Online Letters to the Editor

Dr. Singhi received support for the development of educational presentations (for preparing educational material for postgraduate course in Nutrition by Bioquest Solutions). Dr. Kumar has disclosed that he does not have any potential conflicts of interest. Ramesh Kumar, MD, DM, Department of Pediatrics, Women and Children Hospital, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India; Sunit C. Singhi, MD, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India

obese. Since the data were collected biennially, it would be very interesting to determine if the premorbid weight used in this study was substantially different from the weight determined immediately prior to this value. Since weight change in healthy populations is fairly stable over a 2-year period and percentage weight loss is a very good risk factor for the presence of underlying disease and clinical outcome (3–5), this could be an additional distinguishing factor among the various body mass index categories. Dr. Bistrian consulted for Nestle. Bruce Ryan Bistrian, MD, PhD, MPH, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA

REFERENCES

1. Freeman WD: Cerebral Perfusion Pressure Versus Intracranial Pressure–Driven Therapy on Outcomes. Crit Care Med 2015; 43:e29 2. Kumar R, Singhi S, Singhi P, et al: Randomized controlled trial comparing cerebral perfusion pressure-targeted therapy versus intracranial pressure-targeted therapy for raised intracranial pressure due to acute CNS infections in children. Crit Care Med 2014; 42:1775–1787 3. Prabhakaran P, Reddy AT, Oakes WJ, et al: A pilot trial comparing cerebral perfusion pressure-targeted therapy to intracranial pressure-targeted therapy in children with severe traumatic brain injury. J Neurosurg 2004; 100:454–459 4. Shetty R, Singhi S, Singhi P, et al: Cerebral perfusion pressure– targeted approach in children with central nervous system infections and raised intracranial pressure: Is it feasible? J Child Neurol 2008; 23:192–198 5. Lambertz M, Kraft M, Boenick U: [Evaluation of possible measuring errors from overlaying pressure components in invasive blood pressure recording with external transducers]. Biomed Tech (Berl) 1997; 42:249–255 6. Francke A, Wachsmuth H: [How accurate is invasive blood pressure determination with fluid-filled pressure line systems?]. Anaesthesiol Reanim 2000; 25:46–54 DOI: 10.1097/CCM.0000000000000734

Effect of Prior Weight Loss on Mortality in the Critically Ill Obese To the Editor:

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he convincing report that obesity and severe obesity determined prior to hospitalization are associated with improved mortality but greater financial cost (1) is an important advance in our knowledge of the implications of obesity for clinical outcome. The potential mechanisms posited by the authors for this relationship (a real protective effect of obesity, a differential inflammatory response in the obese, greater nutritional reserve, and distinguishing clinical presentations and treatments) (1) are also reasonable possibilities for the noted improvements in mortality. These results are particularly noteworthy in light of the recent finding that the critically ill obese experience a modest delay in the initiation of nutritional treatment (2), which, however, is not likely to have a meaningful impact on outcome given the substantial increase in lean tissue and caloric reserve in the

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REFERENCES

1. Prescott HC, Chang VW, O’Brien JM Jr, et al: Obesity and 1-Year Outcomes in Older Americans With Severe Sepsis. Crit Care Med 2014; 42:1766–1774 2. Borel AL, Schwebel C, Planquette B, et al: Initiation of nutritional support is delayed in critically ill obese patients: A multicenter cohort study. Am J Clin Nutr 2014; 100:859–866 3. Parekh NR, Steiger E: Percentage of weight loss as a predictor of surgical risk: From the time of Hiram Studley to today. Nutr Clin Pract 2004; 19:471–476 4. Sungurtekin H, Sungurtekin U, Oner O, et al: Nutrition assessment in critically ill patients. Nutr Clin Pract 2008; 23:635–641 5. Windsor JA, Hill GL: Weight loss with physiologic impairment. A basic indicator of surgical risk. Ann Surg 1988; 207:290–296 DOI: 10.1097/CCM.0000000000000648

The authors reply:

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e appreciate the thoughtful comments by Dr. Bistrian (1). Indeed, weight trajectory has been identified as an important predictor of mortality (2, 3), and the biennial Health & Retirement Study (HRS) surveys allow us to calculate weight trajectories for our cohort. Of the 1,404 subjects in our study, 1,052 (74.9%) had weight assessed during each of the two HRS surveys preceding severe sepsis hospitalization. Of these, 401 (38.1%) had greater than or equal to 3% weight loss between surveys, 276 (26.2%) had greater than or equal to 3% weight gain, and 375 (35.6%) had stable weight trajectories (< 3% absolute change in weight). In its strongest form, some argue that the apparent effects of weight are really confounded by weight change, that is, that the apparent increased mortality of normal weight patients relative to patients with obesity is because the “normal weight” patients in fact contain many recently obese patients who had developed severe illness leading to weight loss. To test this hypothesis regarding 1-year mortality in patients hospitalized with severe sepsis, we added percentile weight change as a predictor of our logistic regression, as well as an interaction term between percentile weight change and body mass index (BMI) category (3). We then calculated adjusted probabilities of 1-year mortality by BMI category from this regression; we also calculated probabilities of 1-year mortality by BMI category at given percentile changes in weight. In Table 1, we show adjusted probability of 1-year mortality by BMI category from the January 2015 • Volume 43 • Number 1

Online Letters to the Editor

Table 1. Adjusted Probability of Mortality (Mean, 95% CI) at 1 Year After Severe Sepsis Hospitalization, by Body Mass Index Category Original Analysis (n = 1,404) All Weight Trajectories (%)

Updated Analysis (n = 1,052) All Weight Trajectories (%)

Stable Weight Trajectory (%)

Normal

61.7 (57.6–65.7)

59.2 (54.1–64.4)

59.1 (53.7–64.3

Overweight

53.3 (48.6–58.0)

54.9 (49.2–60.5)

54.3 (48.5–60.1)

Obese

50.6 (43.5–57.7)

52.0 (42.8–61.2)

52.7 (44.1–61.4)

Severely obese

45.8 (35.4–56.4)

40.6 (28.4–52.8)

41.3 (29.3–53.2)

Bolded values are significantly different than normal body mass index category, p < 0.05.

initial analysis of 1,404 subjects (left column) (4), the adjusted probability of 1-year mortality by BMI category in all patients with two presepsis weight recordings (middle column), and adjusted mortality of patients by BMI category at 0% change in weight between the two preceding surveys (right column). Our results are consistent with our initial analysis and not statistically distinguishable from the original report. Reduced mortality with greater BMI categories persists in patients with stable weight trajectories (right column), as well as in patients with declining and rising weight trajectories, respectively (data not shown). Overall, we conclude that the association of BMI with improved mortality after severe sepsis persists after ­considering weight trajectory. We do note, of course, that in this smaller population, the differences between BMI categories are no longer statistically significant. This is a result of lack of precision in the estimates resulting from the smaller sample size not from any change in the best-estimated difference in effects between the groups in this smaller population. Even within this nationally representative, decade-long longitudinal survey, the study population is too small to define the impact of weight trajectory on mortality after severe sepsis to rule in or rule out clinically meaningful effect sizes precisely. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the US government. Supported, in part, by grants T32 HL007749 from the National Institutes of Health (Dr. Prescott) Dr. Prescott and her institution received grant support from a NIH T32 training grant and Dr. Iwashyna received support for article research from the NIH and disclosed government work. His institution received grant support (IIR 11–109) from the NIH/Department of Veterans Affairs HSR&D (Dr. Iwashyna does a lot of work in sepsis research). Hallie C. Prescott, MD, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI; Theodore J. Iwashyna, MD, PhD, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, VA Center for Clinical Management Research, HSR&D Center for Excellence, Ann Arbor, MI, and Institute for Social Research, Ann Arbor, MI

REFERENCES

1. Bistrian BR: Effect of Prior Weight Loss on Mortality in the Critically Ill Obese? Crit Care Med 2015; 43:e30

Critical Care Medicine

2. Zheng H, Tumin D, Qian Z: Obesity and mortality risk: New findings from body mass index trajectories. Am J Epidemiol 2013; 178:1591–1599 3. Zajacova A, Ailshire J: Body mass trajectories and mortality among older adults: A joint growth mixture-discrete-time survival analysis. Gerontologist 2014; 54:221–231 4. Prescott HC, Chang VW, O’Brien JM Jr, et al: Obesity and 1-year outcomes in older Americans with severe sepsis. Crit Care Med 2014; 42:1766–1774 DOI: 10.1097/CCM.0000000000000701

Angiogenic Factors as Promising Therapeutic Targets in Sepsis: Where Are We Now? To the Editor:

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xperimental and clinical evidences indicate that sepsis is associated with significant imbalance of circulating angiogenic factors, most notable with marked increase of angiopoietin-2 and vascular endothelial growth factor (VEGF). The high concentration of angiopoietin-2 and VEGF promotes angiogenesis and inflammation with vascular hypermeability and is associated with worse outcome in sepsis (1). These findings raise the possibility that excess angiogenic factors critically affect the cardiovascular homeostasis during sepsis. For these reasons, several strategies targeting angiopoietin-2/VEGF and their receptors are being explored in preclinical sepsis models. In a recent issue of Critical Care Medicine, Stiehl et al (2) gave the first demonstration of benefit for an RNA interference (RNAi)-based angiopoietin-2-targeting strategy in a clinically relevant model of polymicrobial sepsis. Given the proof that small interfering RNAs can be delivered to human organ and therein modulate gene expression safely and effectively (3), the study by Stiehl et al (2) may provide a major advance in sepsis research and holds promise for translation. However, many important questions still remain in using angiogenic factors as therapeutic targets in sepsis. Consistent with the induction of angiopoietin-2 messenger RNA in lungs reported recently, Stiehl et al (2) confirmed that pulmonary endothelium is indeed an important source of angiopoietin-2 in sepsis using isolated endothelial cells from septic murine lungs. Despite numerous studies that have dealt with angiopoietin-2 function www.ccmjournal.org

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