Online Letter to the Editors

levels with a high rate (25% of samples when obtained on ICU day 3) of false positives (4). The cause for fluctuating β-glucan levels is unknown, but as the β-glucan test relies on an absolute cutoff result for positivity, fluctuations in β-glucan levels during a single Candida infection should give all clinicians pause before using the results to guide clinical management. Finally, not included in current guidelines is a discussion of appropriate patient selection to obtain β-glucan assay testing. Critically ill patients who are neutropenic, hemodialysis dependent, HIV positive, immune compromised or recent history of gastrointestinal surgery or trauma have greater likelihood to produce false positive and/or were not present in appropriate numbers in clinical trials to consider this modality of testing valid. A recent meta-analysis of the utility of β-glucan testing exposed the lack of experience in critically ill patients, with 11 of 16 included studies (69%) focusing on patients with hematologic malignancies (5). Furthermore, only 281 of 2,979 patients (9%) included in this meta-analysis were critically ill in an ICU setting. Of greatest concern with the β-glucan test is the inability to discriminate between candidemia and mould infections, both of which are a cause of morbidity and mortality in critically ill patients who are simultaneously at-risk for either infection. Because therapeutic strategies for mould and yeast infections are different, the diagnostic value of β-glucan testing is marginal, at best. In summary, the β-glucan assay should cause introspection for any clinician considering this test and begs the question regarding how recommending this test became incorporated into these guidelines, let alone carry a “2B” recommendation. Currently, the β-glucan serum assay cannot be routinely recommended until further research in critically ill patients establishes the appropriate patient population, cutoff for a true positive result, timing of collection and clinical setting before it can be recommended for use and included in international guidelines. The authors have disclosed that they do not have any potential conflicts of interest. Velliyur V. Viswesh, PharmD, BCPS, John J. Radosevich, PharmD, BCPS, Department of Pharmacy Services, University of Arizona Medical Center; and Department of Pharmacy Practice and Science, College of Pharmacy, The University of Arizona, Tucson, AZ; Myke R. Green, BS Pharm, PharmD, BCOP, Department of Pharmacy Services, University of Arizona Medical Center; and Section of Hematology/Oncology, Arizona Cancer Center, Tucson, AZ

REFERENCES

1. Dellinger RP, Levy MM, Rhodes A, et al; Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup: Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: 2012. Crit Care Med 2013; 41:580–637 2. Green MR: A modicum of caution for blood (1→3)-β-D-glucan testing for Pneumocystis jurovecii in HIV-infected patients. Clin Infect Dis 2011; 53:1039–1040 3. León C, Ruiz-Santana S, Saavedra P, et al: Value of β-D-glucan and Candida albicans germ tube antibody for discriminating between Candida colonization and invasive candidiasis in patients with severe abdominal conditions. Intensive Care Med 2012; 38:1315–1325 4. Mohr JF, Sims C, Paetznick V, et al: Prospective survey of (1→3)-betaD-glucan and its relationship to invasive candidiasis in the surgical intensive care unit setting. J Clin Microbiol 2011; 49:58–61

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5. Karageorgopoulos DE, Vouloumanou EK, Ntziora F, et al: β-D-glucan assay for the diagnosis of invasive fungal infections: A meta-analysis. Clin Infect Dis 2011; 52:750–770 DOI: 10.1097/CCM.0b013e3182978e35

The authors reply:

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e appreciate the commentary by Viswesh et al (1) elucidating potential confounders that may lead to a positive β-glucan serum assay, as well as finer points relating to the use of the test, for example, impact of timing. Some of these factors mentioned were the reasons that the recommendation is a grade 2 (suggestion). It carries essentially no risk to the patient and in the appropriate clinical s­ cenario may be useful. Dr. Opal served as board member for Arsanis, BioAegis, and Sciclone; consulted for Amplimmune; received royalties from Elsevier; and served on the data monitoring committee for Spectral, Achaogen, and Tetraphase. His institution received grant support from GlaxoSmithKline (preclinical research on genomics regulation), Asahi Kasei (Clinical coordinating center for clinical trial), and Cardeas (Clinical coordinating center for clinical trial). Dr. Dellinger disclosed that he does not have any potential conflicts of interest. Steven M. Opal, MD, Infectious Disease Division, Memorial Hospital of Rhode Island, Providence, RI; R. Phillip Dellinger, MD, MCCM, Cooper Health Systems, Camden, NJ; for the Surviving Sepsis Campaign Guidelines Committee

REFERENCE

1. Viswesh VV, Radosevich JJ, Green MR: Inclusion and Recommendation of (1→3)-β-d-Glucan Testing in the International Guidelines for Management of Severe Sepsis and Septic Shock. Crit Care Med 2013; 41:e487–e488 DOI: 10.1097CCM.0000000000000059

The Worth of the Guidelines: Pediatric Considerations in Severe Sepsis and Septic Shock

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hese updated guidelines are very relevant, and we would like to acknowledge the members of the pediatric subgroup’s great work (1). The recommendations target rich settings, but they also have great importance for developing countries and will guide the therapeutic in children with severe sepsis in these locations, despite the known limitations that may be present. We would like to add some comments that may aid the dynamic process of the surviving sepsis guidelines and help with its applicability in developing countries. As the target population of the pediatric guidelines, we believe that children (excluding newborns) should be the focus. It has already been established that volume resuscitation in newborns, as opposed to children, should be performed in lower rates (10 mL/kg) and longer times (2). Differences in management of vasoactive drugs, antibiotic therapy, and pulmonary hypertension also differ greatly (3). Thus, it is potentially hazardous to standardize their treatment. December 2013 • Volume 41 • Number 12

Online Letter to the Editors

Regarding vascular access, the guidelines highlight the importance of not delaying therapy by lack of central access, emphasizing the use of intraosseous access, and administration of antibiotics by alternative routes (i.e., orally or intramuscularly), as well as beginning peripheral inotropic support until central venous access can be attained. However, the authors do not position themselves about which central catheter insertion site is preferential, not taking into account the risks of infection and deep vein thrombosis associated with the catheter site (4). Thus, the “take-home message” about central catheter insertion sites is still not clear. In relation to the type of solution used for fluid resuscitation, albumin is considered as the first option in the industrialized world. The trials were performed with adult patients, and the conclusions drawn in adults cannot be extrapolated to children for several reasons, such as different physiological response, requirement of more aggressive volume resuscitation, and major volume component in septic shock. A systematic review about fluid resuscitation in children showed that there is insufficient evidence to support the preferential use of colloids in pediatric sepsis (5). These facts associated with lower side effects, cost, and wide availability (considering developing countries) make crystalloids the first choice in fluid resuscitation of children, and albumin should be reserved for specific cases or when there is no response to initial crystalloids use, even in a resourceful setting. Still regarding fluid resuscitation, the presence of pulmonary rates can be a poor marker of fluid overload, since the septic patient presents with generalized inflammation, including pulmonary capillaritis. The same consideration applies to hepatomegaly, especially in mechanically ventilated patients. These possible misinterpretations of the fluid status leading to using diuretics (especially on an early treatment stage) could be deleterious to the hemodynamic status. Other signs of hypervolemia (transthoracic echocardiographic assessment, for instance) should be evaluated, and the wariness front of diuretic use should be emphasized. In conclusion, we believe that applying the above considerations on the extensive work done by the pediatric subgroup will improve the odds of success on an early goal-directed therapy with septic pediatric patients worldwide. The authors have disclosed that they do not have any potential conflicts of interest. Heloísa Amaral Gaspar, MD, Fernanda Ejzenberg, MD, Werther B. Carvalho, PhD, Artur F. Delgado, PhD, Instituto da Crianca, Sao Paulo University, Sao Paulo, Brazil

REFERENCES

1. Dellinger RP, Levy MM, Rhodes A, et al; Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup: Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: 2012. Crit Care Med 2013; 41:580–637 2. Johnson PJ: Normal saline bolus infusion for hypoperfusion in the newborn. Neonatal Netw 2013; 32:41–45 3. Wynn JL, Wong HR: Pathophysiology and treatment of septic shock in neonates. Clin Perinatol 2010; 37:439–479 4. Gray BW, Gonzalez R, Warrier KS, et al: Characterization of central venous catheter-associated deep venous thrombosis in infants. J Pediatr Surg 2012; 47:1159–1166 5. Akech S, Ledermann H, Maitland K: Choice of fluids for resuscitation in children with severe infection and shock: Systematic review. BMJ 2010; 341:c4416 DOI: 10.1097/CCM.0b013e31828e9000

Critical Care Medicine

The author replies:

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e appreciate the insightful and thoughtful comments of Gaspar et al (1). We agree that for the next rendition of the guidelines, the committee should consider addressing advantages and disadvantages of specific access sites for central access. Of note, we did not recommend albumin as the fluid of choice for pediatric patients, rather “either crystalloids or albumin.” The author has disclosed that he does not have any potential conflicts of interest. Joseph A. Carcillo, MD, Children’s Hospital of Pittsburgh, Pittsburgh, PA; for the Surviving Sepsis Campaign Guidelines Subcommittee

REFERENCE

1. Gaspar HA, Ejzenberg F, Carvalho WB, et al: The Worth of the Guidelines: Pediatric Considerations in Severe Sepsis and Septic Shock. Crit Care Med 2013; 41:e488–e489 DOI: 10.1097CCM.0000000000000058

Meaning of the Venoarterial Carbon Dioxide Difference/Arterial-Venous Oxygen Difference Ratio To the Editor:

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n a recent issue of Critical Care Medicine, we have read with interest the article published by Monnet et al (1) investigating the ability of several markers to predict which patients will have an increase in V O2 after a fluid O2 . induced increase in D Monnet et al (1) report that the main predictors of a fluidinduced increase of V O2 was the lactate level and the ratio of the P(v-a)CO2 difference over the C(a-v)O2 . The ratio is proposed as an alternative to the respiratory quotient. We agree with them that in case of tissue hypoxia, Co2 production should be  O2 , Co2 production less reduced than V O2 ; after restoring D should increase less than V O2 . In appearance, this could justify the results of this study. However, we have some concern about this ratio. Ho et al (2) used central venous blood gases rather than mixed venous blood gases even though central and mixed venous Pco2 are probably not interchangeable. Similarly, SvO2 cannot be substituted with central venous oxygen saturation (3). The ratio variation observed in the responders was mainly due to changes in the arteriovenous Pco2 gradient with no significant change in the C(a-v)O2 . As found in this study, the Pco2 gradient in patients is mainly related to cardiac output (4). The relationship between Co2 pressure and Co2 blood content is not always linear and depends on pH and hemoglobin saturation (5); the Pco2 gradient does not only reflect Co2 production but also increases when cardiac output is reduced without any change in Co2 production (4). Selecting only the 14 responders among the 51 patients can have introduced a mathematical coupling, thus explaining the lack of significant relation in the whole group. www.ccmjournal.org

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The worth of the guidelines: pediatric considerations in severe sepsis and septic shock.

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