a dose-dependent manner both with cepted. In any case, whatever the actual
tein expression (p ⬍ .05 for both compar- and without previous reduction of thiols percentage of albumin DA, the commercial
isons). Accompanying these effects with by sodium borohydride (p ⬍ .05 for both solutions all diminished production of tu-
regard to the capacity to produce nitric comparisons). Additionally, albumin de- mor necrosis factor-␣ and interferon-␥.
oxide, an established modulator of in- creased the in vitro binding of activated The intriguing non-oncotic properties
flammation, was a greater improvement polymorphonuclear leukocytes to aortic of albumin continue to be the focus of
in myocardial function, as measured by endothelial cells (2), and the magnitude active investigation. Their clinical rele-
fractional shortening of isolated cardiac of the effect was closely similar for native vance will need to be determined in fur-
myocytes, in animals receiving albumin albumin, sodium borohydride-reduced ther investigations. The in vitro study of
as compared with saline or hydroxyethyl albumin, and albumin alkylated with N- Dr. Bar-Or et al. (4) is of great interest,
starch 200/0.5 (p ⬍ .01 for both compar- ethylmaleimide to block thiol groups although their interpretation of the clin-
isons). (p ⬍ .05 for all comparisons). ical implications is likely to be received
In a new study, Dr. Bar-Or and col- Based on their data, Dr. Bar-Or et al. with justifiable skepticism.
leagues (4) demonstrate that each of six (4) advise caution in the administration The author has not disclosed any po-
commercial albumin solutions markedly of albumin to critically ill patients. How- tential conflicts of interest.
inhibits production of the pro-inflamma- ever, also requiring caution is the specu-
Christian J. Wiedermann, MD, Division
tory cytokines tumor necrosis factor-␣ lation about the implications of in vitro
of Internal Medicine 2, Department of
and interferon-␥ from human peripheral experiments for clinical practice. Dr.
Medicine, Central Hospital of Bolzano,
blood mononuclear cells in vitro (p ⬍ .05 Bar-Or and colleagues (4) are affiliated
Bolzano, Italy
for all comparisons). They also provide with DMI BioSciences, a company en-
evidence that these anti-inflammatory ef- gaged in the development of a synthetic
fects may be partially attributable to tetrapeptide mimetic composed of the REFERENCES
amino acids at the N-terminus of the same amino acid sequence as the N-
1. Walley KR, McDonald TE, Wang Y, et al: Al-
albumin polypeptide chain. A high- terminus of intact human albumin for
bumin resuscitation increases cardiomyocyte
affinity binding site for Cu2⫹ ions is the prevention of myocardial ischemia- contractility and decreases nitric oxide syn-
known to reside at the N terminus, and reperfusion injury (www.dmibio.com/ thase II expression in rat endotoxemia. Crit
the binding and sequestration of these misc/pipeline.html). This mimetic would Care Med 2003; 31:187–194
ions by albumin prevents their participa- directly compete with commercial solu- 2. Lang JD Jr, Figueroa M, Chumley P, et al:
tion in oxidation reactions, thus illustrat- tions of albumin protein. Albumin and hydroxyethyl starch modulate
ing one of the mechanisms underlying Indeed, these investigators provide oxidative inflammatory injury to vascular en-
the antioxidant/anti-inflammatory activ- data in their article to show that a portion dothelium. Anesthesiology 2004; 100:51–58
ity of albumin. The thiol moiety at cys- of the albumin molecules in commercial 3. Quinlan GJ, Mumby S, Martin GS, et al: Albu-
min influences total plasma antioxidant ca-
teine 34 of albumin can also exert direct solutions may have undergone cleavage
pacity favorably in patients with acute lung
antioxidant actions. of the N-terminal aspartyl-alanyl (DA) injury. Crit Care Med 2004; 32:755–759
Incongruously, despite these encour- dipeptide to generate albumin DA and 4. Bar-Or D, Thomas GW, Bar-Or R, et al: Com-
aging results, Dr. Bar-Or and colleagues measurable concentrations of cyclized mercial human albumin preparations for clin-
(4) elected to interpret their data as in- cleavage product (DA-DKP). These re- ical use are immunosuppressive in vitro. Crit
dicative of a potentially deleterious im- sults might suggest advantages of a Care Med 2006; 34:1707–1712
munosuppressive effect. They also call at- small-molecular mimetic over the intact 5. Bar-Or D, Bar-Or R, Rael LT, et al: Heteroge-
tention to prior in vitro evidence (5) that protein. However, the representation of neity and oxidation status of commercial hu-
man albumin preparations in clinical use. Crit
a larger fraction of the albumin in com- albumin DA in commercial solutions may
Care Med 2005; 33:1638 –1641
mercial than in freshly prepared solu- have been overestimated. On the basis of
tions is oxidized at cysteine 34 and might 18 determinations using six commercial DOI: 10.1097/01.CCM.0000257234.87784.91
possibly exacerbate, rather than amelio- solutions, Dr. Bar-Or et al. (4) report that
rate, oxidative stress. However, clinical the percentage of albumin DA averaged The author replies:
data do not support this proposition. In a 15.3%. This value is nearly three times We are a basic research laboratory com-
randomized trial of patients with acute the 5.6% mean of 87 determinations with ponent of a level I trauma program com-
lung injury, albumin infusion increased the same six commercial solutions they mitted to the clinical implications of our
both plasma thiols (p ⬍ .0001) and total observed in another recent study using work. The basic premise of our manuscript
antioxidant capacity (p ⫽ .0015). It, thus, the same methods, namely, high-perfor- “Commercial human albumin preparations
appears that augmentation of the redox mance liquid chromatography coupled for clinical use are immunosuppressive in

982 Crit Care Med 2007 Vol. 35, No. 3


vitro” (1) is to alert clinicians and pharma- script (1), the proportion is for the sum of of commercial albumin products, which
cists that “albumin preparations” contain a all species that lost their N-terminal DA. If our results demonstrate could be im-
significant amount of a chemical (aspartyl- we just estimate the proportion of species proved to the benefit of the patient. Skep-
alanyl diketopiperazine; DA-DKP), which is that represent native albumin minus DA in ticism should be reserved to the unbiased
the result of processing (heating) and stor- this latest manuscript, it is also 5.6% (av- scientist whose patients’ well-being
age of albumin. Diketopiperazines have erage); however, because there are other stands first.
been shown to have significant biological species of albumin minus DA with several The author is an independent contrac-
activities (2, 3). We would hope that Dr. posttranslational modifications (such as tor with Swedish Medical Center. He
Wiedermann agrees that clinicians should cysteinylation), it is more accurate to sum holds ⬎65 patents, is employed by DMI
be aware of the ingredients and impurities all species that have this modification as it BioSciences, and owns stock and stock
present in a medication that they prescribe is a true representation of the level of trun- options in the company. DMI BioSciences
to be administered intravenously to their cation. is currently developing DA-DKP for the
patients (indeed, there is no mention on Dr. Wiedermann also points out that treatment of multiple sclerosis.
the label of albumin preparations of the the concentration of DA-DKP seems in-
presence of a diketopiperazine). consistent with the level of albumin that David Bar-Or, MD, FACEP, Trauma
We certainly did not imply that the lost its N-terminal DA. Again, this is not Research Department, Swedish Med-
administration of commercial albumin inconsistent and is explained by the fact ical Center, Englewood, CO
should be halted. In view of our “in vitro” that some of the albumin derived from
findings, we believe and stand by our con- pooled plasma is already truncated (-DA) REFERENCES
clusion that “. . . administering HSA to before the heating step in the final con-
immunocompromized, critically ill pa- tainer, and the corresponding DA-DKP 1. Bar-Or D, Thomas GW, Bar-Or R, et al: Com-
tients might need to be reevaluated.” In- generated before that step has already mercial human albumin preparations for clin-
flammation is a natural biological re- been eliminated. Furthermore, some of ical use are immunosuppressive in vitro. Crit
sponse to injury. It has its benefits and the DA-DKP in solution will hydrolyze Care Med 2006; 34:1707–1712
2. Borthwick AD, Davies DE, Exall AM, et al:
perils. There are instances in which sup- into a straight dipeptide chain, DA, which
2,5-Diketopiperazines as potent, selective, and
pressing the immune response could be has no known biological activity. orally bioavailable oxytocin antagonists: Syn-
deleterious and other indications when it We agree that the N-terminus of hu- thesis, pharmacokinetics, and in vivo potency.
is beneficial. A hypoalbuminemic cancer man plasma albumin is a high-affinity J Med Chem 2006; 49:4159 – 4170
patient suffering from chemotherapy- binding site for cupric ions and of its role 3. Lucietto FR, Milne PJ, Kilian G, et al: The
induced immunosuppression, for example, as an antioxidant. We also concur with biological activity of the histidine-containing
could be harmed if further immunosup- the role of cysteine 34 free thiol group as diketopiperazines cyclo(His-Ala) and cyclo-
pression is added by the administration of a major extracellular-reducing agent. We (His-Gly). Peptides 2006; 27:2706 –2714
an albumin preparation. A patient with se- have reasons to believe (supported by our 4. Bar-Or D, Bar-Or R, Rael LT, et al: Heteroge-
vere systemic immune response syndrome, unpublished data) that commercial (pro- neity and oxidation status of commercial hu-
man albumin preparations in clinical use. Crit
on the other hand, might benefit from this cessed) albumin products have a greatly
Care Med 2005; 33:1638 –1641
intervention. reduced ability to chelate transition met-
We believe that we have clearly dem- als, not only because of a truncated N- DOI: 10.1097/01.CCM.0000257246.40096.BA
onstrated an immunosuppressive (“anti- terminus. Commercial albumin has a de-
inflammatory”) effect of the commercial monstrably higher percentage of oxidized Endotracheal intubation in the intensive
albumin products. This effect was abol- (cysteinylated, sulfonated) cysteine 34
care unit: Non-anesthesiologists know
ished following the removal by dialysis of than normal human plasma albumin. We
small molecular weight compounds (in- simply stated that a systematic review of
rapid sequence intubation, but is it
cluding DA-DKP). We demonstrated that the composition of HSA commercial prep- accurate in all cases?
a synthetic DA-DKP could reconstitute arations and correlation to morbidity/
the identical in vitro immunosuppressive mortality rates should be accounted for To the Editor:
effect as the commercial human albumin in clinical trials—not all commercial al- We were very surprised when reading
products. These effects are not “. . . at- bumin products are the same! the article by Dr. Jaber and colleagues (1)
tributable to the amino acids at the N- Although we have disclosed our finan- with regard to endotracheal intubation in
terminus of (the intact) albumin . . .” as cial affiliations and conflicts of interest in the intensive care unit (ICU). First, the ref-
Dr. Wiedermann suggests, but to the our publication (1), Dr. Wiedermann ne- erence that supported the use of a rapid
cleaved cyclic product derived from the glects to mention that he has been spon- sequence induction (RSI) with Sellick’s
N-terminal dipeptide DA separated from sored and remunerated by companies di- technique is relevant in the operating room
albumin. Isolated human plasma albu- rectly involved in the manufacture and (2). These guidelines may be used in other
min alone did not have any anti-inflam- marketing of albumin. A Google search clinical contexts, but to the best of our
matory activities in our investigations. (“Wiedermann CJ”) reveals numerous au- knowledge, none has been specially pub-
The proportion of albumin minus DA thorships with employees of these com- lished to be used in the ICU. Second, and of
was not overestimated. The apparent dis- panies and sponsorship activities. We most importance, the use of RSI in the ICU,
crepancy that Dr. Wiedermann suggests is ourselves benefit from industrial funding essentially because of adrenal dysfunction
easily explained. In the first manuscript (4) that can promote the translation of basic induced by etomidate, is extremely contro-
the proportion for albumin minus DA re- research to clinical care. We would hope versial (3, 4). We do not believe, as demon-
ported is only for native albumin that lost that our article might allow insight into strated by the study of Dr. Jaber and col-
its N-terminal DA. In this recent manu- the molecular content and clinical utility leagues (1), when RSI is used in only 36%

Crit Care Med 2007 Vol. 35, No. 3 983


of the patients, that this technique must be The authors reply: ately trained and experienced non-
used in all the cases in the ICU. Being anesthetist physicians in the ICU have a
familiar with a range of induction drugs is We were somewhat perplexed by the similarly high level of airway manage-
important because the specific clinical cir- comments from Dr. Vincent and col- ment for patient safety compared with
cumstances dictate the appropriate induc- leagues to our observational study that anesthesiologists. We think that all inten-
tion method (5). Third, we do not agree described the current practice of physi- sivists, whatever their initial formation
with Dr. Jaber and colleagues (1), who em- cians and reported complications associ- (anesthesiologist or not), in France and
phasize that RSI with Sellick’s technique is ated with endotracheal intubation (ETI) other countries, do the same job. Further
“probably unknown among non-anesthesi- performed in intensive care unit (ICU) investigations should be undertaken to
ologists” (1). In France, many intensivists (1). Their comments give us the oppor- define what is the best way to perform
are non-anesthesiologists, usually called tunity to refer to some data not reported ETI in ICU patients, such as anesthesia
medical intensivists. They first acquired a in our study and at least to correct vari- drugs, the best pre-oxygenation tech-
specialty by studying for 4 or 5 yrs and ous misrepresentations. First, rapid se- nique (4), and fluid management as em-
completed it by an additional formation for quence intubation (RSI) for ETI is the phasized in the editorial by Andrew B.
4 yrs, including 200 hrs of interactive sem- combined administration of a sedative Leibowitz (5), because “there is a dearth
inars and 18 months of clinical practice in and neuromuscular blocking agent to fa- of literature concerning airway manage-
intensive care medicine. For the year 2005– cilitate rapid endotracheal intubation. ment techniques in the ICU.”
2006, 254 students were enrolled. Only This technique was originally described The authors have not disclosed any
50.8% were anesthesiologists, but 13.8% in the anesthesia literature nearly 40 yrs potential conflicts of interest.
were cardiologists, 11.8% pneumologists, ago for the prevention of gastric content
10.6% internists, and 5.5% nephrologists. aspiration (2). RSI can be used with other Samir Jaber, MD, PhD, Intensive Care
Some of them specialized in pediatrics, hypnotic agents with rapid action (pento- Unit, Department of Anesthesiology B,
neurology, gastroenterology, or any other thal, propofol), not only with etomidate. DAR B, CHU de Montpellier, Hôpital
medical specialties. All of them learned RSI Moreover, to our knowledge, there are no Saint Eloi, Montpellier, cedex France;
with Sellick’s technique, but as there is no prospective, randomized, controlled stud- Jean-Yves Lefrant, MD, Fédération Anes-
consensus, they use it only when they think ies providing strict statistical evidence of thésie-Douleur-Urgences-Réanimation,
that it is appropriate. The conclusions an increased risk of immediate complica- Groupe Hospitalo-Universitaire Care-
about the use of this technique drawn by tions in ICU patients when RSI was used meau, Centre Hospitalier Universitaire
Dr. Jaber and colleagues (1) do not seem with and/or without etomidate. As we fo- Nîmes, Nîmes cedex, France
accurate to us and would require further cused on in our study, no significant dif-
investigations. ference was observed between the com- REFERENCES
plicated and noncomplicated ETI patients
for RSI use. Contrary to anesthesia, emer- 1. Jaber S, Amraoui J, Lefrant J-Y, et al: Clinical
François Vincent, MD, Frédéric Gonzalez, gency departments, and pre-hospital condi- practice and risk factors for immediate com-
MD, Yves Cohen, MD, Medico Surgical tions in which RSI showed beneficial effects plications of endotracheal intubation in the
Intensive Care Unit, Assistance Pub- intensive care unit: A prospective, multiple-
to intubate critically ill patients or to empty
center study. Crit Care Med 2006; 34:2355–
lique-Hôpitaux de Paris, Avicenne gastric contents, to date there are no ran- 2361
University Hospital, Bobigny, France domized, controlled studies that evaluate 2. Stept W, Safar P: Rapid induction-intubation
RSI use when intubating the trachea in ICU for prevention of gastric content aspiration.
patients. However, RSI is recommended in Anesth Analg 1970; 49:633– 636
REFERENCES ICUs by several medical societies, especially 3. Molliex S, Berset JC, Billard V, et al: Airway
by two French critical care societies: the management in adult anesthesia except with
1. Jaber S, Amraoui J, Lefrant J-Y, et al: Clinical Société Française d’Anesthésie-Réanima- the exception of difficult intubation: Recom-
practice and risk factors for immediate com- mendations. Ann Fr Anesth Reanim 2003; 22:
tion (3) and the Société de Réanimation de
plications of endotracheal intubation in the 745–749
intensive care unit: A prospective, multiple-
Langue Française.
4. Baillard C, Fosse JP, Sebbane M, et al: Nonin-
center study. Crit Care Med 2006; 34:2355– Second, in our observational study per-
vasive ventilation improves preoxygenation
2361 formed in seven ICUs (1), RSI using the before intubation of hypoxic patients. Am J
2. Practice Guidelines for Management of the Sellick’s technique was applied in 36% of Respir Crit Care Med 2006; 174:171–177
Difficult Airway: An updated report by the ETIs with a significant difference between 5. Leibowitz A: Tracheal intubation in the inten-
American Society of Anesthesiologits Task anesthesiologists and non-anesthesiolo- sive care unit: Extremely hazardous even in
Force on Management of the Difficult Airway. gists (70/171 ⫽ 41% vs. 22/82 ⫽ 27%; the best of hands. Crit Care Med 2006;
Anesthesiology 2003; 98:1269 –1277 p ⬍ .05). As we focused on in our study, 34:2497–2498
3. Jackson WL: Should we use etomidate as an
although 67% of physicians and residents DOI: 10.1097/01.CCM.0000257247.44531.09
induction agent for endotracheal intubation
in patients with septic shock? A critical ap-
were anesthesiologists, there was no dif-
praisal. Chest 2005; 127:1031–1038 ference in difficult intubations between
anesthesiologists and non-anesthesiolo- The future of surgical critical care: A
4. Annane D: ICU physicians should abandon the
use of etomidate! Intensive Care Med 2005; gists. Therefore, it can be suggested that European perspective
31:325–326 most of the operators were experienced in
5. Reynolds SF, Heffner J: Airway management this procedure. The lack of statistically To the Editor:
of the critically ill patient: Rapid sequence significant difference in complication We read with great interest the arti-
intubation. Chest 2005; 127:1397–1412 rates between anesthesiologists and non- cle by Dr. Tisherman and colleagues (1)
DOI: 10.1097/01.CCM.0000257470.40571.92 anesthesiologists shows that appropri- and the accompanying editorial by Dr.

984 Crit Care Med 2007 Vol. 35, No. 3


Shapiro (2) regarding the future of sur- bedside medical care is necessary when The authors reply:
gical critical care (SCC). The lack of in- caring for the most severely ill patients in
terest among young surgical residents to the hospital. There is also ample scien- We appreciate the interest of Drs. De
become involved in the care of critically tific data to support the notion that care Waele and Hoste in our recent article about
ill patients is worrisome. As addressed by provided by full-time intensivists leads to the current structure of surgical critical
Dr. Tisherman et al. and Dr. Shapiro, better outcomes (5). care fellowships in the United States (1).
As an example, in our hospital, the dif- We agree with most of their observations.
another important factor contributing to
ferent adult intensive care units (surgical, Although many factors have contributed to
the decreased interest is the significant
medical, burn, and cardiac surgery) are run the decreased interest of surgical residents
impact of practicing SCC on private life.
by a team of dedicated full-time intensiv- in trauma and surgical critical care, the
SCC practitioners dedicate themselves to
ists, providing 24-hr/7-days a week on-site development of the acute care surgery
a lifelong practice of long working hours
care for our patients. “Multidisciplinarity” model (combining surgical critical care,
and time spent in the hospital during the
has been essential in this team; the basic trauma, and emergency general surgery)
night. In addition, there is an increasing
specialty of the attending intensivists in- has focused primarily on increasing the
demand from patients and their relatives
cludes anesthesiology, nephrology, pul- quantity and diversity of surgical experi-
and increasing liability issues. All these
monology, gastroenterology, hematology, ences for residents and attending surgeons.
factors lead to a high rate of burnout in
and surgery. This has many advantages, We agree that this model may not reduce
critical care, and also SCC, physicians (3).
because surgical problems in the medical work hours, that broadening the scope of
Expanding the role of the trauma and
intensive care unit can be dealt with in care may actually increase the risks of lia-
SCC surgeon to an acute care surgeon,
most cases by the surgical intensivist; like- bility, and that the acute care surgeon will
which would also include emergency gen-
wise, the advice regarding complicated re- become a jack of all trades, but master of
eral abdominal surgery, is proposed as a none.
solution to stimulate interest in a career in spiratory or hematologic conditions in pa-
tients in the surgical intensive care unit is As surgical intensivists, we must sup-
SCC (4). Apparently, the decrease in time port new training paradigms that promote
spent in the operating room is experienced readily available from intensivists who can
put things in a proper perspective. Also, the career satisfaction and discipline longevity,
by many fellows or fellows-to-be as an ob- as well as initiatives to foster the multipro-
stacle for entering a SCC fellowship. Al- interaction with the surgical and medical
departments often happens through the li- fessional practice of critical care medicine.
though attractive from a surgical point of These interests are not mutually exclusive.
aison intensivist, which does not decrease
view, we feel that expanding the role of the It seems clear that we cannot maintain the
the surgical attention to the patient.
acute care surgeon would not abolish the status quo and still recruit sufficient num-
The disinterest of U.S. residents in
grounds for the lack of interest in SCC. bers of trainees. Consequently, many insti-
SCC is worrying, indeed, but the question
When, apart from trauma surgery, tutions are adopting the acute care surgery
remains whether expanding the expertise
emergency abdominal surgical interven- model by establishing a separate service for
of the acute care surgeon will counter the
tions will also be performed by the acute emergency general surgery, whereas others
reasons for this decreased interest and
care surgeon, this is unlikely to reduce have linked emergency general surgery
whether increasing time in the operat-
working hours and the pressure on the ing room will benefit the critically ill with trauma coverage, usually with an ad-
night and weekend shifts, as the majority of patient and, in the end, the develop- ditional attending surgeon assigned for
emergency surgical interventions are per- ment of critical care medicine in the backup.
formed outside office hours. The problem United States. As we develop and implement these
of liability may also increase when the models, there is much we can learn from
acute care surgeon is expected to cover our European counterparts. We agree with
Jan J. De Waele, MD, Eric A. J. Hoste,
both emergency abdominal and trauma Drs. De Waele and Hoste that patients gain
MD, PhD, Intensive Care Unit, Ghent
surgery; beyond this, the acute care sur- from the care of full-time intensivists who
University Hospital, Ghent, Belgium
geon also is responsible for the critically ill provide continuous bedside patient care.
patient. It is difficult, if not impossible, to However, surgical intensivists are essen-
stay up to date in all these rapidly evolving REFERENCES tially nonexistent in Europe, and the
specialties, and spending more time in the 1. Tisherman SA, Angood PB, Barie PS, et al: unique realities of surgical critical care
operating room inevitably means less time Structure of surgical critical care and trauma practice in North America must be ac-
at the bed of the critically ill patient, in fellowships. Crit Care Med 2006; 34:2282– knowledged and incorporated. The chal-
whom conditions may rapidly deteriorate 2286 lenge for acute care surgery, with increased
and ad hoc medical decision making is of- 2. Shapiro MJ: Where have all the surgical inten- operative responsibilities for the surgeon, is
ten necessary. sivists gone? Crit Care Med 2006; 34:2485– to ensure that an intensivist is available for
In Belgium—and this is the same in 2486
the patient every day, around the clock.
3. Guntupalli KK, Fromm RE Jr: Burnout in the
most European countries— critical care Surgeons must maintain their commit-
internist-intensivist. Intensive Care Med 1996;
medicine has evolved to become a sepa- 22:625– 630 ment to the intensive care unit, providing
rate specialty, with full-time intensivists 4. Cryer HM 3rd: The future of trauma care: At equivalent value as our non-surgical, full-
taking care of the critically ill patient. the crossroads. J Trauma 2005; 58:425– 436 time intensivist colleagues. Many groups
This was first observed in academic cen- 5. Pronovost PJ, Angus DC, Dorman T, et al: accomplish this by separating trauma/
ters some 20 –30 yrs ago but is now also Physician staffing patterns and clinical out- emergency general surgery call from criti-
becoming a reality in many larger com- comes in critically ill patients: A systematic cal care coverage. We must strive to provide
munity hospitals. One of the reasons is review. JAMA 2002; 288:2151–2162 first-rate surgical critical care coverage for
the increased perception that continuous DOI: 10.1097/01.CCM.0000257469.33018.67 all surgical patients. It is of concern that

Crit Care Med 2007 Vol. 35, No. 3 985


according to a survey by Nathens et al. (2), contribution of bacterial colonization of It, hence, appears that coating the lu-
only 61% of level I trauma centers and 22% the endotracheal tube (ETT) in the patho- men of the ETT with bactericidal agents
of level II centers provide an intensivist genesis of ventilator-associated pneumo- is potentially a promising strategy to re-
model of care in the trauma intensive care nia is still debated, we and others have duce bacterial translocation from the lu-
unit. continued to explore the benefits and men of the ETT to the lower airways. The
If trauma surgery, emergency general methods to reduce/prevent bacterial col- goal of both laboratory and clinical stud-
surgery, and surgical critical care are to onization on the inner surface of ETTs. ies should be the total prevention, not
move forward for the benefit of both pa- The recent study by Dr. Rello and col- just decrease, in bacterial colonization of
tients and practitioners, we need to ad- leagues (2) presented the results of a clin- the lumen of the ETT during the course
dress models of care, shared team respon- ical study to test the “respiratory infec- of prolonged tracheal intubation. Coating
sibilities, and clinical coverage schemes tion control device,” a silver-coated ETT the lumen of a tracheal tube with bacte-
in a creative way. We should not dismiss developed to prevent bacterial growth ricidal agents, alone, is of no long-term
the European model of separation of crit- within the lumen of the ETT. The inves- benefit. Accumulated secretions within
ical care medicine from primary special- tigators found delayed bacterial coloniza- the ETT must be removed meticulously
ties, just as we must recognize the value tion on the inner surface of the ETT and and regularly with the Mucus Shaver, or
of surgeons who are skilled critical care in tracheal aspirates. Overall, there was a similar device, to preserve long-term
practitioners. As critical care medicine lower quantitative bacterial colonization efficacy of the bactericidal coating.
becomes increasingly sophisticated and of the ETT and tracheal aspirates. How-
specialized, surgeons may need to dedi- ever, it is important to emphasize that Gianluigi Li Bassi, MD, Section on Pul-
cate their time to the intensive care unit ultimately, all ETTs were colonized. A monary and Cardiac Assist Devices,
and the operating room, but not simul- previous study by Olson et al. (3) in dogs Pulmonary and Critical Care Medicine
taneously. Continued dialog with our col- evaluated the bacterial burden within the Branch, NHLBI, NIH, Bethesda, MD;
leagues, both surgical and non-surgical, ETT, following instillation of Pseudomo- Lorenzo Berra, MD, Massachusetts
from around the world will be invaluable nas aeruginosa into the buccal pouch of General Hospital, Anesthesia and Crit-
in making these decisions. dogs. Similar to results described in pa- ical Care Department, Boston, MA;
The authors have not disclosed any tients, the silver coating only delayed Theodor Kolobow, MD, Section on Pul-
potential conflicts of interest. monary and Cardiac Assist Devices,
bacterial colonization of the inner surface
Pulmonary and Critical Care Medicine
of the ETT and the lumen of the ETT was
Samuel A. Tisherman, MD, FACS, FCCM, Branch, NHLBI, NIH, Bethesda, MD
again colonized after 3.2 ⫾ 0.8 days of
University of Pittsburgh, Pittsburgh, PA; mechanical ventilation.
Peter B. Angood, MD, FACS, FCCM, Joint In a previous study in sheep intubated REFERENCES
Commission on Accreditation of Health- for 24 hrs, we showed significant ab- 1. Adair CG, Gorman SP, Feron BM, et al: Impli-
care, Oakbrook Terrace, IL; Philip S. sence/reduction in bacterial colonization cations of endotracheal tube biofilm for ven-
Barie, MD, MBA, FACS, FCCM, New in the ETT, the ventilator circuit, and tilator-associated pneumonia. Intensive Care
York Hospital/Cornell Campus, De- lower respiratory tract using silver-based Med 1999; 25:1072–1076
partment of Surgery, New York, NY; coated ETT (4). Our results in a more 2. Rello J, Kollef M, Diaz E, et al: Reduced bur-
Lena M. Napolitano, MD, FACS, FCCM, den of bacterial airway colonization with a
recent clinical study were equally good novel silver-coated endotracheal tube in a ran-
University of Michigan Health System, (5). However, when our studies in sheep
Ann Arbor, MI domized multiple-center feasibility study. Crit
were extended beyond 24 hrs, the pro- Care Med 2006; 34:2766 –2772
gressive build-up of colonized secretions 3. Olson ME, Harmon BG, Kollef MH: Silver-
REFERENCES on the lumenal surface of the coated coated endotracheal tubes associated with re-
ETTs greatly impaired its bactericidal duced bacterial burden in the lungs of me-
1. Tisherman SA, Angood PB, Barie PS, et al: chanically ventilated dogs. Chest 2002; 121:
Structure of surgical critical care and trauma
properties (6).
We had previously described a novel 863– 870
fellowships. Crit Care Med 2006; 34:2282– 4. Berra L, De Marchi L, Yu ZX, et al: Endotra-
2286 device, the “Mucus Shaver,” a device de-
cheal tubes coated with antiseptics decrease
2. Nathens AB, Maier RV, Jurkovich GJ, et al: The signed to totally remove all secretions bacterial colonization of the ventilator cir-
delivery of critical care services in U.S. trauma from within the lumen of the ETT (7). cuits, lungs, and endotracheal tube. Anesthe-
centers: Is the standard being met? J Trauma Laboratory studies have shown that sil- siology 2004; 100:1446 –1456
2006; 60:773–784 ver-based coated ETTs, regularly cleaned 5. Panzeri M, Marelli C, Brambillasca P, et al:
DOI: 10.1097/01.CCM.0000257249.55518.6F with the Mucus Shaver, retained full bac- Evaluation of bactericidal coated tracheal tube
tericidal activity for 168 hrs (and possibly on prevention of bacterial colonization. Inten-
much, much longer) without impairment sive Care Med 2005; 31:S78
Silver-coated endotracheal tubes: Is in bactericidal properties, provided the 6. Berra L, Curto F, Li Bassi G, et al: Antibacte-
the bactericidal effect time limited? rial-coated tracheal tubes cleaned with the
silver-based coated ETT was cleaned with Mucus Shaver: A novel method to retain long-
the Mucus Shaver once every 6 hrs (6). term bactericidal activity of coated tracheal
To the Editor: The total absence of bacterial coloniza- tubes. Intensive Care Med 2006; 32:888 – 893
In the intubated patient, bacterial bio- tion of the inner ETT surface for extended 7. Kolobow T, Berra L, Li Bassi G, et al: Novel
film within the lumen of endotracheal periods of time demonstrated the efficacy system for complete removal of secretions
tubes has been implicated as a reservoir of silver-based coated ETTs only, when within the endotracheal tube: The Mucus
of bacteria that can lead to ventilator- combined with the regular use of the Shaver. Anesthesiology 2005; 102:1063–1065
associated pneumonia (1). Although the Mucus Shaver. DOI: 10.1097/01.CCM.0000257477.44926.90

986 Crit Care Med 2007 Vol. 35, No. 3


The authors reply: REFERENCES in the albumin group. Furthermore, any
difference may represent only a difference
The pathogenesis of ventilator-associ- 1. Rello J, Kollef M, Diaz E, et al: Reduced bur-
in intravascular volume resulting from
ated pneumonia is complex and depends den of bacterial airway colonization with a
the study design. Last, the cardiovascular
on the interaction of multiple risk fac- novel silver-coated endotracheal tube in a ran-
domized multiple-center feasibility study. Crit component of the SOFA score is signifi-
tors. We agree that abrogating bacterial cantly affected by clinical decisions to use
Care Med 2006; 34:2766 –2772
colonization on the endotracheal tube 2. Cook DJ, Walter SD, Cook RJ, et al: Incidence or not to use vasoactive agents, and in an
should be the ultimate goal, but using of and risk factors for ventilator-associated unblinded trial, this introduces signifi-
the respiratory infection control device pneumonia in critically ill patients. Ann In- cant potential for bias.
(1) to delay colonization and the onset of tern Med 1998; 129:433– 440 The respiratory component of the
ventilator-associated pneumonia is note- 3. Freeman BD, Borecki IB, Coopersmith CM, et SOFA score is not reported; the PaO2/FIO2
worthy because the risk increases with al: Relationship between tracheostomy timing ratio is reported instead. The increases
the duration of intubation. For example, and duration of mechanical ventilation in crit-
for the albumin and control groups were
ically ill patients. Crit Care Med 2005; 33:
the cumulative risk increased during the from 215 to 257 and 238 to 248, respec-
2513–2520
first 5 days, peaked at 3.3% on day 5, and 4. Berra L, Curto F, Li Bassi G, et al: Antibacte- tively. All these figures represent a SOFA
subsequently decreased to 2.3% on day rial-coated tracheal tubes cleaned with the score of 2, and so, it appears that the
10 and 1.3% on day 15 in a large study Mucus Shaver: A novel method to retain long- nominated outcome measure was un-
(2). A more recent, large observational term bactericidal activity of coated tracheal changed in both groups. The authors
study has confirmed that most patients are tubes. Intensive Care Med 2006; 32:888 – 893 present no data on the use of mechanical
experiencing shorter intubation times and 5. Spronk PE, Rommes JH, Schultz MJ: Comment ventilation or positive end-expiratory
are no longer intubated after 10 days (3). on “Antibacterial-coated tracheal tubes cleaned pressure, which significantly affect the
with a Mucus Shaver” by Berra et al. Intensive PaO2/FIO2 ratio and represent another po-
With delayed colonization, patients may be
Care Med 2006; 32:2080 –2081
extubated before infection can develop. tential source of bias.
We applaud Dr. Li Bassi and col- DOI: 10.1097/01.CCM.0000257459.13130.07 The neurologic component of the
leagues for the promising results ob- SOFA score is not reported; the authors
tained by cleaning antibacterial-coated instead report the Glasgow Coma Score
Albumin supplementation and organ
tracheal tubes with the “Mucus Shaver” (GCS). The GCS increased from 13 to 15
function in the albumin group and 14 to 15 in the
(4); however, their study had several lim-
itations (5). Although between-group dif- control group; i.e., in both groups the
ferences looked promising, the controlled To the Editor: neurologic SOFA score decreased from 1
study included only 12 sheep. The strat- The recent article by Dr. Dubois and to 0. Again, there appears to be no differ-
egy was limited to the lumen of the tube, colleagues (1) adds data to the long- ence. As the GCS in both groups in-
with an internal coating of silver-sulfadi- running debate about the usefulness of creased to the maximum possible, a dif-
azine in polyurethane, thereby failing to albumin supplementation in critically ference can only result from a greater
address the problems in the throat and care. The accompanying editorial high- potential for improvement in the albumin
lights some of the limitations of the group. It was not possible for the GCS in
subglottic space, which are potential res-
study, notably that it was unblinded and the control group to increase to 16!
ervoirs of pathogenic bacteria (5).
the control group did not receive intra- We welcome the conduct of high-
Multicentered, randomized, controlled
vascular volume expansion to equal that quality, randomized, controlled trials in
clinical trials are needed to determine
of the albumin administered to the in- critical care and hope the data from this
whether either strategy will prevent ven-
tervention group. As a result, differ- pilot study will inform the design of a
tilator-associated pneumonia. More than
ences in intravascular volume may con- large, definitive trial. The report high-
1,500 patients have been enrolled in a found interpretation of any specific effect of lights the importance of using robust pa-
phase III study of the respiratory infec- albumin. tient-centered outcome measures, such
tion control device, and statistical analy- An additional issue is that the claimed as mortality, of adhering to a predeter-
sis is underway. Regardless of the out- effects may be an artifact of the outcome mined analysis plan, and of faithfully re-
come, we predict that a bundle approach measure used and unconventional re- porting a study’s stated outcome mea-
will be required to block the multifacto- porting. The stated primary outcome sures. We trust that any large phase III
rial processes that contribute to the de- measure was a change in the Sequential trial will be designed in such a way that
velopment of ventilator-associated pneu- Organ Failure Assessment (SOFA) score claimed differences between groups are
monia. We would welcome the addition from baseline to day 7; this was reported not the subject of unnecessary uncer-
of other preventive strategies supported to be greater in the albumin group than the tainty.
by adequate clinical trials. control group (3.1 vs. 1.4; p ⫽ .03) because
Dr. Rello has consulted for Wyeth and of differences in the cardiovascular, respi- Simon Finfer, MB BS, FRCA, FRCP,
Intrabiotics. He has also received grant ratory, and neurologic components. FJFICM, Intensive Care Research,
funding from BARD. Dr. Kollef has not dis- There are a number of issues that re- Royal North Shore Hospital, Sydney;
closed any potential conflicts of interest. quire clarification. Specifically, the base- John Myburgh, MBBCh, PhD, FANZCA,
line cardiovascular SOFA score in the FJFICM, Intensive Care Research, St.
Jordi Rello, MD, PhD, Joan XXIII Uni- control group was zero and, therefore, George Hospital, Sydney; Rinaldo
versity Hospital, Tarragona, Spain; there is no potential for improvement. Bellomo, FRACP, FJFICM, MD, Inten-
Marin Kollef, MD, Washington Univer- Any observed difference would have to be sive Care Research, The Austin Medi-
sity School of Medicine, St. Louis, MO the result of a higher baseline SOFA score cal Centre, Melbourne, Australia

Crit Care Med 2007 Vol. 35, No. 3 987


REFERENCE teral nutrition formulas resulted in a 46% tion of published evidence into clinical
lower risk of nosocomial pneumonia com- practice and to have critical care practi-
1. Dubois M-J, Orellana-Jimenez C, Melot C, et pared with patients given a standard enteral tioners recognize nutrition not only as a
al: Albumin administration improves organ
formula (p ⫽ .007) (5). A similar meta- way to deliver calories and nutrients, but
function in critically ill hypoalbuminemic pa-
analysis of nine studies found that ICU pa- also as a powerful therapeutic tool.
tients: A prospective, randomized, controlled,
pilot study. Crit Care Med 2006, 34:2536 – tients given enteral immunonutrition for- International guidelines can play an
2540 mulas had a 55% lower risk of bacteremia important role in this changing behavior
compared with patients receiving standard process. For instance, the Surviving Sep-
DOI: 10.1097/01.CCM.0000257235.05199.9A
formula (p ⫽ .0002) (5). sis Campaign Guidelines for the Treat-
Better nutrition plays a major role in ment of Patients with Severe Sepsis and
High-quality enteral nutrition reducing mortality and morbidity among Septic Shock (4) does not contain any
essential for reducing morbidity and acutely ill patients. I hope Critical Care nutritional advice among its 44 recom-
Medicine can publish more good studies mendations. This and other international
mortality in acute care patients
on acute care nutrition. guidelines should consider reviewing the
The author of this letter received no literature and include nutrition advice in
To the Editor: outside financial support. The author has their recommendations.
I appreciated the recent excellent article not disclosed any financial interest in We appreciate Dr. Curtis’ comments,
by Dr. Pontes-Arruda and colleagues (1), food, food supplement, or pharmaceutical and we hope to see new nutrition studies
which reports that enteral feeding with en- companies. published, debated, and eventually incor-
riched levels of eicopentaenoic acid, ␥-lin- porated into clinical practice.
olenic acid, and antioxidant vitamins re- Luke Curtis, MD, MS, CIH, Norwegian The author has consulted for Abbott
duced mortality by 19.4% (p ⫽ .037) in American Hospital, Chicago, IL Laboratories; received honoraria from
mechanically ventilated patients with sepsis Abbott Laboratories, Eli Lilly, and Baxter
and septic shock, compared with patients REFERENCES Healthcare; and received grant support
receiving standard enteral formula. from Abbott Laboratories and Baxter
Recent additional research has indi- 1. Pontes-Arruda A, Aragão AMA, Albuquerque Healthcare.
JD: Effects of enteral feeding with eicosapen-
cated that better nutritional status, early
taenoic acid, ␥-linolenic acid, and antixoidants
enteral feeding, and the use of immu- in mechanically ventilated patients with se-
Alessandro Pontes-Arruda, MD, PhD,
nonutrition enteral formulas (which con- vere sepsis and septic shock. Crit Care Med Fernandes Távora Hospital, Ildefonso
tain larger amounts of such nutrients as 2006; 34:2325–2333 Albano, Fortaleza, CE Brazil
omega-3 fats, RNA, arginine, glutamine, 2. Schneider SM, Veyres P, Pivot X, et al: Mal-
zinc, and vitamins) can significantly re- nutrition is an independent risk factor associ- REFERENCES
duce both morbidity and mortality in ated with nosocomial infections. Br J Nutr
2004; 92:105–111 1. Pontes-Arruda A, Aragão AMA, Albuquerque
acutely ill patients. A study of 630 hospi-
3. Artinian V, Krayem H, DiGiovine B: Effects of JD: Effects of enteral feeding with eicosapen-
talized patients reported that that the
early enteral feeding on the outcome of criti- taenoic acid, ␥-linolenic acid, and antioxidants
odds ratio risk of nosocomial infections in mechanically ventilated patients with se-
cally ill mechanically ventilated patients.
was 4.98 times as great (95% confidence vere sepsis and septic shock. Crit Care Med
Chest 2006; 129:960 –967
interval, 4.6 – 6.4) in severely malnour- 4. Galban C, Montejo JC, Mesejo A, et al: An 2006; 34:2325–2333
ished patients compared with adequately immune-enhancing diet reduces mortality 2. Gadek JE, DeMichele SJ, Karlstad MD, et al:
nourished patients (2). A study of 4,049 rate and episodes of bacteriemia in septic in- Effect of enteral feeding with eicosapentaenoic
critically ill, mechanically ventilated pa- vasive care unit patients. Crit Care Med 2000; acid, gamma-linolenic acid and antioxidants
tients found that enteral feeding within 28:643– 648 in patients with acute respiratory distress syn-
48 hrs of intubation reduced hospital 5. Montejo JC, Zarazaga A, Lopez-Martinez J, et drome. Crit Care Med 1999; 27:1409 –1420
3. Singer P, Theilla M, Fisher H, et al: Benefit of
mortality by 27% (p ⫽ .001) compared al: Immunonutrition in the intensive care
unit: A systemic review and consensus state- an enteral diet enriched with eicosapentaenoic
with patients not given enteral feeding in
ment. Clin Nutr 2003; 22:221–233 acid and gamma-linolenic acid in ventilated
the first 48 hrs (3). This significantly lower patients with acute lung injury. Crit Care Med
mortality rate was seen, even though the DOI: 10.1097/01.CCM.0000257471.74561.7B 2006; 34:1033–1038
incidence of ventilator-associated pneumo- 4. Dellinger RP, Carlet JM, Mansur H, et al: Sur-
nia was 34% higher in the patients who The author replies: viving Sepsis Campaign Guidelines for man-
received enteral nutrition in the first 48 Indeed, nutritional support plays an agement of severe sepsis and septic shock. Crit
hrs (3). important role in improving outcomes Care Med 2004; 32:858 – 872
A prospective, randomized study of 181 and reducing mortality in critical illness. DOI: 10.1097/01.CCM.0000257722.50567.96
intensive care unit (ICU) patients found For instance, the use of an enteral diet
that mortality and the rate of nosocomial enriched with eicosapentaenoic acid,
infections were both significantly reduced ␥-linolenic acid, and antioxidants proved Saving lives in severe sepsis with the
in patients given an enteral formula sup- to be an effective therapy not only for help of enteral nutrition
plemented with arginine, messenger RNA, patients with severe sepsis and septic
and omega-3 containing fish oil compared shock requiring mechanical ventilation To the Editor:
with patients given a standard enteral for- (1), but also for patients with acute respi- We read, with great interest, the article
mula (4). A meta-analysis of 11 studies in- ratory distress syndrome (2) and acute by Dr. Pontes-Arruda and colleagues (1)
volving ICU patients found that the use of lung injury (3). However, there is still a about the effects of an enteral diet enriched
nutrient-enriched immunonutrition en- long journey for us to start the transla- with eicosapentaeonic acid, ␥-linolenic

988 Crit Care Med 2007 Vol. 35, No. 3


acid, and antioxidants in acute respiratory in the methodology of the article cannot the lack of space should not be considered
distress syndrome (ARDS) patients with se- convince us that a single modification in as a failure in the methodology.
vere sepsis and septic shock. As a group enteral diet in a short period of time and In our trial, the patients in both groups
long interested in the management of crit- on a scarce number of severe sepsis and were well balanced in terms of source of in-
ically ill patients with sepsis, the conclu- septic shock patients with ARDS could be fection, number of medical/surgical patients
sions of this article seem amazing. one of the cornerstones in the treatment enrolled, and the amount or type of fluids
In a field in which different groups are of these patients. received. Moreover, many questions consid-
looking for the magic bullet in the treat- ered by Drs. Ortiz-Leyba and Garnacho-
ment of sepsis, with moderate to modest Carlos Ortiz-Leyba, MD, PhD, José Montero as omissions, were well defined in
results, these authors have found a 19.4% Garnacho-Montero, MD, PhD, Servi- the article itself. For instance, regarding
absolute risk reduction for mortality and cio de Cuidados Críticos y Urgencias, the adequacy and timing of the antibiotic
a number needed to treat of 5 at day 28. Hospital Universitario Virgen del therapy, we mentioned that all patients
These results are better than those from Rocío, Sevilla, Spain were treated in accordance with the Sur-
the early goal-directed therapy (reduction viving Sepsis Campaign recommendations
for mortality, 16%; number needed to (2), which means that all patients included
treat, 6 – 8) (2). REFERENCES received broad-spectrum antibiotics within
Although these are the best published the first hour of recognition of severe sepsis.
results among the assorted weaponry for 1. Pontes-Arruda A, Aragão AMA, Albuquerque The definition of a new respiratory
JD: Effects of enteral feeding with eicosapen-
sepsis, a lot of confounding factors, bias, dysfunction was also stated in the article.
taenoic acid, ␥-linolenic acid, and antioxidants
and omissions need to be solved before in mechanically ventilated patients with se-
We consider a new respiratory failure as
accepting the results. It is well known vere sepsis and septic shock. Crit Care Med. the development of a new respiratory fail-
that the outcome of septic patients is 2006; 34:2325–2333 ure requiring new ventilator support
different in terms of focus, the etiological 2. Rivers E, Nguyen B, Havstad S, et al: Early within the 28-day follow-up period. All
agent, and the type of patient. However, goal-directed therapy in the treatment of se- patients were submitted to the same ven-
these first two variables have not been vere sepsis and septic shock. N Engl J Med tilator weaning protocol. We do not un-
considered in the methods. Moreover, the 2001; 345:1368 –1377 derstand how this simple definition can
number of medical and surgical sepsis 3. Garnacho-Montero J, García-Garmendia JL, generate confusion and surprise.
cases in each group is not exposed. Al- Barrero-Almodovar A, et al: Impact of ade- Finally, we would like to restate that we
quate empirical antibiotic therapy on the out-
though adequate antibiotic therapy has are not dealing with a single-trial result. In
come of patients admitted to the intensive
been recognized as one of the interven- care unit with sepsis. Crit Care Med 2003;
fact, the study diet we used (Oxepa, Abbott
tions associated with a lower mortality 31:2742–2751 Laboratories, Abbott Park, IL) has been exten-
rate in sepsis (3), there were no refer- 4. The National Heart, Lung, and Blood Institute sively examined as a therapeutic tool for the
ences about this issue in the publication, Acute Respiratory Distress Syndrome (ARDS) treatment of patients with pulmonary pathol-
and there were no references about the Clinical Trials Network: Comparison of two ogies and undergoing mechanical ventilation
timing of administration. fluid-management strategies in acute lung in- by different research groups, with highly con-
The authors established that all patients jury. N Engl J Med 2006; 354:2564 –2575 sistent findings. Two other trials showed sim-
were treated according the Surviving Sepsis 5. Pacht ER: Enteral therapy to decrease morbid- ilar results regarding the improvement in ox-
Campaign Guidelines and early goal-directed ity and improve survival in acute respiratory ygenation status, ventilator-free days, and
distress syndrome: Its time has come. Crit
therapy, but we cannot know which of the intensive care unit (ICU)-free days, both in
Care Med 2006; 34:2492–2493
two groups received more fluids, more va- acute respiratory distress syndrome (3) and
sopressors, and inotropics. How can it be DOI: 10.1097/01.CCM.0000257472.00249.02 acute lung injury (4). In a recently performed
concluded that the study group is associ- meta-analysis of these three trials, the use of
ated with a lower development of cardio- The author replies: an enteral diet enriched with eicosapenta-
vascular dysfunction (p ⬍ .001) without The use of nutrition intervention en- enoic acid, ␥-linolenic acid, and antioxidants
considering these factors in the hemody- riched in eicosapentaenoic acid, ␥-linolenic in mechanically ventilated patients is associ-
namic support? Similar concerns arise acid, and antioxidants as a therapeutic ated not only with a significant improvement
about the results of ventilator-free and in- strategy to reduce both pulmonary and sys- in the oxygenation status, but also with
tensive-free days. A recently published arti- temic inflammation represents a new and more ventilator-free days (standardized
cle (4) shows that a conservative strategy of innovative approach, sustained not only by mean difference, 0.556; p ⬍ .0001), more
fluid management for patients with acute one but for several “gold standard” clinical ICU-free days (SMD, 0.508; p ⬍ .0001) and
lung injury improved lung function and trials, all of them based in solid scientific with a 60% reduction in the risk of mor-
shortened the duration of mechanical ven- background. tality (odds ratio, 0.404; p ⫽ .001) (5). For
tilation and intensive care, but how much Regarding our article published in Crit- this reason, we totally agree with Dr.
fluid did each group receive? ical Care Medicine (1), we would like to Pacht’s editorial. Although the adoption of
Other aspects of the article appear con- restate that although many variables were evidence-based medicine is not mandatory,
fusing. Because the totality of patients were collected during clinical trials, the space in our ICU, we choose not to ignore it. We
ARDS patients (PaO2/FIO2 ratio, ⬍200), the available for publication is restricted, as do believe that if the current evidence is
development of new respiratory dysfunc- well as the amount of tables and figures. taken into consideration, the use of an en-
tion in both groups was surprising. Because we or any other author were not teral diet enriched in eicosapentaenoic
With all these considerations, we are allowed to publish every single aspect of the acid, ␥-linolenic acid, and antioxidants is
less optimistic than Dr. Pacht in his edi- trial, this involuntary absence of informa- among the most important strategies to be
torial on the article (5) because the flaws tion in the published article occasioned by adopted in the treatment of mechanically

Crit Care Med 2007 Vol. 35, No. 3 989


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 forward for the diagnosis and outcome with patients with severe CAP (PSI IV–V,
use this type of enteral support in recom- prediction in patients with sepsis (1). 79.1 [45.8 –154.1]; p ⫽ .31). sTREM-1
mended patients should be considered bad Measurement of sTREM-1 was advocated levels at admission in patients with a sub-
practice. in plasma and serum (1) and bronchoal- sequent failure were similar (79.1 [45.0 –
veolar fluid (2). Importantly, more than 126.2]; p ⫽ .39) to patients with a subse-
Alessandro Pontes-Arruda, MD, PhD, half of these patients had sepsis because quent successful outcome.
Fernandes Távora Hospital, Ildefonso of respiratory tract infections. Indeed, a We found no significant correlation
Albano, Fortaleza, CE Brazil prompt diagnosis of community-acquired between sTREM-1 levels, independent if
pneumonia has important therapeutic assessed with the use of immunoblot
REFERENCES and prognostic implications (3). Microbi- technique or enzyme-linked immunosor-
ological culture results often remain neg- bent assay using several antibodies (from
1. Pontes-Arruda A, Aragão AMA, Albuquerque R&D Systems (2) and others), before and
ative and are only available after a delay of
JD: Effects of enteral feeding with eicosapen- after ultracentrifugation, in plasma or se-
taenoic acid, ␥-linolenic acid, and antioxidants
24 – 48 hrs. A novel approach to rapidly
estimate the presence of an infection is rum, respectively. Similarly, sTREM-1
in mechanically ventilated patients with se-
the use of biomarkers. concentrations did not correlate with
vere sepsis and septic shock. Crit Care Med
2006; 34:2325–2333 We measured sTREM-1 concentra- other markers of infection, i.e., C-reactive
2. Dellinger RP, Carlet JM, Mansur H, et al: Sur- tions by the immunoblot technique, as protein (r ⫽ .03; p ⫽ not significant
viving Sepsis Campaign Guidelines for the well as by enzyme-linked immunosorbent [NS]), procalcitonin (r ⫽ ⫺.03; p ⫽ NS),
Management of Severe Sepsis and Septic assay, using previously described anti- and leukocyte count (r ⫽ .03; p ⫽ NS).
Shock. Crit Care Med 2004; 32:858 – 872
bodies (1, 2) in plasma and serum of a In conclusion, circulating sTREM-1
3. Gadek JE, DeMichele SJ, Karlstad MD, et al: levels are not helpful for the assessment
Effect of enteral feeding with eicosapentaenoic
well-documented cohort of 302 consecu-
of etiology and severity in patients with
acid, gamma-linolenic acid and antioxidants tive patients admitted to the emergency
CAP or in predicting outcome of the dis-
in patients with acute respiratory distress syn- department with community-acquired
ease. Conversely, measurement of the lo-
drome. Crit Care Med 1999; 27:1409 –1420 pneumonia (CAP) (4). CAP was defined as
cal production of sTREM-1 in bronchoal-
4. Singer P, Theilla M, Fisher H, et al: Benefit of suggested (5), and the Pneumonia Sever-
an enteral diet enriched with eicosapentaenoic
veolar fluid might provide more reliable
ity Index (PSI) was calculated as previ-
acid and gamma-linolenic acid in ventilated results (2). This, however, is not a cost-
ously described (6). All patients were fol-
patients with acute lung injury. Crit Care Med efficient approach in the routine care of
lowed up after 6 wks. Cure was defined as patients with CAP.
2006; 34:1033–1038
5. Pontes-Arruda A, DeMichele SJ, Anand S, et al:
resolution of clinical, laboratory, and ra-
Enteral nutrition with eicosapentaenoic acid diographic signs and improvement as re-
Beat Müller, MD, Mikael M. Gencay,
(EPA), gamma-linolenic acid (GLA) and anti- duction of clinical, laboratory, and radio-
PhD, Department of Internal Medi-
oxidants in critical illness: A meta-analysis graphic findings. Treatment success
cine, University Hospital Basel, Swit-
evaluation of outcome data. Crit Care Med represented the sum of the rates for cure
2006; 34(Suppl):A95
zerland; Sebastien Gibot, MD, Depart-
and improvement. Treatment failure in-
ment of Intensive Care and Exper-
DOI: 10.1097/01.CCM.0000257478.43093.47 cluded death and recurrence or persis- imental Physiology, Hopital Central,
tence of clinical, laboratory, and radio- Nancy Cedex, France; Daiana Stolz, MD,
logic signs at follow-up. Lukas Hunziker, MD, Michael Tamm,
Circulating levels of soluble triggering In the 251 patients with a successful
receptor expressed on myeloid cells MD, Mirjam Christ-Crain, MD, Depart-
outcome at follow-up, sTREM-1 levels at ment of Internal Medicine, University
(sTREM)-1 in community-acquired admission were (median [interquartile Hospital Basel, Switzerland
pneumonia range]) 85.2 [44.3–156.8] and were un-
changed at follow-up (68.8 [42.9 –135.3];
To the Editor: p ⫽ .17) (Fig. 1). sTREM-1 concentra-
REFERENCES
Soluble triggering receptor expressed tions in mild CAP (defined as PSI I–III, 1. Gibot S, Cravoisy A, Kolopp-Sarda M-N, et al:
on myeloid cells (sTREM)-1 has been put 93.3 [44.1–165.2]) were similar compared Time-course of sTREM (soluble triggering re-

990 Crit Care Med 2007 Vol. 35, No. 3


ceptor expressed on myeloid cells)-1, procal- mograms in 1,737 patients treated with two the speakers’ bureaus for Pfizer and
citonin, and C-reactive protein plasma con- to four separate doses or with continuous Sanofi-Aventis and has received recent
centrations during sepsis. Crit Care Med 2005; infusion showed Cmin ⬍10 mg/L in as research funding from Sanofi-Aventis.
33:792–796 much as 45.1% of patients receiving inter-
2. Gibot S, Cravoisy A, Levy B, et al: Soluble
mittent infusion but in only 7.9% of those Pierluigi Viale, MD, Clinic of Infectious
triggering receptor expressed on myeloid cells
and the diagnosis of pneumonia. N Engl J Med receiving continuous infusion (2). Consid- Diseases, Department of Medical and
2004; 350:451– 458 ering that only 5% to 25% of simultaneous Morphological Research, Medical
3. Meehan TP, Fine MJ, Krumholz HM, et al: serum concentrations of vancomycin may School, University of Udine, Italy;
Quality of care, process, and outcomes in el- diffuse in epithelial lining fluid (3), it may Federico Pea, MD, Institute of Clinical
derly patients with pneumonia. JAMA 1997; be supposed that several VAP patients Pharmacology & Toxicology, Depart-
278:2080 –2084 might experience underexposure when re- ment of Experimental and Clinical Pa-
4. Christ-Crain M, Stolz D, Bingisser R, et al: ceiving this regimen, especially in the pres- thology and Medicine, Medical School,
Procalcitonin-guidance of antibiotic therapy ence of normal renal function or of patho- University of Udine, Italy
in community-acquired pneumonia—A ran-
physiological conditions enhancing the
domized trial. Am J Respir Crit Care Med
volume of distribution or renal clearance (4). REFERENCES
2006; 174:84 –93
5. Niederman MS, Mandell LA, Anzueto A, et al: Conversely, continuous infusion, by
ensuring higher and more sustained se- 1. Shorr AF, Combes A, Kollef MH, et al: Methi-
Guidelines for the management of adults with
rum levels, should be considered more cillin-resistant Staphylococcus aureus pro-
community-acquired pneumonia: Diagnosis,
longs intensive care unit stay in ventilator-
assessment of severity, antimicrobial therapy, appropriate with the intent of enhancing
associated pneumonia, despite initially
and prevention. Am J Respir Crit Care Med clinical efficacy with vancomycin (2, 4).
appropriate antibiotic therapy. Crit Care Med
2001; 163:1730 –1754 Accordingly, a recent retrospective study 2006; 34:700 –706
6. Fine MJ, Auble TE, Yealy DM, et al: A predic- in patients treated with vancomycin for 2. Kitzis MD, Goldstein FW: Monitoring of van-
tion rule to identify low-risk patients with MRSA VAP showed that continuous infu- comycin serum levels for the treatment of
community-acquired pneumonia. N Engl
sion was independently associated with a staphylococcal infections. Clin Microbiol In-
J Med 1997; 336:243–250
lower mortality rate (5). fect 2006; 12:92–95
DOI: 10.1097/01.CCM.0000257480.45965.8C In their article, Dr. Shorr and cowork- 3. Lamer C, de Beco V, Soler P, et al: Analysis of
ers (1) analyzed 107 cases of S. aureus vancomycin entry into pulmonary lining fluid
VAP. However, it was not stated how by bronchoalveolar lavage in critically ill pa-
What does it mean: Appropriate tients. Antimicrob Agents Chemother 1993;
many additional MRSA cases did not
therapy for methicillin-resistant 37:281–286
reach the target Cmin in the first 24 hrs
Staphylococcus aureus? 4. Pea F, Viale P: The antimicrobial therapy puzzle:
and had to be excluded or how many of Could pharmacokinetic-pharmacodynamic rela-
the included MRSA patients had lower tionships be helpful in addressing the issue of
To the Editor: than target Cmin subsequently, thereby appropriate pneumonia treatment in critically
We read with interest the article by Dr. probably experiencing undertreatment. ill patients? Clin Infect Dis 2006; 42:1764 –
Shorr and colleagues (1), in which the It is often stressed that in controlled 1771
authors defined the negative impact that clinical trials assessing new anti-MRSA 5. Rello J, Sole-Violan J, Sa-Borges M, et al:
methicillin-resistant Staphylococcus au- drugs, active comparators should be cho- Pneumonia caused by oxacillin-resistant
reus (MRSA) may have on the outcome of sen with care. Accordingly, when using Staphylococcus aureus treated with glycopep-
tides. Crit Care Med 2005; 33:1983–1987
ventilator-associated pneumonia (VAP). vancomycin, continuous infusion, proba-
Nevertheless, we feel some concerns with bly the most efficacious dosing regimen, DOI: 10.1097/01.CCM.0000257473.18308.64
regard to the statement that protocols should be chosen for optimal compari-
finalized to improve initially appropriate son. This means that the results of pre- The authors reply:
antibiotic administration are unlikely to vious trials should be reassessed in the We appreciate the comments of Drs.
have much effect on containing the costs light of potential underexposure. Viale and Pia on our recent article regard-
associated with MRSA in the intensive Interestingly, ⬎60% of Italian inten- ing the differential impact of methicillin-
care unit. Although we share some of sivists declare they use vancomycin in resistant Staphylococcus aureus (MRSA)
their concerns and we join in advocating continuous infusion (personal unpub- on outcomes in ventilator-associated
new options for treating MRSA infec- lished data); so, it may be difficult for pneumonia (VAP). They raise a concern
tions, we would like to argue briefly them to participate in comparative stud- regarding the definition of appropriate
about their definition of “appropriate an- ies in which the comparator schedule is therapy that we used for our analysis.
timicrobial therapy.” completely different from this. Indeed, in Specifically, we defined as appropriate
The authors stated that all patients the management of multi-drug resistant therapy for MRSA the administration of
initially received vancomycin at 15 mg/kg Gram-positive infections optimization in vancomycin at a dose of 15 mg/kg to
twice daily and that a target trough se- the usage of old drugs still remains a target a trough level of 15–20 mg/L. As
rum level (Cmin) of 15–20 mg/L was de- clinical priority and a scientific chal- we state in the article, this definition was
fined as appropriate. In our opinion, it is lenge, whose dignity may be considered chosen because of the recent recommen-
questionable that the conventionally rec- of similar importance to that of the as- dations for vancomycin therapy in the
ommended twice-daily regimen of vanco- sessment of the possible therapeutic role joint American Thoracic Society/Infec-
mycin may be appropriate for initial VAP of new compounds. tious Disease Society of America position
treatment. A recent retrospective study as- Dr. Pea is a consultant and on the statement on various forms of health-
sessing vancomycin serum levels 36 – 48 speakers’ bureaus for Pfizer and Sanofi- care-associated and nosocomial pneumo-
hrs after starting therapy according to no- Aventis. Dr. Viale is a consultant and on nia. We concur that this definition cer-

Crit Care Med 2007 Vol. 35, No. 3 991


tainly has limitations (1, 2). The optimal cus aureus health-care-associated pneumonia: looked at specific, selected populations (4,
regimen for the dosing of vancomycin in Specific evaluation of vancomycin pharmacoki- 6, 12); thus, of the 12 cited studies, only
pneumonia is unknown. However, it does netic indices. Chest 2006; 130:947–955 seven were in an unselected general hospi-
4. Hidayat LK, Hsu DI, Quist R, et al: High dose
seem clear that the conventional U.S. tal population. The authors also failed to
vancomycin therapy for methicillin-resistant
practice of administering 1 gm every 12 balance this section with a mention of stud-
Staphylococcus aureus infections: Efficacy and
hrs and not monitoring trough levels is toxicity. Arch Intern Med 2006; 166:2138 – 2144 ies that did not demonstrate a benefit of
inadequate. We concur with Drs. Viale METs (13) or outreach (14, 15).
DOI: 10.1097/01.CCM.0000257248.77811.55
and Pia that more study is needed to The MERIT study is the only large
determine how and if to use vancomycin randomized, controlled study in this area.
for MRSA pneumonia. The findings of the International It not only showed that METs failed to
They suggest a role for continuous Conference on Medical Emergency reduce the primary (composite) outcome
infusion that has certain theoretical ben- but it also demonstrated that MET calling
Teams are biased and misleading
efit. No patient in our analysis received systems failed to identify sick patients
continuous-infusion vancomycin. More (sensitivity, 30%; specificity, 50%). If the
importantly, several recent studies sug- To the Editor: fully powered study was undertaken and
gest that even driving up the trough level We read with interest the consensus it showed the same magnitude of differ-
with vancomycin does not improve out- findings on medical emergency teams ence between groups as the MERIT study,
comes in VAP (3, 4). For example, Jeffres (METs) (1). We congratulate the authors then the number needed to treat to pre-
et al. (3) found that mortality rates in for their considerable efforts in further- vent one event would be approximately
MRSA VAP were similar among those ing debate in this area of practice. How- 2,000. This would hardly be an effective
with low, moderate, and high vancomy- ever, their appraisal of the evidence for treatment.
cin trough levels. More concerning, Hi- METs is biased and their summary of the Debate needs to consider that one ex-
dayat and colleagues (4) confirmed that literature is misleading. We agree with planation for the negative result in the
pushing the trough levels of vancomycin the more measured tones expressed in MERIT study is that maybe rapid response
through aggressive dosing schemes has the accompanying editorial (2). system do not work. Perhaps we should not
no impact on outcomes but came at the The authors drew considerable atten- be pursuing a noneffective intervention on
expense of increased rates of nephrotox- tion to the problems in the MERIT study the basis of misplaced enthusiasm.
icity. Given these data coupled with our (3). Although there are limitations of this
findings, we share their concern that study, they were wrong not to give a Richard J. Price, FRCA, Anaesthetics,
many practicing intensivists seem hesi- similar critique to the studies that they Gartnavel Hospital; Brian H. Cuthbertson,
tant either to adjust their approach to the cited in favor of METs. Most of these FRCA, Health Services Research Unit,
use of vancomycin or to adopt novel ther- studies had major flaws. Lack of a power University of Aberdeen; Christopher J.
apies for MRSA VAP. calculation was common to most. A short Cairns, FRCA, Intensive Care Unit,
implementation period was also a feature Stirling Royal Infirmary
Andrew F. Shorr, MD, MPH, Pulmonary in studies by Bellomo et al (4, 5) and
and Critical Care Medicine, WA Hospital Sebat et al (6). Not all of the 12 studies
Center, Washington, DC; Alain Combes, cited as demonstrating an outcome ben- REFERENCES
MD, PhD, Service Reanimation Medicale, efit examined or demonstrated significant 1. DeVita MA, Bellomo R, Hillman K, et al:
Pr Gilbert, Institut de Cardiologie, Groupe differences in each of the endpoints to Findings of the First Consensus Conference
Hospitalier Pitie-Salpetriere, Paris, France; which they were referenced. None of the on Medical Emergency Teams. Crit Care Med
Marin H. Kollef, MD, Pulmonary and cited studies actually investigated cost, 2006; 34:2463–2478
Critical Care Medicine, Barnes-Jewish only speculated on it. As a further exam- 2. Teplick R, Anderson AE: Rapid response sys-
Hospital, Washington University, St. ple, only six studies reported the inci- tems: Move a bit more slowly. Crit Care Med
Louis, MO; Jean Chastre, MD, Service dence of cardiac arrest as an endpoint. In 2006; 34:2507–2509
Reanimation Medicale, Pr Gilbert, In- two studies (7, 8), cardiac arrest call was 3. Merit Study Investigators: Introduction of
the medical emergency team (MET) system:
stitut de Cardiologie, Groupe Hospi- the endpoint; this is clearly very different
A cluster randomised controlled trial. Lancet
talier Pitie-Salpetriere, Paris, France from a cardiac arrest. Of the remaining
2005; 365:2091–2097
four studies, a significant reduction was 4. Bellomo R, Goldsmith D, Uchino S, et al: A pro-
only found in two (4, 9). The total num- spective before-and-after trial of a medical emer-
REFERENCES
ber of cardiac arrests from these two gency team. Med J Aust 2003; 179:283–287
1. Shorr AF, Combes A, Kollef MH, et al: Methicil- studies is only 107. The positive results 5. Bellomo R, Goldsmith D, Uchino S, et al:
lin-resistant Staphylococcus aureus prolongs may be attributed to the accompanying Prospective controlled trial of effect of med-
intensive care unit stay in ventilator-associated education packages. ical emergency team on postoperative mor-
pneumonia, despite initially appropriate antibi- The authors failed to mention that some bidity and mortality rates. Crit Care Med
otic therapy. Crit Care Med 2006; 34:700 –706 of the cited studies only examined planned 2004; 32:916 –921
2. American Thoracic Society, Infectious Dis- 6. Sebat F, Johnson D, Musthafa AA, et al: A
review of discharged intensive care patients
eases Society of America: Guidelines for the multidisciplinary community hospital pro-
(10, 11). These studies are not applicable to
management of adults with hospital-acquired, gram for early and rapid resuscitation of
ventilator-associated, and healthcare-associ- a general hospital population. It was mis- shock in nontrauma patients. Chest 2005;
ated pneumonia. Am J Respir Crit Care Med leading to cite these studies, and we rein- 127:1729 –1743
2005; 171:388 – 416 force the point that authors should “help 7. Buist MD, Moore GE, Bernard SA, et al: Effects
3. Jeffres MN, Isakow W, Doherty JA, et al: Predictors the reader understand the patient popula- of a medical emergency team on reduction of
of mortality for methicillin-resistant Staphylococ- tion being described” (1). Three studies incidence of and mortality from unexpected

992 Crit Care Med 2007 Vol. 35, No. 3


cardiac arrest in hospital: Preliminary study. that, if known, would trigger the RRS (4, current emphasis on the “team” has ob-
BMJ 2002; 324:1– 6 5). To be effective, an afferent arm on a scured other important components of the
8. DeVita MA, Braithwaite RS, Mahidhara R, et general care floor environment must meet rapid response system (RRS). It is our opin-
al: Use of medical emergency team responses
the following criteria: a) it must be invisible ion that all four components of the system
to reduce hospital cardiopulmonary arrests.
to the patient (thus removing any compli- are underdeveloped and understudied. We
Qual Safe Health Care 2004; 13:251–254
9. Goldhill DR, Worthington L, Mulcahy A, et ance issues with probes, cuffs, or cannulas); hope that as rapid response systems ma-
al: The patient-at-risk team: Identifying and b) it must integrate into existing nurse ture, all four components will improve. We
managing seriously ill ward patients. Anaes- workflows and infrastructure, removing agree that attention to crisis detection
thesia 1999; 54:853– 860 the need for additional staffing; c) it must needs to increase. There are two compo-
10. Ball C, Kirkby M, Williams S: Effect of criti- be customizable to allow for individual vari- nents to monitoring (and neither replaces
cal care outreach team on patient survival to ability; and d) it must filter out the noise of the other): monitoring devices and bedside
discharge from hospital and readmission to clinically insignificant blips in vital signs caregivers. We hope our article will foster
critical care: Non-randomised population that so often trigger false alarms in most an impetus for monitoring more (perhaps
based study. BMJ 2003; 327:1014
traditional monitors. Examples of technical all) patients more effectively. Investigations
11. Garcea G, Thomasset S, McClelland L, et al:
solutions to address these points are now are needed to generate data: 1) to demon-
Impact of a critical care outreach team on
critical care readmissions and mortality. Acta becoming commercially available (e.g., www. strate the financial return on investment of
Anaesthesiol Scand 2004; 48:1096 –1100 hoana.com). Advantages of modern systems high-cost devices; 2) to identify the ideal
12. Pittard AJ: Out of our reach? Assessing the include the ability to noninvasively moni- monitor for detecting patients developing a
impact of introducing a critical care out- tor for RRS criteria, the capacity to set and crisis; 3) to choose appropriate alert levels;
reach service. Anaesthesia 2003; 58:882– 885 customize alarms, invisibility to the pa- and 4) to identify caregiver skill gaps. The
13. Kenward G, Castle N, Hodgetts T, et al: Eval- tient, and acceptable levels of false alarms. quality improvement impact of RRS is also
uation of a medical emergency team one year The article by Dr. DeVita and colleagues (1) underrecognized. Each event is an oppor-
after implementation. Resuscitation 2004; is helpful in that it focuses attention not tunity to discover why crises occur. Finally,
61:257–263
simply on the response (i.e., the rapid re- there seem to be gaps in knowledge, judg-
14. Story DA, Shelton AC, Poustie SJ, et al: The
sponse team) but also on how the system ment, and skills of crisis responders. Many
effect of critical care outreach on postopera-
tive serious adverse events. Anaesthesia and its providers learn of impending pa- organizations are improving crisis response
2004; 59:762–766 tient deterioration. skills, often using simulation education.
15. Leary T, Ridley S: Impact of an outreach Dr. Jacobs is the Director of Medical Af- We welcome the healthy scientific skep-
team on readmissions to a critical care unit. fairs for Hoana Medical, a manufacturer of ticism expressed by Dr. Price and col-
Anaesthesia 2003; 58:328 –332 noninvasive continuous vigilance systems, leagues. We agree that historical control,
DOI: 10.1097/01.CCM.0000257474.01932.2F and has stock options with the company. single-center interventions have obvious
limitations. We reported brief summaries of
Joshua Jacobs, MD, University of Hawaii, all studies cited so that readers can rapidly
Requirements of the afferent arm of John A. Burns School of Medicine, De- access and judge them for themselves. Ac-
rapid response systems partment of Medicine, Division of Medical cordingly, we disagree that our summary of
Informatics, Honolulu, HI the literature is biased or misleading. Our
article reports the findings of an expert
To the Editor: REFERENCES panel and is not a scientific review of the
In their report on rapid response sys- 1. DeVita MA, Bellomo R, Hillman K, et al: Find- literature, per se. Although many of the
tems (RRS), Dr. DeVita and colleagues (1) ings of the First Consensus Conference on conclusions reached by the panel, which
draw the elegant analogy between the re- Medical Emergency Teams. Crit Care Med included patient safety and human factors
sponse to unexpected patient deteriora- 2006; 34:2463–2478 engineering experts, were evidence-based,
tion and organic systems with afferent 2. Teplick R, Anderson AE: Rapid response sys- some were consensus-based in the absence
and efferent arms and feedback loops. In tems: Move a bit more slowly. Crit Care Med of evidence. Significant considerations
the accompanying editorial, Dr. Teplick 2006; 34:2507–2509 were the well-documented risk (both the
and Ms. Anderson point out that the af- 3. Hillman KM, Bristow PJ, Chey T, et al: Ante- number of patients at risk and the potential
cedents to hospital deaths. Intern Med J 2001;
ferent arm of the RRS has the most room harm), potential for large benefit, lack of
31:343–348
for improvement (2). It is axiomatic that 4. Harrison GA, Jacques TC, Kilborn G, et al: The
alternative strategies showing some evi-
if clinicians do not know about a patient’s prevalence of recordings of the signs of critical dence of success, lack of any evidence of
deteriorating condition, they cannot do conditions and emergency responses in hos- harm, limited cost, and, of course, benefit
anything about it. Many studies show pital wards—The SOCCER study. Resuscita- shown by the few reports to date (with all of
that the signs of patient deterioration are tion 2005; 65:149 –157 their imperfections) (1).
present hours before cardiopulmonary 5. Meyer G, Lavin MA: Vigilance: The essence of We want to put the debate into proper
arrest (3). nursing. Online J Iss Nurs June 23, 2005. context. Data supporting RRS exceed that
Unfortunately, the present generation Available at: http://nursingworld.org/ojin/ supporting hospital cardiac arrest teams,
of continuous monitoring systems often topic22/tpc22_6.htm. Accessed September 19, trauma teams, and even intensive care
2006
generate false positives for RRS activa- unit specialists. Complex medical inter-
tion, leading to provider frustration and DOI: 10.1097/01.CCM.0000257232.82866.7A ventions that involve system change and
unnecessary costs. This problem of over- the delivery of other bundles of care are
sensitivity is matched by a problem of The authors reply: difficult, perhaps impossible, to study in a
undersensitivity: many patients on gen- We thank Dr. Jacobs for his comments. randomized clinical trial because systems
eral medical-surgical floors have signs We too have become concerned that the of care may be too complex to adequately

Crit Care Med 2007 Vol. 35, No. 3 993


control and measure. Our consensus panel FCCM, Consultants in Critical Care, the widespread applicability of these re-
decided, accordingly, not to kill common Glenbrook, NV sults. Of note, overall control arm mor-
sense on the altar of pure scientific ortho- tality in multicenter, randomized, con-
doxy. The point is straightforward: provide REFERENCES trolled trials of treatments for sepsis is
suddenly critically ill patients with critical generally reported to be approximately
1. DeVita MA, Bellomo R, Hillman K, et al: Find-
care resources systematically. 30% to 35% (4, 5).
ings of the First Consensus Conference on
Dr. Price and colleagues draw conclu- Medical Emergency Teams. Crit Care Med There are also concerns about the in-
sions from MERIT (2) that we feel are un- 2006; 34:2463–2478 ternal validity of both studies. In addition
warranted, specifically because of MERIT’s 2. Hillman K, Chen J, Cretikos M, et al: Intro- to the obvious lack of randomization and
construction. First, MERIT was too short duction of the medical emergency team (MET) the potential for a “Hawthorne effect” in
an intervention. Single-center reports were system: A cluster randomised controlled trial. the after (or intervention) group, a change
much longer. The study by Bellomo et al., Lancet 2005; 365:2091–2097
in the outcome of interest (i.e., mortality)
which included all hospitalized patients, 3. Bellomo R, Goldsmith D, Uchino S, et al: A
prospective controlled trial of the medical
over time undoubtedly confounds interpre-
used a preparation time before the intro- tation of the results of the study by Micek
emergency team. Med J Aust 2003; 179:
duction of the RRS of 9 months (twice as 283–288 and colleagues. Friedman et al. (6) demon-
long as in MERIT) and an additional 2 4. DeVita MA, Braithwaite RS, Mahidhara R, et strated a progressive decline in sepsis mor-
months run-in period (3). A similar time al: Use of medical emergency team (MET) re- tality over time (between 1958 and 1997).
frame for changing culture was used for the sponses to reduce hospital cardiac arrests. The EPISEPSIS study also reported a sig-
results of DeVita et al (4). Time is impor- Qual Safety Healthcare 2004; 13:251–254 nificant improvement in survival from se-
tant. In MERIT, staff in medical emergency 5. Jones, Bellomo R, Bates S, et al: Long-term
effect of a medical emergency team on cardiac
vere sepsis during the past decade (7). This
treatment hospitals did not activate the apparent natural regression resulting from
arrests in a teaching hospital. Crit Care 2005;
RRS as instructed, despite the presence of medical progress is further compounded by
9:R808 –R815
identifying criteria in most cases, high- the effect of regression to the mean. There
lighting the need for longer and more in- DOI: 10.1097/01.CCM.0000257250.35337.66
are questions regarding the internal valid-
tensive education for cultures and systems ity of the study by Rivers and colleagues,
to change behavior. Second, making as- Early goal-directed therapy of septic such as the lack of blinding. There are also
sumptions on the number needed to treat shock: We honestly remain skeptical questions about the components of EGDT,
from MERIT is fraught with danger be-
such as the recommendation for liberal use
cause of the following: 1) it ignores the
To the Editor: of blood transfusions that is contradictory
marked degree of medical emergency treat-
We read with interest the recent arti- to other high-level evidence (8). These is-
ment-like activity in control hospitals and
cle by Dr. Micek and colleagues (1), sug- sues give rise to the honest skepticism we
wide confidence intervals for the outcome
gesting that early protocolized resuscita- have regarding the widespread use of this
measures; and 2) it ignores the change in
tion using goal-directed therapy (EGDT) therapy.
behavior and outcome compared with base- should be routine for all patients with Although EGDT offers great promise
line that both arms experienced. We note a septic shock, and the accompanying edi-
recent study of an established RRS that the for the treatment of patients with severe
torial by Dr. Carlet (2). We would like to sepsis, we believe it is premature to rec-
number needed to prevent a cardiac arrest point out that we remain honestly skep-
was calculated at 17 (5). ommend the widespread application of
tical of the results of this study and the EGDT because of the limitations in the
Finally, the purpose of the consensus original trial which form the basis for
conference was to provide a roadmap for evidence as it currently exists. Before rec-
recommending EGDT (3). There are a ommending early goal-directed therapy
the future with the following: 1) organiz- number of reasons why the results of
ing nomenclature; 2) reviewing data; 3) for all patients with severe sepsis, not just
these studies may not be applicable in those patients presenting to the emer-
identifying areas in which research is other settings.
warranted; and 4) providing expert guid- gency department, a well-designed mul-
There are concerns about the external
ance based on data and real world con- ticenter, randomized trial evaluating this
validity of both the study by Dr. Micek
siderations. Although the science of sys- intervention should be conducted.
and colleagues (1) and the previously re-
tems research in this sphere of health ported study by Rivers and colleagues (3).
care is still in its infancy, we assert there Sandra Peake, PhD, FJFICM, Intensive
The evidence supporting the introduction
is sufficient data with which to act. of goal-directed cardiovascular resuscita- Care, The Queen Elizabeth Hospital, Ad-
tion in the authors’ institution is primar- elaide, SA, Australia, School of Medicine,
Michael A. DeVita, MD, Department ily based on the results of a single-center University of Adelaide, Adelaide, SA, Aus-
of Critical Care Medicine, University study of severe sepsis patients presenting tralia; Steve Webb, PhD, FJFICM, Inten-
of Pittsburgh School of Medicine; to an urban emergency department. It is sive Care, Royal Perth Hospital, Perth,
Rinaldo Bellomo, MD, Austin Hospital, unknown whether the results of such a WA, Australia, University of Western
Heidelberg, Melbourne, Australia; single-center study could be reproduced Australia, Perth, WA, Australia;
Kenneth Hillman, MBBS, FRCA, FANZCA, in other settings. Despite similar reduc- Anthony Delaney, MBBS, FJFICM, In-
FJFICM, Intensive Care, University of tions in absolute mortality in both the tensive Care Unit, Royal North Shore
New South Wales; John Kellum, MD, trials by Micek et al. and Rivers et al., the Hospital, St. Leonards, NSW, 2065,
Department of Critical Care Medicine, high control (or before) group mortality Australia, Northern Clinical School,
University of Pittsburgh School of Med- observed in both studies (49.2 and 48.3%, University of Sydney, St. Leonards,
icine; Maurene Harvey, RN, MPH, respectively, at 28 days) potentially limits NSW, Australia

994 Crit Care Med 2007 Vol. 35, No. 3


REFERENCES the number of patients who had an ob- patients with septic shock. JAMA 2002; 288:
jective measure of intravascular volume, 862– 871
1. Micek ST, Roubinian N, Heuring T, et al: Be- 3. Rivers E, Nguyen B, Havstad S, et al: Early
namely, central venous pressure. This ap-
fore-after study of a standardized hospital or- goal-directed therapy in the treatment of se-
der set for the management of septic shock.
proach to care, which was standard in
vere sepsis and septic shock. N Engl J Med
Crit Care Med 2006; 34:2707–2713 both the experimental and control arm in
2001; 345:1368 –1377
2. Carlet J: Early goal-directed therapy of septic the study by Rivers et al. has recently 4. Trzeciak S, Dellinger RP, Abate NL, et al:
shock in the emergency room: Who could been shown to be achievable in two other Translating research to clinical practice: A
honestly remain skeptical? Crit Care Med real-life settings (3–5). Second, we tar- 1-year experience with implementing early
2006; 34:2842–2843 geted improvement in the appropriate- goal-directed therapy for septic shock in the
3. Rivers E, Nguyen B, Havstad S, et al: Early ness and timeliness of the initially admin- emergency department. Chest 2006; 129:
goal-directed therapy in the treatment of se- istered antimicrobial therapy. Numerous 225–232
vere sepsis and septic shock. N Engl J Med studies have demonstrated the impor- 5. Shapiro NI, Howell MD, Talmor D, et al: Im-
2001; 345:1368 –1377 plementation and outcomes of the multiple
tance of appropriate antimicrobial ther-
4. Abraham E, Reinhart K, Opal S, et al: Efficacy urgent sepsis therapies (MUST) protocol. Crit
and safety of tifacogin (recombinant tissue
apy as it relates to hospital survival in
Care Med 2006; 34:1025–1032
factor pathway inhibitor) in severe sepsis: A patients with severe sepsis (6, 7). The
6. Garnacho-Montero J, Garcia-Garmendia JL,
randomized controlled trial. JAMA 2003; 290: duration of time from the onset of shock Barrero-Almodovar A, et al: Impact of ade-
238 –247 to the administration of antimicrobial quate empirical antibiotic therapy on the out-
5. Bernard GR, Vincent J-L, Laterre P-F, et al: therapy also appears to have a direct as- come of patients admitted to the intensive
Efficacy and safety of recombinant human ac- sociation with patient outcome (8). Con- care unit with sepsis. Crit Care Med 2003;
tivated protein C for severe sepsis. N Engl sequently, one cannot discount the effect 31:2742–2751
J Med 2001; 344:699 –709 our improvement had in the rapidity and 7. Harbarth S, Garbino J, Pugin J, et al: Inappro-
6. Friedman G, Silva E, Vincent JL: Has the mor- overall number of patients who received priate initial antimicrobial therapy and its effect
tality of septic shock changed with time. Crit on survival in a clinical trial of immunomodu-
appropriate antimicrobial therapies in
Care Med 1998; 26:2078 –2086 lating therapy for severe sepsis. Am J Med 2003;
7. Brun-Buisson C, Meshaka P, Pinton P, et al:
our study. We feel these simple perfor-
115:529 –535
EPISEPSIS: A reappraisal of the epidemiology mance measures can be readily achieved
8. Kumar A, Roberts D, Wood KE, et al: Duration
and outcome of severe sepsis in French inten- in settings outside of our own institution of hypotension before initiation of effective
sive care units. Intensive Care Med 2004; 30: and positively impact the outcome in pa- antimicrobial therapy is the critical determi-
580 –588 tients with septic shock. nant of survival in human septic shock. Crit
8. Hebert PC, Wells G, Blajchman MA, et al: A All performance improvement projects Care Med 2006; 34:1589 –1596
multicenter, randomized, controlled clinical are subject to enhanced outcomes di- DOI: 10.1097/01.CCM.0000257482.38723.1E
trial of transfusion requirements in critical rectly after intensive education and train-
care. N Engl J Med 1999; 340:409 – 417 ing related to the intervention, and our
DOI: 10.1097/01.CCM.0000257481.37623.3B study is no exception. We clearly state Selenium in Intensive Care (SIC)
this as a limitation in our article. Addi- study: The XX files are still
The authors reply: tionally, we agree that the natural ten- unresolved
We appreciate the comments of Dr. dency over time is to have regression to
Peake and colleagues regarding our re- the mean, particularly when dealing with
cently published study. Their concerns internal improvement projects. Nonethe- To the Editor:
regarding the external and internal valid- less, the larger point to be made is that First, I would like to congratulate Dr.
ity of our study, however, are defensible. institution of standardized order sets or Angstwurm and colleagues on their thor-
First, the objection about the high rate of some other systematic approach for the ough study and the recent publication in
mortality in the before group in our study management of patients with septic Critical Care Medicine (1). Their trial
compared with the control arm in recent shock can consistently improve the deliv- represents another fundamental, clear,
severe sepsis studies is an unfair compar- ery of recommended therapies and as a and convincing piece of evidence that
ison. As pointed out in the editorial to result may improve patient outcomes. emphasizes the importance of an ade-
our article by Dr. Carlet (1), we included quate selenium status for a positive out-
only patients with septic shock, a popu- Scott T. Micek, PharmD, Department come of patients in the intensive care
lation that has a significantly higher mor- of Pharmacy, Barnes-Jewish Hospital, unit. It is high time that such results are
tality rate at baseline compared with that St. Louis, MO; Marin H. Kollef, MD, taken serious and are translated into clin-
in the trials referenced by Dr. Peake and Division of Pulmonary and Critical ical practice.
colleagues. In fact, the mortality rate in a Care Medicine, Washington University However, I cannot fully agree, at
recent study of patients with septic shock School of Medicine present, with the generalized conclusion
is as high as 63% in the control arm (2). drawn by the authors, i.e., “. . . high-dose
Lost in translation appears to be the sodium-selenite reduces mortality rate in
underlying goals of our institution’s sur- REFERENCES patients with severe sepsis or septic
viving sepsis initiative, which were pro- shock.” The data presented support this
1. Carlet J: Early goal-directed therapy of septic
cess improvements related to fluid resus- claim only for males with low selenium
shock in the emergency room: Who could
citation and antimicrobial therapy. Our honestly remain skeptical? Crit Care Med status, not for all septicemia patients. The
first goal was to improve the early, ag- 2006; 34:2842–2843 findings need to be discussed in view of
gressive fluid resuscitation, specifically 2. Annane D, Sebille V, Charpentier C, et al: sex-specific peculiarities of selenium me-
the initial amount of fluid in the patient’s Effect of treatment with low doses of hydro- tabolism and individual baseline sele-
bolus. Additionally, we sought to improve cortisone and fludrocortisone on mortality in nium status.

Crit Care Med 2007 Vol. 35, No. 3 995


The biological effects of selenium de- nium metabolism into account. Because and females regarding age (62 yrs, 69
ficiency or selenium supplementation dif- these data are not at hand, a prophylactic yrs), comorbidities, Acute Physiology and
fer considerably between the sexes. We supplementation before and during hos- Chronic Health Evaluation III score (93
and others observed in transgenic mice pitalization within the recommended vs. 97), shock, or drop in platelet count
that males displayed stronger phenotypes daily range represents a globally applica- (44.4% vs. 36.8%). Death was attributable
than females on inactivation of the sele- ble strategy to both men and women to to sepsis in 95% of males and only 76% of
nium transport protein selenoprotein P, avoid life-threatening deficiencies of sele- females. Therefore, we cannot conclude
which is the major determinant of sele- nium in the clinic. statistical differences in selenium effects
nium status (2). In human trials, the che- The author has received grant support between males and females, and both
mopreventive effects of selenium show a from the German Science Foundation genders were put together in the final
clear bias for males, and data for effects of and the German Cancer Foundation. analysis. During followup, there was no
selenium on female participants are usu- difference in selenium whole blood levels
ally limited or inconclusive (3). This may Lutz Schomburg, PhD, Charité Berlin, between genders after substitution (Se1:
be caused by sex-specific differences in Insitute for Experimental Endocrinol- male, 1.89 ⫾ 0.49 ␮mol/L, female, 2.04 ⫾
hepatic selenoprotein biosynthesis as de- ogy Charitéplatz, Berlin, Germany 0.64 ␮mol/L). In addition, the 28-day
scribed recently in experimental animals mortality rate was dependent on the max-
(4). If these findings hold true for hu- REFERENCES imum serum selenium levels in both fe-
mans and if hepatically derived seleno- males and males, as well as in both con-
protein P does, indeed, translate supple- 1. Angstwurm MW, Engelmann L, Zimmermann trol and selenium substitution group.
mented selenium into biological effects T, et al: Selenium in Intensive Care (SIC): Nevertheless, the sex-specific differences
(as suggested by the authors), it is not Results of a prospective randomized, placebo- in transgenic mice in hepatic selenopro-
controlled, multiple-center study in patients
surprising that the effectiveness of selen- tein biosynthesis are important and
with severe systemic inflammatory response
ite supplementation was mainly observed syndrome, sepsis, and septic shock. Crit Care
should be kept in mind during the plan-
in males. Unfortunately, the number of Med 2007; 35:118 –126 ning of the following next large multi-
female patients in the Selenium in Inten- 2. Burk RF, Hill KE, Selenoprotein P: an extra- center trial.
sive Care study, as well as in cancer pre- cellular protein with unique physical charac- Selenium levels in serum are low in
vention trials, are usually disproportion- teristics and a role in selenium homeostasis. septic patients already at admission (1)
ately low. Therefore, it currently appears Annu Rev Nutr 2005; 25:215–235 associated with increasing severity of dis-
to be difficult to unequivocally conclude a 3. Knekt P, Aromaa A, Maatela J, et al: Serum ease (2). The mortality in severe sepsis is
potential benefit for the full patient pop- selenium and subsequent risk of cancer inversely related to selenium levels dur-
ulation. The design of follow-up studies among Finnish men and women. J Natl Can- ing follow-up. In control patients, the
cer Inst 1990; 82:864 – 868
should consider this need of additional urinary selenium loss was low (0.13
4. Riese C, Michaelis M, Mentrup B, et al: Se-
data. lenium-dependent pre- and posttranscrip-
␮mol/L). Therefore, not a selenium loss
Moreover, as shown in the Selenium tional mechanisms are responsible for sex- but a redistribution of selenoproteins has
in Intensive Care study and cancer trials ual dimorphic expression of selenoproteins to be postulated. Low selenium levels in
alike, the available data point to a strong in murine tissues. Endocrinology 2006; 147: septic patients at admission cannot be
correlation of selenium status with mor- 5883–5892 used to define a total body selenium defi-
tality and tumor risk, respectively, if the 5. Reid ME, Duffield-Lillico AJ, Garland L, et ciency (3). Despite the acute phase reac-
individual belongs to the lowest tertile or al: Selenium supplementation and lung can- tion, selenium levels increase, even during
quartile of study participants (5). In the cer incidence: An update of the nutritional the acute phase reaction in the selenium-
publication by Angstwurm et al., this prevention of cancer trial. Cancer Epidemiol treated patients (1). Selenoprotein P as the
Biomarkers Prev 2002; 11:1285–1291
finding is well reflected by a direct corre- major determinant of selenium in plasma
lation between selenium concentration DOI: 10.1097/01.CCM.0000257479.88792.A5 might be attached to the endothelium or
and survival rate (Table 5). Remarkably, disappear in other organs but seems to be
the subgroup with the highest baseline The authors reply: regenerated after selenium supplementa-
selenium levels had no further reduction We thank Dr. Schomburg for his impor- tion. This clearly demonstrates a higher
in mortality. Monitoring the selenium tant comments on the results of the Sele- demand of selenium in severely ill patients.
status of patients before or during septi- nium in Intensive Care (SIC) study, the It is right that those patients with
cemia could, thus, restrict selenium sup- first multicenter, randomized, placebo- higher selenium levels at admission had no
plementation to those patients in need. controlled, double-blind study on the adju- benefit from the selenium supplementa-
Even though no adverse effect has been vant treatment of patients with severe sep- tion, but these patients were less ill. There-
observed in their study, the amount of sis and septic shock with high doses of fore, only the most ill patients should be
sodium-selenite given (i.e., 15 mg within selenium (1). treated with selenium.
14 days) raises concern because it clearly Indeed, our conclusion that adjuvant The selenium dosage is high and ex-
exceeds tolerable upper intake levels. selenium treatment reduces mortality is ceeds the long-term upper tolerable level,
Therefore, it might be prudent to inter- only shown in males, not in females (Ta- but this level is defined for healthy people
vene with selenium and to correct for ble 4). However, these results have to be with normal levels and demand of sele-
excessive loss, only in those cases in interpreted with caution, as we did not nium, but obviously severely septic pa-
which a deficiency has been asserted. randomize the patients by gender; the tients have a higher demand of selenium.
I am confident that the authors agree 138 males and 51 females were distrib- In our study, no adverse effects were seen
on the need for conducting larger studies uted differently between groups. There in these patients, even in those without
that take the sexual dimorphism of sele- were different characteristics of males septic shock syndrome. The short high-

996 Crit Care Med 2007 Vol. 35, No. 3


dose selenium supplementation, there- The authors have not disclosed any with severe systemic inflammatory response
fore, seems to be safe. potential conflicts of interest. syndrome, sepsis, and septic shock. Crit Care
The measurement of selenium as a pre- Med 2006; 35:118 –126
requisite for selenium substitution might 2. Forceville X, Vitoux D, Gauzit R, et al: Se-
Matthias Angstwurm, MD, Roland lenium, systemic immune response syn-
be a good parameter. The determinations of Gärtner, MD, Medizinische Klinik,
selenium content, as well as selenoprotein drome, sepsis, and outcome in critically ill
Ziemssenstr 1, Munich, Germany patients. Crit Care Med 1998; 26:1536 –
P, one possible actor of selenium at the
1544
endothelial site, however, are not yet rap-
idly available. Further studies should deter-
REFERENCES 3. Angstwurm MWA, Gaertner R: Practicalities of
selenium supplementation in critically ill pa-
mine more parameters of selenium metab- 1. Angstwurm MWA, Engelmann L, Zimmermann tients. Curr Opin Clin Nutr Metab Care 2006;
olism and confirm the optimistic results of T, et al: Selenium in Intensive Care (SIC): Re- 9:233–238
the first prospective and double-blind con- sults of a prospective randomized, placebo-
ducted SIC study (1). controlled, multiple-center study in patients DOI: 10.1097/01.CCM.0000257253.49826.3A

Crit Care Med 2007 Vol. 35, No. 3 997