The
n e w e ng l a n d j o u r na l
David W. Eyre, B.M., B.Ch. University of Oxford Oxford, United Kingdom [email protected]
Mark H. Wilcox, M.D. University of Leeds Leeds, United Kingdom
A. Sarah Walker, Ph.D. University of Oxford Oxford, United Kingdom Since publication of their article, the authors report no further potential conflict of interest. 1. Curry SR, Muto CA, Schlackman JL, et al. Use of multilocus
variable number of tandem repeats analysis genotyping to determine the role of asymptomatic carriers in Clostridium difficile transmission. Clin Infect Dis 2013;57:1094-102. 2. Eyre DW, Griffiths D, Vaughan A, et al. Asymptomatic
of
m e dic i n e
Clostridium difficile colonisation and onward transmission. PLoS One 2013;8(11):e78445. 3. Walker AS, Eyre DW, Wyllie DH, et al. Relationship between bacterial strain type, host biomarkers, and mortality in Clostridium difficile infection. Clin Infect Dis 2013;56:1589-600. 4. Walker AS, Eyre DW, Wyllie DH, et al. Characterisation of Clostridium difficile hospital ward-based transmission using extensive epidemiological data and molecular typing. PLoS Med 2012;9(2):e1001172. 5. Martin J, Eyre DW, Mawer D, et al. Investigating Clostridium difficile transmission using whole genome sequencing (WGS): few cases follow direct contact with a symptomatic donor. In: Program and abstracts of the 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy, Denver, September 10–13, 2013. abstract (http://www.abstractsonline.com/Plan/ ViewAbstract.aspx?sKey=4b5f3af7-f74e-42e7-8194-6e6c4457 e565&cKey=015195b4-9fdc-489d-8993-493d9187954b&mKey =%7b7DD36E88-52C3-4FF1-A5DF-1D00766558B8%7d). DOI: 10.1056/NEJMc1313601
Long-Term Cognitive Impairment after Critical Illness To the Editor: In the study describing neurocognitive outcomes in patients in intensive care units (ICUs) reported by Pandharipande et al. (Oct. 3 issue),1 patients with Richmond Agitation– Sedation Scale (RASS) scores of −3 (movement or eye opening to voice but no eye contact) or higher were assessed daily for delirium. (Scores on the RASS range from −5 to 4, with lower scores in dicating less arousal, higher scores indicating more agitation, and O indicating an alert and calm state.) Recent data strongly suggest that sedation confounds delirium assessment, especially with the Confusion Assessment Method for the ICU (CAM-ICU), in which the presence or absence of delirium is determined on the basis of a series of queries; failure to respond to questioning or commands is considered evidence of inattention and an acute change in mental status, both contributing to the diagnosis of delirium. Patients who are awake in the ICU have a much lower prevalence of delirium than more sedated patients.2-5 The strongest evidence from sedation-interruption studies shows that as sedation decreases and RASS scores increase, the rate of delirium assessed with the CAM-ICU drops precipitously. Importantly, patients with sedationassociated “delirium” (CAM-ICU assessments that are positive during sedation but negative after wakening) and patients without delirium had similar outcomes (length of stay, duration of mechanical ventilation, discharge to home, and 1-year mortality), with both groups having much 184
better outcomes than patients with delirium that remains present when they are awake.6 This degree of confounding of delirium prevalence with sedation depth should be acknowledged and included as an identified covariate in future studies of cognitive outcomes in ICU patients. Gilles L. Fraser, Pharm.D. Richard R. Riker, M.D. Maine Medical Center [email protected]
Douglas C. Coursin, M.D. University of Wisconsin Madison, WI No potential conflict of interest relevant to this letter was reported. 1. Pandharipande PP, Girard TD, Jackson JC, et al. Long-term
cognitive impairment after critical illness. N Engl J Med 2013; 369:1306-16. 2. Riker R, Shehabi Y, Wisemandle W, Rocha M. Relationship between delirium incidence assessed with CAM-ICU and level of sedation assessed by RASS in adult ICU patients. Crit Care Med 2012;40:Suppl 12:1092. abstract. 3. Robbins T, Bruce H, Fraser G, Riker RR, Keene A. Does level of sedation confound assessment of ICU delirium with the CAM-ICU? Crit Care Med 2008;36:A18. 4. Gusmao-Flores D, Martins JCS, Amorin D, Quarantini LC. Tools for diagnosing delirium in the critically ill: is calibration needed for the less sedated patient? Intensive Care Med 2013 October 3 (Epub ahead of print). 5. Haenggi M, Blum S, Brechbuehl R, Brunello A, Jakob SM, Takala J. Effect of sedation level on the prevalence of delirium when assessed with CAM-ICU and ICDSC. Intensive Care Med 2013;39:2179-9. 6. Patel SB, Poston JT, Pohlman A, Hall JB, Kress JP. Survival in drug related versus non-drug related delirium. Am J Respir Crit Care Med 2013;187:A5237. abstract. DOI: 10.1056/NEJMc1313886
n engl j med 370;2 nejm.org january 9, 2014
The New England Journal of Medicine Downloaded from nejm.org at NYU WASHINGTON SQUARE CAMPUS on June 4, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
correspondence
To the Editor: The study by Pandharipande et al. reports a very high incidence of low cognitive performance in ICU survivors. At 3-month followup, 40% of patients had a cognitive score similar to that of patients with moderate traumatic brain injury. This was calculated by a comparison with the population age-adjusted mean cognitive score. Ten years ago, the general belief was that cardiac surgical patients also had a very high risk of cognitive decline, owing to the use of cardiopulmonary bypass.1 It has now become apparent that the problem of cognitive decline after cardiac surgery has been overestimated, in part because patients with coronary artery disease already have a lower cognitive performance than healthy controls before they undergo surgery.2 In ICU patients, defining low cognitive performance without taking the level of education, sex, and preadmission coexisting conditions into account may also result in an overestimation of the incidence of cognitive decline. Diederik Van Dijk, M.D., Ph.D. University Medical Center Utrecht, the Netherlands [email protected] No potential conflict of interest relevant to this letter was reported. 1. Newman MF, Kirchner JL, Phillips-Bute B, et al. Longitudi-
nal assessment of neurocognitive function after coronary-artery bypass surgery. N Engl J Med 2001;344:395-402. [Erratum, N Engl J Med 2001;344:1876.] 2. Selnes OA, Gottesman RF, Grega MA, Baumgartner WA, Zeger SL, McKhann GM. Cognitive and neurologic outcomes after coronary-artery bypass surgery. N Engl J Med 2012;366:250-7. DOI: 10.1056/NEJMc1313886
The authors reply: We thank Fraser et al. for their letter asserting that sedative agents “confound” delirium assessments. Haenggi et al.1 recently reported that — regardless of which delirium-monitoring instrument was used — reduced arousal led to more positive delirium assessments, which is not surprising given that inattention (whether from disease, sedatives, or both) is a pivotal symptom of delirium per the reference standard Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5).2 Without compelling and consistent data to suggest that delirium should not be diagnosed in the context of sedation, the full syndromic criteria for delirium should serve, whenever present, as a clarion call
for health care teams to improve patient safety by reducing potentially unnecessary pharmacologic contributors to brain dysfunction. Methodologically, most delirium studies assess delirium symptoms first and then consider causal factors. In a recent analysis of data from the BRAIN-ICU (Bringing to Light the Risk Factors and Incidence of Neuropsychological Dysfunction in ICU Survivors) study, we specifically examined the association between sedative-associated delirium and global cognition scores after adjusting for other contributors to delirium (e.g., sepsis, hypoxemia, and renal or hepatic failure) and found that a longer duration of sedative-associated delirium was independently associated with worse global cognition at 3- and 12-month follow-up (P = 0.002 and P = 0.04, respectively). Importantly, in our study and another study,3 delirium (including sedative-associated delirium) has been associated with an increased risk of death and cognitive impairment. The abstract by Patel et al. cited by Fraser et al. is hypothesis-generating only, because their study design could not accurately separate sedative-associated delirium from other delirium. In addition, sedative-associated delirium may be benign in some settings (e.g., elective surgery) yet dangerous in others (e.g., sepsis). If some iatrogenic delirium is benign, studies to date may have underestimated the risk of delirium by including patients with sedative-associated delirium. As a community, however, we are far from concluding that sedation-associated delirium is innocuous — a fact acknowledged in the DSM-5 and the International Classification of Diseases, 10th Revision, which includes codes for medicationinduced delirium. We agree with Van Dijk that educational level, sex, and coexisting conditions must be considered when estimating the incidence of cognitive decline after critical illness. We therefore assessed global cognition with the age-adjusted Repeatable Battery for the Assessment of Neuropsychological Status and executive function with the age-, sex-, and education-adjusted Trail Making Test, Part B. We also reported a high incidence of cognitive impairment among young patients without coexisting conditions (Fig. S2 in the Supplementary Appendix, available with the full text of our article at NEJM.org) and adjusted for age, educational level, and preexisting
n engl j med 370;2 nejm.org january 9, 2014
185
The New England Journal of Medicine Downloaded from nejm.org at NYU WASHINGTON SQUARE CAMPUS on June 4, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
The
n e w e ng l a n d j o u r na l
conditions (Charlson comorbidity index and the Framingham Stroke Risk Profile) in all regression models. Pratik P. Pandharipande, M.D., M.S.C.I. Timothy D. Girard, M.D., M.S.C.I. E. Wesley Ely, M.D., M.P.H. Vanderbilt University Medical Center Nashville, TN [email protected]
of
m e dic i n e
Since publication of their article, the authors report no further potential conflict of interest. 1. Haenggi M, Blum S, Brechbuehl R, Brunello A, Jakob SM,
Takala J. Effect of sedation level on the prevalence of delirium when assessed with CAM-ICU and ICDSC. Intensive Care Med 2013;39:2171-9. 2. Diagnostic and statistical manual of mental disorders. 5th ed. Arlington, VA: American Psychiatric Association, 2013. 3. Ely EW, Shintani A, Truman B, et al. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA 2004;291:1753-62. DOI: 10.1056/NEJMc1313886
Pancreatic Atrophy from Sorafenib To the Editor: Before concluding that sorafenib can cause diarrhea owing to pancreatic atrophy, clinicians need to know what sorafenib does to pancreatic secretion. Hescot et al. (Oct. 10 issue)1 mention that the level of steatorrhea in one patient was 7.5 g per 24 hours — a trivial level of pancreatic steatorrhea. They also note that the patient’s fecal elastase level was twice the upper limit of the normal range. These findings do not support a diagnosis of pancreatic exocrine insufficiency, since the fecal elastase level should be decreased, not increased. Finally, the traditional view is that 90% or more of pancreatic lipase secretion must be lost before symptomatic steatorrhea occurs.2 Clinicians need to know that the 20% and 35% decreases in the volume of the pancreas on volumetric computed tomography in the patients described by Hescot et al. actually represent a clinically significant loss of pancreatic lipase secretion. Stephen Sullivan, M.D. University of Victoria Victoria, BC, Canada [email protected] No potential conflict of interest relevant to this letter was reported. 1. Hescot S, Vignaux O, Goldwasser F. Pancreatic atrophy — a
new late toxic effect of sorafenib. N Engl J Med 2013;369:1475-6.
The Authors Reply: From our point of view, as mentioned in the title of our letter (“Pancreatic Atrophy — A New Late Toxic Effect of Sorafenib”), the take-home message to our colleagues is that sorafenib may induce pancreatic atrophy and not exclusively thyroid atrophy. With regard to pancreatic function, our patients did not receive sorafenib long enough after the emergence of symptoms of exocrine dysfunction for us to observe irreversible toxicity. We interrupted the treatment with sorafenib as soon as pancreatic atrophy was documented. After the interruption of treatment, the clinical symptoms, steatorrhea, and their biologic correlates resolved within 2 weeks; this confirms that pancreatic atrophy remained associated with residual active pancreatic parenchyma and that the pancreatic exocrine dysfunction was probably induced by sorafenib. Ségolène Hescot, M.D. Olivier Vignaux, M.D. François Goldwasser, M.D., Ph.D. Université Paris Descartes Paris, France [email protected]
2. DiMagno EP, Go VLW, Summerskill WHJ. Relations between
Since publication of their letter, the authors report no further potential conflict of interest.
DOI: 10.1056/NEJMc1313753
DOI: 10.1056/NEJMc1313753
pancreatic enzyme outputs and malabsorption in severe pancreatic insufficiency. N Engl J Med 1973;288:813-5.
Meta-Analysis and the Surgeon General’s Report on Smoking and Health To the Editor: Fifty years ago, on January 11, Luther L. Terry. That report made substantial use 1964, the landmark report on smoking and of a meta-analysis performed by statistician Wilhealth1 was made public by U.S. Surgeon General liam G. Cochran,2,3 who was a professor of sta186
n engl j med 370;2 nejm.org january 9, 2014
The New England Journal of Medicine Downloaded from nejm.org at NYU WASHINGTON SQUARE CAMPUS on June 4, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
n e w e ng l a n d j o u r na l
David W. Eyre, B.M., B.Ch. University of Oxford Oxford, United Kingdom [email protected]
Mark H. Wilcox, M.D. University of Leeds Leeds, United Kingdom
A. Sarah Walker, Ph.D. University of Oxford Oxford, United Kingdom Since publication of their article, the authors report no further potential conflict of interest. 1. Curry SR, Muto CA, Schlackman JL, et al. Use of multilocus
variable number of tandem repeats analysis genotyping to determine the role of asymptomatic carriers in Clostridium difficile transmission. Clin Infect Dis 2013;57:1094-102. 2. Eyre DW, Griffiths D, Vaughan A, et al. Asymptomatic
of
m e dic i n e
Clostridium difficile colonisation and onward transmission. PLoS One 2013;8(11):e78445. 3. Walker AS, Eyre DW, Wyllie DH, et al. Relationship between bacterial strain type, host biomarkers, and mortality in Clostridium difficile infection. Clin Infect Dis 2013;56:1589-600. 4. Walker AS, Eyre DW, Wyllie DH, et al. Characterisation of Clostridium difficile hospital ward-based transmission using extensive epidemiological data and molecular typing. PLoS Med 2012;9(2):e1001172. 5. Martin J, Eyre DW, Mawer D, et al. Investigating Clostridium difficile transmission using whole genome sequencing (WGS): few cases follow direct contact with a symptomatic donor. In: Program and abstracts of the 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy, Denver, September 10–13, 2013. abstract (http://www.abstractsonline.com/Plan/ ViewAbstract.aspx?sKey=4b5f3af7-f74e-42e7-8194-6e6c4457 e565&cKey=015195b4-9fdc-489d-8993-493d9187954b&mKey =%7b7DD36E88-52C3-4FF1-A5DF-1D00766558B8%7d). DOI: 10.1056/NEJMc1313601
Long-Term Cognitive Impairment after Critical Illness To the Editor: In the study describing neurocognitive outcomes in patients in intensive care units (ICUs) reported by Pandharipande et al. (Oct. 3 issue),1 patients with Richmond Agitation– Sedation Scale (RASS) scores of −3 (movement or eye opening to voice but no eye contact) or higher were assessed daily for delirium. (Scores on the RASS range from −5 to 4, with lower scores in dicating less arousal, higher scores indicating more agitation, and O indicating an alert and calm state.) Recent data strongly suggest that sedation confounds delirium assessment, especially with the Confusion Assessment Method for the ICU (CAM-ICU), in which the presence or absence of delirium is determined on the basis of a series of queries; failure to respond to questioning or commands is considered evidence of inattention and an acute change in mental status, both contributing to the diagnosis of delirium. Patients who are awake in the ICU have a much lower prevalence of delirium than more sedated patients.2-5 The strongest evidence from sedation-interruption studies shows that as sedation decreases and RASS scores increase, the rate of delirium assessed with the CAM-ICU drops precipitously. Importantly, patients with sedationassociated “delirium” (CAM-ICU assessments that are positive during sedation but negative after wakening) and patients without delirium had similar outcomes (length of stay, duration of mechanical ventilation, discharge to home, and 1-year mortality), with both groups having much 184
better outcomes than patients with delirium that remains present when they are awake.6 This degree of confounding of delirium prevalence with sedation depth should be acknowledged and included as an identified covariate in future studies of cognitive outcomes in ICU patients. Gilles L. Fraser, Pharm.D. Richard R. Riker, M.D. Maine Medical Center [email protected]
Douglas C. Coursin, M.D. University of Wisconsin Madison, WI No potential conflict of interest relevant to this letter was reported. 1. Pandharipande PP, Girard TD, Jackson JC, et al. Long-term
cognitive impairment after critical illness. N Engl J Med 2013; 369:1306-16. 2. Riker R, Shehabi Y, Wisemandle W, Rocha M. Relationship between delirium incidence assessed with CAM-ICU and level of sedation assessed by RASS in adult ICU patients. Crit Care Med 2012;40:Suppl 12:1092. abstract. 3. Robbins T, Bruce H, Fraser G, Riker RR, Keene A. Does level of sedation confound assessment of ICU delirium with the CAM-ICU? Crit Care Med 2008;36:A18. 4. Gusmao-Flores D, Martins JCS, Amorin D, Quarantini LC. Tools for diagnosing delirium in the critically ill: is calibration needed for the less sedated patient? Intensive Care Med 2013 October 3 (Epub ahead of print). 5. Haenggi M, Blum S, Brechbuehl R, Brunello A, Jakob SM, Takala J. Effect of sedation level on the prevalence of delirium when assessed with CAM-ICU and ICDSC. Intensive Care Med 2013;39:2179-9. 6. Patel SB, Poston JT, Pohlman A, Hall JB, Kress JP. Survival in drug related versus non-drug related delirium. Am J Respir Crit Care Med 2013;187:A5237. abstract. DOI: 10.1056/NEJMc1313886
n engl j med 370;2 nejm.org january 9, 2014
The New England Journal of Medicine Downloaded from nejm.org at NYU WASHINGTON SQUARE CAMPUS on June 4, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
correspondence
To the Editor: The study by Pandharipande et al. reports a very high incidence of low cognitive performance in ICU survivors. At 3-month followup, 40% of patients had a cognitive score similar to that of patients with moderate traumatic brain injury. This was calculated by a comparison with the population age-adjusted mean cognitive score. Ten years ago, the general belief was that cardiac surgical patients also had a very high risk of cognitive decline, owing to the use of cardiopulmonary bypass.1 It has now become apparent that the problem of cognitive decline after cardiac surgery has been overestimated, in part because patients with coronary artery disease already have a lower cognitive performance than healthy controls before they undergo surgery.2 In ICU patients, defining low cognitive performance without taking the level of education, sex, and preadmission coexisting conditions into account may also result in an overestimation of the incidence of cognitive decline. Diederik Van Dijk, M.D., Ph.D. University Medical Center Utrecht, the Netherlands [email protected] No potential conflict of interest relevant to this letter was reported. 1. Newman MF, Kirchner JL, Phillips-Bute B, et al. Longitudi-
nal assessment of neurocognitive function after coronary-artery bypass surgery. N Engl J Med 2001;344:395-402. [Erratum, N Engl J Med 2001;344:1876.] 2. Selnes OA, Gottesman RF, Grega MA, Baumgartner WA, Zeger SL, McKhann GM. Cognitive and neurologic outcomes after coronary-artery bypass surgery. N Engl J Med 2012;366:250-7. DOI: 10.1056/NEJMc1313886
The authors reply: We thank Fraser et al. for their letter asserting that sedative agents “confound” delirium assessments. Haenggi et al.1 recently reported that — regardless of which delirium-monitoring instrument was used — reduced arousal led to more positive delirium assessments, which is not surprising given that inattention (whether from disease, sedatives, or both) is a pivotal symptom of delirium per the reference standard Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5).2 Without compelling and consistent data to suggest that delirium should not be diagnosed in the context of sedation, the full syndromic criteria for delirium should serve, whenever present, as a clarion call
for health care teams to improve patient safety by reducing potentially unnecessary pharmacologic contributors to brain dysfunction. Methodologically, most delirium studies assess delirium symptoms first and then consider causal factors. In a recent analysis of data from the BRAIN-ICU (Bringing to Light the Risk Factors and Incidence of Neuropsychological Dysfunction in ICU Survivors) study, we specifically examined the association between sedative-associated delirium and global cognition scores after adjusting for other contributors to delirium (e.g., sepsis, hypoxemia, and renal or hepatic failure) and found that a longer duration of sedative-associated delirium was independently associated with worse global cognition at 3- and 12-month follow-up (P = 0.002 and P = 0.04, respectively). Importantly, in our study and another study,3 delirium (including sedative-associated delirium) has been associated with an increased risk of death and cognitive impairment. The abstract by Patel et al. cited by Fraser et al. is hypothesis-generating only, because their study design could not accurately separate sedative-associated delirium from other delirium. In addition, sedative-associated delirium may be benign in some settings (e.g., elective surgery) yet dangerous in others (e.g., sepsis). If some iatrogenic delirium is benign, studies to date may have underestimated the risk of delirium by including patients with sedative-associated delirium. As a community, however, we are far from concluding that sedation-associated delirium is innocuous — a fact acknowledged in the DSM-5 and the International Classification of Diseases, 10th Revision, which includes codes for medicationinduced delirium. We agree with Van Dijk that educational level, sex, and coexisting conditions must be considered when estimating the incidence of cognitive decline after critical illness. We therefore assessed global cognition with the age-adjusted Repeatable Battery for the Assessment of Neuropsychological Status and executive function with the age-, sex-, and education-adjusted Trail Making Test, Part B. We also reported a high incidence of cognitive impairment among young patients without coexisting conditions (Fig. S2 in the Supplementary Appendix, available with the full text of our article at NEJM.org) and adjusted for age, educational level, and preexisting
n engl j med 370;2 nejm.org january 9, 2014
185
The New England Journal of Medicine Downloaded from nejm.org at NYU WASHINGTON SQUARE CAMPUS on June 4, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
The
n e w e ng l a n d j o u r na l
conditions (Charlson comorbidity index and the Framingham Stroke Risk Profile) in all regression models. Pratik P. Pandharipande, M.D., M.S.C.I. Timothy D. Girard, M.D., M.S.C.I. E. Wesley Ely, M.D., M.P.H. Vanderbilt University Medical Center Nashville, TN [email protected]
of
m e dic i n e
Since publication of their article, the authors report no further potential conflict of interest. 1. Haenggi M, Blum S, Brechbuehl R, Brunello A, Jakob SM,
Takala J. Effect of sedation level on the prevalence of delirium when assessed with CAM-ICU and ICDSC. Intensive Care Med 2013;39:2171-9. 2. Diagnostic and statistical manual of mental disorders. 5th ed. Arlington, VA: American Psychiatric Association, 2013. 3. Ely EW, Shintani A, Truman B, et al. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA 2004;291:1753-62. DOI: 10.1056/NEJMc1313886
Pancreatic Atrophy from Sorafenib To the Editor: Before concluding that sorafenib can cause diarrhea owing to pancreatic atrophy, clinicians need to know what sorafenib does to pancreatic secretion. Hescot et al. (Oct. 10 issue)1 mention that the level of steatorrhea in one patient was 7.5 g per 24 hours — a trivial level of pancreatic steatorrhea. They also note that the patient’s fecal elastase level was twice the upper limit of the normal range. These findings do not support a diagnosis of pancreatic exocrine insufficiency, since the fecal elastase level should be decreased, not increased. Finally, the traditional view is that 90% or more of pancreatic lipase secretion must be lost before symptomatic steatorrhea occurs.2 Clinicians need to know that the 20% and 35% decreases in the volume of the pancreas on volumetric computed tomography in the patients described by Hescot et al. actually represent a clinically significant loss of pancreatic lipase secretion. Stephen Sullivan, M.D. University of Victoria Victoria, BC, Canada [email protected] No potential conflict of interest relevant to this letter was reported. 1. Hescot S, Vignaux O, Goldwasser F. Pancreatic atrophy — a
new late toxic effect of sorafenib. N Engl J Med 2013;369:1475-6.
The Authors Reply: From our point of view, as mentioned in the title of our letter (“Pancreatic Atrophy — A New Late Toxic Effect of Sorafenib”), the take-home message to our colleagues is that sorafenib may induce pancreatic atrophy and not exclusively thyroid atrophy. With regard to pancreatic function, our patients did not receive sorafenib long enough after the emergence of symptoms of exocrine dysfunction for us to observe irreversible toxicity. We interrupted the treatment with sorafenib as soon as pancreatic atrophy was documented. After the interruption of treatment, the clinical symptoms, steatorrhea, and their biologic correlates resolved within 2 weeks; this confirms that pancreatic atrophy remained associated with residual active pancreatic parenchyma and that the pancreatic exocrine dysfunction was probably induced by sorafenib. Ségolène Hescot, M.D. Olivier Vignaux, M.D. François Goldwasser, M.D., Ph.D. Université Paris Descartes Paris, France [email protected]
2. DiMagno EP, Go VLW, Summerskill WHJ. Relations between
Since publication of their letter, the authors report no further potential conflict of interest.
DOI: 10.1056/NEJMc1313753
DOI: 10.1056/NEJMc1313753
pancreatic enzyme outputs and malabsorption in severe pancreatic insufficiency. N Engl J Med 1973;288:813-5.
Meta-Analysis and the Surgeon General’s Report on Smoking and Health To the Editor: Fifty years ago, on January 11, Luther L. Terry. That report made substantial use 1964, the landmark report on smoking and of a meta-analysis performed by statistician Wilhealth1 was made public by U.S. Surgeon General liam G. Cochran,2,3 who was a professor of sta186
n engl j med 370;2 nejm.org january 9, 2014
The New England Journal of Medicine Downloaded from nejm.org at NYU WASHINGTON SQUARE CAMPUS on June 4, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
