Issue Of Intensive Care Medicine Research Articles

Organ dysfunction and children sepsis: building a concept

In the February 2018 in an issue of Intensive Care Medicine , Schlapbach et al. published a prospective multicentric binational cohort study on the following organ dysfunction scores: sequential organ failure assessment (SOFA), quick SOFA (qSOFA) and Pediatric Logistic Organ Dysfunction-2 (PELOD-2) in a large pediatric cohort admitted to the ICU with infection.

Candida colonization of respiratory tract: to treat or not to treat, will we ever get an answer?

In non-immunocompromised intensive care unit (ICU)patients Candida isolation from various sites is common[1]. The association with the risk of invasive candidiasis(IC) is the rational for the use of predictive scores whichinclude the colonization status.However the meaning of Candida spp. recovery fromthe lung is definitely more intriguing. Apart from ICepisodes occurring in deeply immunosuppressed subjectswho may develop true fungal pneumonia, Candidarespiratory tract (RT) isolation should not be considered amarker of lung infection. This issue was addressed byMeersseman et al. [2] who did not identify any autopsy-proven case of Candida pneumonia among 135 autopsieswith histopathological evidence of bacterial infection andhigh rate of Candida isolation from endotracheal aspirate(EA) and/or bronchoalveolar lavage (BAL) (57 %).However there is growing convincing evidence, basedon animal studies and human observations, that Candidaspp. is not definitely an innocent bystander in the respi-ratory tract of ICU ventilated patients [3–13] (Table 1).Beta-glucan (BG), a component of yeast cell wall, mayact as a lung proinflammatory agent causing alveolarmacrophage and neutrophil dysfunction. Additionally,within the environmental biofilm there is a strong inter-play, through quorum-sensing (QS) molecules, betweenand both Gram-positive and Gram-negativebacteria [14]. Live Candida albicans instillation in ratshas been observed to increase the susceptibility to developexperimental Pseudomonas aeruginosa (PA), Escherichiacoli (Ec), and Staphylococcus aureus (Sa) pneumonia,fostering the production of lung inflammatory cytokines(tumor necrosis factor alpha [TNF-alpha], interleukin-6[IL-6], and interferon-gamma [INF-c]) and inhibitingalveolar macrophage phagocytosis [3, 5]. From a clinicalviewpoint, Candida airway colonization has been shownto be associated with prolonged duration of mechanicalventilation, ICU/hospital length of stay, and increasedmortality [8–11]. One of the first reports of this possiblerelationship dates back to almost 10 years ago, whenAzoulay et al. [6] identified Candida bronchial isolationas an independent risk factor for the development of PAventilator-associated pneumonia (VAP) (9 vs 4.8 % innon-colonized patients, p = 0.048). These data werestrengthened just 1 year later by Nseir et al. [7] whoobserved a protective role of antifungal treatment on PAVAP occurrence in a cohort of patients with Candidatracheobronchial colonization. However, recently, the useof nebulized amphotericin B (NAB) was not able toprovide any clinical improvement, albeit increasing therate of Candida decolonization (adjusted HR 2.2; 95 %CI 1.6–3) [13]. Hence the clinical usefulness of respira-tory tract Candida colonization (CC) eradication inmechanically ventilated patients is still a matter of debateand the paper by Albert et al. [15] in the current issue ofIntensive Care Medicine is the first interventional trialaiming to describe the biochemical and clinical effect ofantifungal treatment in ICU patients with VAP and RTCc. In this double-blind, placebo-controlled, multicenterstudy 60 patients were enrolled: 29 in the placebo groupand 31 in the antifungal strategy group. A comparative

Sepsis without borders

Sepsis without borders

Prognostication of neurologic outcome after cardiac arrest: standardization of neurological examination conditions is needed

Dear Editor, We read with great interest the study by Kamps and colleagues [1] in the October 2013 issue of Intensive Care Medicine. Accurate neurological prognostication in comatose patients after cardiac arrest is a daily concern in general ICUs [2], especially the effect of therapeutic hypothermia on prognostication accuracy [3]. The authors should be congratulated for their tenacity in obtaining original data from the authors of all the studies included in the meta-analysis. We were nevertheless specifically intrigued by the overall high false positive rate (FPR) of bilaterally absent cornea reflexes. In the aggregated data analysis, seven patients with bilateral cornea reflex absence ultimately had a favorable recovery. The study by Bisschops and colleagues [4], in which neurological signs were retrospectively recorded, accounts for a majority of these patients (four patients, of nine patients with a favorable recovery) with a FPR of 45 %. The exclusion of this study from the meta analysis might have revealed very different results, as only the six studies with neurological signs recorded prospectively would have been taken into account. More generally, the study by Kamps and colleagues [1] raises important issues on whether neurological signs, such as absence of motor response or cornea reflexes, intrinsically are poorly reliable for predicting neurological recovery after cardiac arrest (and are thus unsuitable in this setting). Discrepancies between study results in the meta-analysis by Kamps and colleagues [1] might at least partly reflect large discrepancies in daily practice, in terms of assessment methods of brainstem reflexes, timing of neurological examination after rewarming from hypothermia, and ruling out of potential insidious confounders (such as persistent effect of sedatives or morphinics). Standardization of neurological examination conditions after cardiac arrest is urgently needed to answer this question.

A Janus role for MerTK in the outcome of septic shock

Severe sepsis remains a clinical challenge today, even indeveloped countries, because of the increased age of thepatients and the high burden of antibiotic resistance [1]. Inaddition, in recent years, we have become increasinglyaware that, even in the early stages of sepsis, a high pro-portion of patients experience a severe dysfunction ofnative and adaptive immunity, which is closely related topatients’ outcome [2]. In this context, understanding thefunctionality of receptors able to modulate the immuneresponse, and in particular to downregulate inflammation,has great importance for designing new therapeutic strat-egies. Among these molecules, a main role is occupied bythe TAM family of receptor tyrosine kinases, which isformed by three members, i.e., Tyro3, AxI, and Mer, thathave two vitamin K-dependent ligands, i.e., the growtharrest-specific protein (Gas)6 and Protein S [3]. In theSeptember 2013 issue of Intensive Care Medicine, Gui-gnant et al. [4] explored by an elegant experimental studythe expression of TAM receptors in circulating immunecells in patients with septic shock and after trauma, and inhealthy volunteers. A significant early alteration of MerTKexpression on monocytes and neutrophils was observed inpatients with septic shock, and a persistent MerTK over-expression after septic shock was associated with adverseoutcome. The ex vivo analysis showed also a differentMerTK surface expression of healthy monocytes after48 h incubation with plasma from septic or traumapatients, supporting the difference in TAM expressionbetween infection-induced inflammation and sterileinflammation (i.e., trauma). The study provides newimportant data on the mechanisms of immune response insepsis, but the true reasons for the observed alterations inMerKT expression and their role in the complex patho-physiological context of sepsis remain to be clarified.TAM receptors are under the control of Toll-likereceptors (TLR), and are widely expressed by cells of theinnateimmunesystem[5].ActivationofTAMreceptorsbytheir ligands triggers a cascade of intracellular events thatculminate in the inhibition of nuclear factor-kappaB (NF-jB), a crucial proinflammatory molecule, and results indownregulation of inflammation [6]. When expressed bymonocytes and granulocytes, these receptors (and in par-ticular MerTK) can also mediate the phagocytosis ofapoptoticcells[7],whichisfundamentalinordertoremovedead cells without triggering inflammation. Several datanow exist that underline the importance of MerTK activa-tion in the elimination of potential autoantigens derived byapoptotic cells, in the inhibition of the production of pro-inflammatory cytokines, and in the prevention of theexpansion of autoreactive lymphocytes [8–10]. The func-tional impairment of MerTK promotes not onlyautoimmunity but also atherosclerosis, while its overex-pression is linked to poor prognosis in cancer [11].The strong relationships existing between TAMreceptors and a proinflammatory molecule such as tumornecrosis factor-alpha (TNF-a) are reinforced by theobservation that they can interact with a common protein,the matrix metalloproteinase TNF-a converting enzyme,also known as ‘‘a disintegrin and a metalloproteinase 17’’(ADAM17). In order to provide the mature, soluble,secretable form of TNF-a, ADAM17 cleaves the mem-brane form of this important proinflammatory cytokine[12]. Interestingly, ADAM17 is also able to cleave the

Do physicians’ beliefs influence treatment options at the end of life?

Do physicians’ beliefs influence treatment options at the end of life?

Praying for healthy minds and healthy bodies in ICU survivors

Advances in intensive care practice and technology allow severely ill patients to survive conditions that would have been fatal 50 years ago; however, survival of critical illness is often associated with psychiatric sequelae, and this is just beginning to be understood. In a study in this issue of Intensive Care Medicine, Amal Jubran and colleagues [1] describe the prevalence of post-traumatic stress disorder (PTSD) in patients in a weaning unit. PTSD is an important problem. It is associated with poor quality of life and an increased risk of suicide, but it is amenable to intervention, particularly if it is implemented early. This study, conducted in patients well enough and lucid enough to be interviewed, suggests that PTSD is common both in the weaning unit and after discharge. In contrast to earlier questionnaire-based studies, patients included in this study were rigorously assessed by the gold standard, an interview by an experienced clinician. A simple questionnaire, however, w... Language: en

Are macrolides now obligatory in severe community-acquired pneumonia?

In this issue of Intensive Care Medicine, Martin-Loechesand colleagues [1] present an analysis of a cohort of 218patients with community-acquired pneumonia requiringmechanical ventilation enrolled into a larger, observa-tional, multi-center European study. The major finding ofthe study in this issue was that the 42 patients whoreceived a macrolide antibiotic had half the mortality rateof other patients after adjusting for severity of illness atpresentation.That macrolide antibiotics appear to confer a signifi-cant survival advantage in patients with severecommunity-acquired pneumonia is not a new concept,with multiple observational and retrospective studiesdemonstrating substantial mortality benefits [2–7]. How-ever, as has been pointed out in many editorials andreviews, none of these studies are prospective, random-ized controlled trials. In the absence of scientificallyirrefutable evidence, at what point does the weight of datain favor of using macrolides become so overwhelmingthat their use is obligatory?If we look at the potential downsides of making mac-rolides obligatory, then there is an obvious economic costif they are not needed. However, relative to most costs inhealth care, the economic burden is trivial. Unnecessarymacrolide use could perceivably contribute to increasedantibiotic resistance to this class of antibiotics in thecommunity, but the reality is that patients hospitalizedwith community-acquired pneumonia account for a min-ute portion of total antibiotic use, and this is not asustainable argument given the already widespread use ofthis class of agents in the outpatient setting for upper andlower respiratory tract infections. Overuse of macrolides,like any antibiotic, could theoretically lead to selectionfor multi-resistant pathogens. However, the risk of thisseems to be smaller than for broad-spectrum beta-lactams,third-generation cephalosporins and fluroquinolones,which all have well-documented track records of thisadverse side effect. As with all antibiotics, drug reactionscan occur, but macrolides are generally a very safe classof antibiotics. An increased incidence of arrhythmias hasbeen reported with macrolides because of prolongation ofthe Q-T interval, but overall the risk is no greater than thatassociated with fluroquinolones [8].If there is no major downside to adding a macrolide,the next question is whether these are the best agents orwhether other antibiotics or antibiotic combinations havean equivalent or greater beneficial effect. One of theproposed (and I think the least likely) potential explana-tions for the benefit of macrolides is coveringunrecognized ‘atypical’ pathogens (such as Legionellaspp. or Mycoplasma). If this were the mechanism, thenthere should be equivalent benefit from fluroquinolonesand tetracyclines. However, just as previous observationalstudies have shown [9, 10], the current study by Martin-Loeches and colleagues [1] also clearly demonstrates thatfluroquinolones do not give the same apparent protectiveeffect as macrolides. Although much more limited, thereare also some data suggesting that tetracyclines are alsonot as efficacious as macrolides [10].That the benefit of macrolides is almost certainly notdriven by undiagnosed atypical pathogens invalidates the

The ART of caring for patients with HIV infection in the ICU

The ART of caring for patients with HIV infection in the ICU

Oxford American Handbook of Critical Care PDA

Oxford American Handbook of Critical Care PDA . By Kellum, John A., Gunn, Scott R., Singer, Mervyn, Webb, Andrew . New York : Oxford University Press , 2008 ; $49.95 (CD for PDA installation [Palm or Windows Mobile platforms] ). Oxford American Handbook of Critical Care PDA (personal digital assistant) is a digital version of the American issue of the Oxford Handbook of Critical Care. This item comes with a computer installation CD and is suited for either the Palm or Windows Mobile operating platforms. System requirements include either Palm OS version 5.0 or later or Windows Mobile version 2003 or later, with a touch screen. The program requires at least 9 megabytes of available memory to install. Installation is fairly straightforward and allows quick access to the product. The program is divided into initial chapters on techniques for respiratory therapy, cardiovascular therapy, renal therapy, and gastrointestinal therapy. Sections on nutrition issues and special support surfaces follow. Next are chapters covering monitoring of cardiovascular, neurologic, laboratory, and miscellaneous areas. A brief section on fluids follows, with the next several sections providing an overview of drugs used for respiratory, cardiovascular, renal, gastrointestinal, neurologic, hematologic, and miscellaneous conditions. Clinical condition chapters are next with coverage of resuscitation, then respiratory, cardiovascular, renal, gastrointestinal, hepatic, neurologic, hematologic, and metabolic disorders. Chapters then address poisoning, infection and inflammation, trauma and burns, physical disorders, pain and postoperative intensive care, and obstetric emergencies. The penultimate section covers death and the dying patient, with the final chapter covering intensive care unit organization and management. Authors from the University of Pittsburgh are paired with United Kingdom authors to give the text a universal appeal. This PDA product is a nice offering and covers a wide range of issues in intensive care medicine. The PDA interface (I used the Palm-based version) is smooth and easy to navigate. The chapters are organized in a user-friendly manner, and there are links to related material for topics covered elsewhere in the text. Forward and back arrows, coupled with a “home” button and a search function, make moving about the program quite simple. The font is easy to read, and the sections for each link are relatively short. This may lead to one minor criticism—some of the links and sections provide only a small amount of text on a given topic. This seems to be a function of the authors’ goal of providing a brief, useable handbook, as well as the streamlined PDA interface. Overall, this is a minor issue, and the technical aspects of this product are solid and allow rapid reference when information is needed. The clinical sections provide excellent information in a straightforward manner. Some chapters feature links and references for “key paper(s).” These feature landmark or important papers highlighting that chapter’s contents. This is in contrast to a format with full references accompanying each section. Hence, this is a potential criticism, but the text information appears up to date and well researched. Occasional tables for drug doses and other items work well in the PDA format, and the zoom process for certain tables is integrated seamlessly within the program. The monitoring sections even feature some guidance for line placement and other procedures, although without diagrams/photos. I used this product during several clinical shifts and found that searching for relevant information was quite easy. One downside may be the relatively short sections of information within each link. Because of this, the main value of this reference may be for general knowledge and management principles, instead of specific treatment regimens. This fits the purpose of this program, and I believe that with the comprehensive coverage and easy maneuverability, the authors have met their goals. Overall, Oxford American Handbook of Critical Care PDA is a very useful program with much relevance for emergency physicians and other emergency medicine and critical care practitioners. I believe that this program will meet the needs of a broad audience. From a knowledge standpoint, the included information is most applicable to residents, medical students, and other trainees, and this is in line with the handbook format for this product. Packaging useable information and an easy-to-navigate format makes this a highly functional product, which should find its way onto the PDAs of a wide variety of emergency care providers. Congratulations to the authors and publishers for a job well done!

Prevention of ventilator-associated pneumonia after cardiac surgery: prepare and defend!

Prevention of ventilator-associated pneumonia after cardiac surgery: prepare and defend!

Soluble triggering receptor expressed on myeloid cells-1 and diagnosis of ventilator-associated pneumonia

Dear Sir: The quest for a reliable diagnostic marker of ventilator-associated pneumonia (VAP) is still ongoing and whether determination of the alveolar concentration of the soluble form of the triggering receptor expressed on myeloid cells (TREM)-1 could be a valuable candidate is debated. Unfortunately, the study reported in this issue of Intensive Care Medicine will just generate further perplexity [1]. First, the presented work is the result of an ancillary study originating from the series reported last year in this same journal [2], which the authors should have clearly acknowledged. This fact raises concerns regarding the quality of the samples’ conservation (since 2001) especially if they have been subject to freeze/thaw cycles that rapidly degrade sTREM-1. Because alveolar sampling was initially not dedicated to sTREM-1 measurement, bronchoalveolar lavage (BAL) fluid was centrifuged at 250g for 10 min, a procedure largely insufficient to eliminate cell particulates that express membranebound TREM-1 (alveolar macrophages or neutrophils): this may have led to artificially increased sTREM-1 concentrations. Second, the effects of previous antibiotherapy of the diagnosis of VAP are not discussed. VAP was diagnosed by the presence of C2% cells containing intracellular organisms (ICO) or quantitative culture of C10 cfu/ml. Although previous antibiotics do not seem to interfere with ICO percentage [2], this is obviously not the case for quantitative cultures. Unfortunately, no data are presented on the number of VAP diagnosed by ICO percentage or quantitative culture: a subset of patients may have been classified as no VAP just because \2% ICO and \10 cfu/ml were observed while antibiotics were given. By the way, we have no idea on the final diagnosis that was retained in the no-VAP patients. Despite the fact that all these limitations by themselves preclude the drawing of any conclusion, another problematic issue must be pointed out. The authors used a commercially available assay, namely the human TREM-1 Quantikine assay from RnD Systems (Minneapolis, USA), to measure sTREM-1 concentrations. It happens that this assay was recalled by RnD systems during the early summer of 2008 because of its inability to properly measure soluble TREM-1 concentration. I want to believe that the authors were not aware of that. Of note, the three studies [3–5] reporting good performances of BAL sTREM-1 measurement in diagnosing VAP used an ELISA technique (Duoset, RnD Systems) different from the one employed in the two studies [1, 6] showing limited sTREM-1 usefulness (Quantikine). It may well be that sTREM-1 measurement will finally prove to be disappointing in diagnosing VAP, but the current study is just not interpretable.

Should we discharge comatose patients from intensive care to die in their own bed at home after withdrawal of mechanical ventilation?

In an intensive care unit (ICU), mechanical ventilation(MV) and vasopressive agents (VA) are commonly usedlife-sustaining treatments. Sometimes it is decided towithdraw these treatments for reasons of futility, dispro-portion or at the request of the patient, in almost all casesresulting in death of the patient within minutes or hours.There are significant differences among countries,resulting in percentages of withdrawal of mechanicalventilation of between 1 and 10% of all ICU admissions[1–4]. The time until death seems mostly dependent onthe severity of illness and organ failure and on whichtreatments are withdrawn. After withdrawal of life-sus-taining treatment, possibly distressing symptoms canoccur, and these should be prevented and suppressed withopioids, sedatives and other medicaments. Most patientsin whom life-sustaining intensive care measures arewithdrawn die in the ICU (almost 90%) or shortly afterdischarge from the ICU on a hospital ward (approxi-mately 10%). There are only a few publicationsmentioning discharge of patients to home directly fromthe ICU in order to die [5–10]. In this issue of IntensiveCare Medicine, Huang et al. [11] report their experiencesfrom an ICU in Taiwan. The authors did a retrospectiveobservational study in a tertiary medical center. Thepatients were transported from the ICU to their homes onventilator support. Blood pressure was maintained withistered for comfort. After arrival at the patient’s home, thepatient was placed in a bed in the main hall of the house,after which mechanical ventilation was withdrawn, theendotracheal tube removed and administration of vaso-active drugs stopped. Sedatives and opiods werecontinued. Death occurred in minutes to hours. Between2003 and 2007, 969 of the patients admitted to theauthors’ ICU died, 346 (36%) of them after being dis-charged to the patient’s own home, where mechanicalventilation was withdrawn.According to the sparse literature, this practice isremarkable from the Western perspective. For example,Steinhauser et al. [12] determined the factors consideredimportant at the end of life by patients, their families, andphysicians and other care providers. They measured themain rank scores for nine preselected attributes (freedomof pain; at peace with God; presence of family, mentallyaware; treatment choices followed, finances in order; feellife was meaningful; resolve conflicts and die at home),with 1 being most important and 9 being least important.All groups ranked ‘die at home’ the least important and‘free of pain’ the most important. An analysis exploringthe quality of the dying experience on the ICU showed thatfamily members of dying patients also rank pain control asthe most important aspect for quality of dying on the ICU[13]. On the other hand, when asked directly, most peoplewould prefer to die at home in their own familiar envi-ronment. Especially patients with terminal cancer or otherchronic diseases, between a half and three quarters ofwhom would ideally choose a death at home, under aquarter actually die there. Most of them die in the hospital.But most of these patients with terminal malignantdiseases are completely conscious and would experiencebeing at home, which is not the case with most of the

Once is not enough: clinical trials in sepsis

In this issue of Intensive Care Medicine, the steering committee members of the PROWESS-Shock trial present a balanced discussion of the controversies surrounding recombinant human activated protein C (rhAPC) and the challenges intrinsic to designing an industry-sponsored trial [1]. The investigators have taken important steps to be transparent about financial conflicts of interest, to safeguard data monitoring and to ensure the validity of statistical analysis. The purpose of the upcoming PROWESS-Shock Trial is to prospectively test rhAPC in a high-risk septic population—those patients with vasopressor-dependent shock for C4 h. The need for this trial, years after the regulatory approval of rhAPC for a similar indication, is a cautionary tale that contains important lessons for health care providers who manage patients with sepsis, the pharmaceutical industry and the Food and Drug Administration (FDA). The following is an excerpt from a letter written to Dr. Jay P. Siegel, Director of the Office of Therapeutics Research and Review, FDA, on 22 October 2001 by four of the ten dissenting members of the FDA advisory panel that considered the safety and efficacy of rhAPC (Personal communication, Suffredini A for the authors, Cross AE, Munford R, Suffredini A, Warren S):

Interactions between respiration and systemic hemodynamics. Part I: basic concepts

The topic of cardiorespiratory interactions is of extreme importance to the practicing intensivist. It also has a reputation for being intellectually challenging, due in part to the enormous volume of relevant, at times contradictory literature. Another source of difficulty is the need to simultaneously consider the interrelated functioning of several organ systems (not necessarily limited to the heart and lung), in other words, to adopt a systemic (as opposed to analytic) point of view. We believe that the proper understanding of a few simple physiological concepts is of great help in organizing knowledge in this field. The first part of this review will be devoted to demonstrating this point. The second part, to be published in a coming issue of Intensive Care Medicine, will apply these concepts to clinical situations. We hope that this text will be of some use, especially to intensivists in training, to demystify a field that many find intimidating.

ARDS and knowledge translation

Knowledge translation is an important step for translational research. In this issue of Intensive Care Medicine, a new mini-series of basic research-related reviews is published. Three invited reviews focus on the role of extracellular matrix in ventilator-induced lung injury and mechanotransduction. The major challenges in the diagnosis and management of acute respiratory distress syndrome are discussed, which promote further awareness of knowledge translation in intensive care.

Comment on “Pulse oximetry” by Jubran

Dear Sir: Refering to the Physiological Note of Amal Jurban “Pulse Oximetry” which was published in the issue of Intensive Care Medicine of July 24th 2004, we would like to make two additional statements. One very useful clinical application of pulse oximetry which has not been mentioned in the article above is that the cyclical respiratory induced changes in the amplitude of the pulse oximeter waveform can be used to detect normotensive hypovolemia. According to several studies [1, 2], systolic pressure variation and its dDown component have been shown to be sensitive factors in estimating intravascular volume in patients undergoing mechanical ventilation. Therefore respiratory-induced waveform variability of the pulse oximetric signal is a useful measurement in the detection of mild hypovolemia. Furthermore, as far as limitations of pulse oximetry are concerned, an important question which evokes is what happens with increasing bilirubin concentrations. According to several studies [3] hyperbilirubinemia does not interfere with hemoglobin saturation measured by pulse oximetry, while others [4] suggest that a bilirubin concentration below 17mg/dl is a safe limit above which measurements exceed normal values. The later stands for multiwavelength oximeters because in severe jaundice the O2Hb values are not identical with the real blood concentration of this hemoglobin deritive. In this situation pulse oximetry is more valid.

Care for the dying in intensive care in The Netherlands

Withdrawal of treatment and palliative end-of-life careare the most challenging ethical issues in intensive caremedicine. This article reviews existing legislation andguidelines concerning withholding and withdrawingtreatment, euthanasia, palliative sedation and palliativeadministration of opioids in adult patients in the ICU inthe Netherlands. Although Dutch ICU physicians supportthe idea of national guidelines addressing end-of-life carefor ICU patients [1], these still do not exist.

Immunonutrition in the critically ill: from old approaches to new paradigms

In this issue of Intensive Care Medicine, Keift et al. [1]report the results of a multicenter, randomized, double-blind, controlled trial comparing an enteral formula en-riched with arginine, glutamine, antioxidants and con-taining omega 3 fatty acids with an isocaloric, non-isonitrogenous standard enteral formula, in a mixedpopulation of 597 critically ill patients. When analyzedboth using an efficacy analysis (those fed for more than48 h) and by an intention-to-treat analysis, the authorsfailed to demonstrate any difference in clinical outcomesin the overall analysis or several subgroup analyses.Mortality, infectious complications, ICU length of stay,and duration of mechanical ventilation were the samebetween the two groups. Although the lack of a treatmenteffect on clinical outcomes has been shown in other trials,given the highly controversial nature of the topic of im-munonutrition in critically ill patients, this article is sig-nificant, particularly since this is the largest and one ofthe more robust randomized trials of immune-enhancingdiets in an ICU population.When the results of this large trial are added to theexisting trials, in the form of a meta-analysis, the overalltreatment effect is consistent with no effect on mortality(relative risk [RR] 1.05 and 95% confidence intervals [CI]0.89, 1.25), infectious complications (RR 0.97, CI0.81,1.15) or length of stay in ICU (weighted mean dif-ference [WMD] 1.59, CI 3.25,0.08) [2]. After 20 yearsof research, 18 randomized trials of 2,348 critically illpatients, and countless millions of research dollars, why isit that we are unable to demonstrate a positive treatmenteffect associated with these immune-enhancing products?Do we need more trials like this one to prove the virtuesof these special nutrients? Or, do we have to ask ourselveswhether there are fundamental problems with our ap-proach to proving the hypothesis that certain nutrientswith immunologic and metabolic properties will improvethe outcomes of critically ill patients? We have arguedbefore that there are significant methodological limita-tions to the existing literature that limit the inferences wecan make from these studies [3]. As we argue below,perhaps the problem is further compounded by the factthat multiple nutrients are combined into single nutri-tional products and tested in heterogeneous patient pop-ulations.For any sick patient, “metabolic resuscitation” of thegastrointestinal tract by providing adequate nutrition, ingeneral, and defined immuno-modulating substratesspecifically, to maintain gut-barrier integrity and functionand to reduce regional oxidative stress, will have to beconsidered as key therapeutic strategies. However, withina given patient over time or across different patientpopulations, the severity of “gut failure”, the amount ofbacterial translocation, the degree of cellular immunedysfunction, the balance of inflammation/anti-inflamma-tion, and the regional and systemic generation of reactiveoxygen species will vary. Generally speaking, electivesurgical patients experience minimal activation of cy-tokines and some degree of suppression of the cellulardefense function following surgical stress, putting them athigher risk for acquired infectious morbidity and mor-tality. It follows that nutrients, such as arginine, thatstimulate the cellular defense system may reduce infec-tious complications in the elective surgical patient. Incontrast, the associated changes to the systemic inflam-matory response accompanying critical illness are farmore intense, complex, variable, and less well-defined,but best characterized by an over-amplified inflammatory

Airway resistance—an old friend re-visited

Accurate interpretation of physiologic data underpins the effective management of patients receiving mechanical ventilation. The assessment of respiratory mechanics, for exarfiple, has recently assumed increasing importance, reflecting an improved understanding of the potential consequences of inappropriate machine settings [1 3]. While the latest equipment offers expanded options for monitoring and information processing, the correct interpretation and use of the data remain the clinician's unique responsibility. A significant number of therapeutic decisions (e. g., regarding mode selection, bronchodilator use, and pressure support) hinge on the perceived contributions to overall resistance of valves, endotracheal tube and native airway. In this issue of Intensive Care Medicine, Conti and colleagues [4] demonstrate the error of partitioning resistance between tube and patient on the basis of reasonable but unwarranted assumptions. The work is carefully done, the conclusions valid, and the implications clear. But even when each resistance component is accurarely determined, a more fundamental question must be asked: What do we understand by the term "resistance"? The simplified equation of motion for the respiratory system [5] assigns single lumped constants ("resistance" [Rrs] and "compliance" [Crs]) to the flow (~r)-related and volume (V)-related components of the applied transstructural pressure (Papp):