Letters
Cause of an Elevated Lactate Level To the Editor An article in the Diagnostic Test Interpretation series discussed elevated lactate levels in a non–critically ill patient.1 We wish to underscore the importance of considering infection as a cause of lactic acidosis early in the clinical course of similar patients. Infection is one of the leading causes of death in nonHodgkin lymphoma2; patients with lymphoma can become immunocompromised as a consequence of the underlying cancer or secondary to myeloablative therapies. Although this patient was not currently neutropenic, his absolute lymphocyte count of 200/μL was very low. A history of advanced, refractory lymphoma and signs of immune suppression should increase clinical suspicion for infection. At presentation, a diagnosis of severe sepsis would not be unreasonable in this patient because he demonstrated multiple clinical criteria (tachycardia, leukopenia), possible tissue hypoperfusion (hyperlactatemia), and a presumed abdominal source. The absence of other markers of organ dysfunction was heartening but not inconsistent with early sepsis. Fever is an insensitive marker of infection because it may be absent in nearly half of patients with sepsis at presentation.3 Although hyperlactatemia in sepsis can have multiple causes, lactate elevations correlate with poorer outcomes; cryptic shock, a syndrome of hyperlactatemia with lactate levels greater than 4.0 mmol/L in the absence of hypotension, is associated with in-hospital mortality rates approaching 30%, similar to septic shock.4 This patient originally met diagnostic criteria for cryptic shock. One additional detail deserves mention. Although the patient initially received fluid resuscitation given concern for hypovolemia and sepsis, this therapy is insufficient for the latter diagnosis. In a study of patients with septic shock, every hour of delay in prescribing antibiotics within the first 6 hours was associated with an increased mortality rate of 7.6%.5 Given the considerable risk of an occult infection in patients such as the one described, physicians should have a low threshold for initiating empirical broad-spectrum antibiotic coverage in addition to appropriate supportive care. For the purposes of their case discussion, the authors explained why infection was unlikely (although the stated absence of “significant leukocytosis” is not reassuring in this context). However, clinicians must remain wary of missing cases of severe sepsis in high-risk patients, especially during the proximal phases of care. As the authors noted, type B lactic acidosis is a diagnosis of exclusion, and empirical treatment of other more dangerous causes of lactic acidosis should not be deferred until this diagnosis is made. Kai E. Swenson, AB Charles R. Wira, MD Author Affiliations: Department of Emergency Medicine, Yale School of Medicine, New Haven, Connecticut. Corresponding Author: Kai E. Swenson, AB, Department of Emergency Medicine, Yale School of Medicine, 464 Congress Ave, New Haven, CT 06511 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
1. Chen M, Kim TY, Pessegueiro AM. Elevated lactate levels in a non–critically ill patient. JAMA. 2015;313(8):849-850. 2. Rovira J, Valera A, Colomo L, et al. Prognosis of patients with diffuse large B cell lymphoma not reaching complete response or relapsing after frontline chemotherapy or immunochemotherapy. Ann Hematol. 2015;94(5):803-812. 3. Kaukonen KM, Bailey M, Pilcher D, Cooper DJ, Bellomo R. Systemic inflammatory response syndrome criteria in defining severe sepsis. N Engl J Med. 2015;372(17):1629-1638. 4. Levy MM, Dellinger RP, Townsend SR, et al. The Surviving Sepsis Campaign: results of an international guideline-based performance improvement program targeting severe sepsis. Intensive Care Med. 2010;36(2):222-231. 5. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006;34(6):1589-1596.
In Reply We agree that sepsis is an important consideration in the initial presentation of a patient with an elevated lactate level, especially in an immunocompromised patient. Delaying treatment for sepsis can have devastating consequences and we appreciate Mr Swenson and Dr Wira putting this aspect into perspective. Even though antibiotics were not administered to this particular patient, we agree that type B lactic acidosis is a diagnosis of exclusion and that diagnostic tests and therapies for other life-threatening etiologies of lactic acidosis, such as antibiotics for possible sepsis, should not be withheld while a diagnosis is being made. Given the aim and scope of the Diagnostic Test Interpretation series, the discussion was focused predominantly on the differential for a persistently elevated lactate level in a patient who was not critically ill to highlight the various possible interpretations and limitations of this diagnostic test. Meng Chen, MD Tiffany Y. Kim, MD Antonio M. Pessegueiro, MD Author Affiliations: David Geffen School of Medicine, University of California, Los Angeles. Corresponding Author: Antonio M. Pessegueiro, MD, Department of Medicine, David Geffen School of Medicine, University of California, 757 Westwood Plaza, Los Angeles, CA 90095 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
Clinician Understanding of Cholesterol Treatment Guidelines To the Editor Dr Ganda’s Viewpoint1 focused on the similarities and differences among 4 major international cholesterol treatment guidelines. The review highlighted the complex nature of clinical practice guidelines and the challenges faced by clinicians in their interpretation. Physicians are often faced with the difficulty of reconciling conflicting information and managing conclusions from experts whose viewpoints may be nuanced by conflicts of interest.2 Given that 1 in 4 US adults takes cholesterol-lowering drugs, including more than 40% of adults aged 60 years or older,3 we were concerned when Ganda presented ezetimibe as a forthcoming treatment option for cholesterol lowering. The pre-
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(Reprinted) JAMA June 16, 2015 Volume 313, Number 23
Copyright 2015 American Medical Association. All rights reserved.
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2381
Letters
liminary results of the IMPROVE-IT trial were first presented at the American Heart Association’s scientific sessions in November 2014. As of this writing, the results have not yet appeared in a peer-reviewed publication. Therefore, it may not have been suitable to incorporate the results of this study in a review article, given the broad audience, the potential for rapid uptake, and the resulting farreaching treatment implications. Readers may assume the results are well established and have been appropriately critiqued. In fact, the initial results of the IMPROVE-IT trial are already being referenced in direct-to-physician educational mailings. We think it ought to have been made clear that a publication of the trial results was not yet available and that the results apply to a select secondary prevention population in patients co-treated with statins presenting with acute coronary syndrome. We are concerned about the risks of disseminating the findings prior to the due process of expert peer scrutiny.
hypothesis. Contrary to the data in clinical trials, a significant proportion of patients taking statin therapy are unable to intensify the statin dose to meet the current recommendations for high-risk patients.3 My Viewpoint addressed the clinical dilemma in such patients and presented the possibility of an alternative approach of combining ezetimibe with the highest tolerated statin dose. The full publication of the IMPROVE-IT trial may provide insight into this approach. Om P. Ganda, MD Author Affiliation: Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts. Corresponding Author: Om P. Ganda, MD, Joslin Diabetes Center, Harvard Medical School, 1 Joslin Pl, Boston, MA 02215 ([email protected]). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. IMPROVE-IT Study Team. Cholesterol-lowering drug with different action adds to statin’s reduction of cardiovascular risk. Abstract presented at: American Heart Association Scientific Sessions; November 15-19, 2014; Chicago, IL. Abstract LBCT.02.
Todd C. Lee, MD, MPH Emily G. McDonald, MD Author Affiliations: Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada. Corresponding Author: Emily G. McDonald, MD, Department of Medicine, McGill University Health Centre, Royal Victoria Hospital, 1001 Decarie Blvd, Montreal, QC H4A 3J1, Canada ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Ganda OP. Deciphering cholesterol treatment guidelines: a clinician’s perspective. JAMA. 2015;313(10):1009-1010.
2. Improved Reduction of Outcomes: Vytorin Efficacy International Trial: a multicenter, double-blind, randomized study to establish the clinical benefit and safety of Vytorin (ezetimibe/simvastatin tablet) vs simvastatin monotherapy in high-risk subjects presenting with acute coronary syndrome. http://my.americanheart.org/idc/groups/ahamah-public/@wcm/@sop/@scon /documents/downloadable/ucm_469669.pdf. Accessed March 10, 2015. 3. Stroes ES, Thompson PD, Corsini A, et al; European Atherosclerosis Society Consensus Panel. Statin-associated muscle symptoms: impact on statin therapy: European Atherosclerosis Society Consensus Panel statement on assessment, aetiology and management. Eur Heart J. 2015;36(17):1012-1022.
2. Graham R, Mancher M, Wolman DM, Greenfield S, Steinberg E. Clinical Practice Guidelines We Can Trust. Washington, DC: National Academies Press; 2011. 3. Gu Q, Paulose-Ram R, Burt VL, Kit BK. Prescription cholesterol-lowering medication use in adults aged 40 and over: United States, 2003-2012. December 2014. http://www.cdc.gov/nchs/data/databriefs/db177.pdf. Accessed April 30, 2015.
In Reply Drs Lee and McDonald reaffirm the need to provide a perspective for clinicians faced with the challenges in the interpretation of divergent guidelines in an important area of cholesterol management. In this context, they bring up an important point regarding the potential implications of commenting on the results of a clinical trial that have been presented in a scientific meeting but have only been published in an abstract form. I agree that the final interpretation of any clinical trial must await full peer review. The results of the IMPROVE-IT trial have been disseminated widely in both professional and lay media since their presentation at the American Heart Association’s annual scientific sessions in November 2014.1 A more accessible reference to the IMPROVE-IT trial results2 is now included in the online version of my Viewpoint. Ezetimibe is the first nonstatin drug that has been shown to have modest but significant benefits when combined with a statin in high-risk patients, thus supporting the cholesterol
2382
Guidelines for Letters Letters discussing a recent JAMA article should be submitted within 4 weeks of the article's publication in print. Letters received after 4 weeks will rarely be considered. Letters should not exceed 400 words of text and 5 references and may have no more than 3 authors. Letters reporting original research should not exceed 600 words of text and 6 references and may have no more than 7 authors. They may include up to 2 tables or figures but online supplementary material is not allowed. All letters should include a word count. Letters must not duplicate other material published or submitted for publication. Letters not meeting these specifications are generally not considered. Letters being considered for publication ordinarily will be sent to the authors of the JAMA article, who will be given the opportunity to reply. Letters will be published at the discretion of the editors and are subject to abridgement and editing. Further instructions can be found at http://jama.com/public /InstructionsForAuthors.aspx. A signed statement for authorship criteria and responsibility, financial disclosure, copyright transfer, and acknowledgment and the ICMJE Form for Disclosure of Potential Conflicts of Interest are required before publication. Letters should be submitted via the JAMA online submission and review system at http: //manuscripts.jama.com. For technical assistance, please contact [email protected]. Section Editor: Jody W. Zylke, MD, Deputy Editor.
JAMA June 16, 2015 Volume 313, Number 23 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Carleton University User on 06/21/2015
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Cause of an Elevated Lactate Level To the Editor An article in the Diagnostic Test Interpretation series discussed elevated lactate levels in a non–critically ill patient.1 We wish to underscore the importance of considering infection as a cause of lactic acidosis early in the clinical course of similar patients. Infection is one of the leading causes of death in nonHodgkin lymphoma2; patients with lymphoma can become immunocompromised as a consequence of the underlying cancer or secondary to myeloablative therapies. Although this patient was not currently neutropenic, his absolute lymphocyte count of 200/μL was very low. A history of advanced, refractory lymphoma and signs of immune suppression should increase clinical suspicion for infection. At presentation, a diagnosis of severe sepsis would not be unreasonable in this patient because he demonstrated multiple clinical criteria (tachycardia, leukopenia), possible tissue hypoperfusion (hyperlactatemia), and a presumed abdominal source. The absence of other markers of organ dysfunction was heartening but not inconsistent with early sepsis. Fever is an insensitive marker of infection because it may be absent in nearly half of patients with sepsis at presentation.3 Although hyperlactatemia in sepsis can have multiple causes, lactate elevations correlate with poorer outcomes; cryptic shock, a syndrome of hyperlactatemia with lactate levels greater than 4.0 mmol/L in the absence of hypotension, is associated with in-hospital mortality rates approaching 30%, similar to septic shock.4 This patient originally met diagnostic criteria for cryptic shock. One additional detail deserves mention. Although the patient initially received fluid resuscitation given concern for hypovolemia and sepsis, this therapy is insufficient for the latter diagnosis. In a study of patients with septic shock, every hour of delay in prescribing antibiotics within the first 6 hours was associated with an increased mortality rate of 7.6%.5 Given the considerable risk of an occult infection in patients such as the one described, physicians should have a low threshold for initiating empirical broad-spectrum antibiotic coverage in addition to appropriate supportive care. For the purposes of their case discussion, the authors explained why infection was unlikely (although the stated absence of “significant leukocytosis” is not reassuring in this context). However, clinicians must remain wary of missing cases of severe sepsis in high-risk patients, especially during the proximal phases of care. As the authors noted, type B lactic acidosis is a diagnosis of exclusion, and empirical treatment of other more dangerous causes of lactic acidosis should not be deferred until this diagnosis is made. Kai E. Swenson, AB Charles R. Wira, MD Author Affiliations: Department of Emergency Medicine, Yale School of Medicine, New Haven, Connecticut. Corresponding Author: Kai E. Swenson, AB, Department of Emergency Medicine, Yale School of Medicine, 464 Congress Ave, New Haven, CT 06511 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
1. Chen M, Kim TY, Pessegueiro AM. Elevated lactate levels in a non–critically ill patient. JAMA. 2015;313(8):849-850. 2. Rovira J, Valera A, Colomo L, et al. Prognosis of patients with diffuse large B cell lymphoma not reaching complete response or relapsing after frontline chemotherapy or immunochemotherapy. Ann Hematol. 2015;94(5):803-812. 3. Kaukonen KM, Bailey M, Pilcher D, Cooper DJ, Bellomo R. Systemic inflammatory response syndrome criteria in defining severe sepsis. N Engl J Med. 2015;372(17):1629-1638. 4. Levy MM, Dellinger RP, Townsend SR, et al. The Surviving Sepsis Campaign: results of an international guideline-based performance improvement program targeting severe sepsis. Intensive Care Med. 2010;36(2):222-231. 5. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006;34(6):1589-1596.
In Reply We agree that sepsis is an important consideration in the initial presentation of a patient with an elevated lactate level, especially in an immunocompromised patient. Delaying treatment for sepsis can have devastating consequences and we appreciate Mr Swenson and Dr Wira putting this aspect into perspective. Even though antibiotics were not administered to this particular patient, we agree that type B lactic acidosis is a diagnosis of exclusion and that diagnostic tests and therapies for other life-threatening etiologies of lactic acidosis, such as antibiotics for possible sepsis, should not be withheld while a diagnosis is being made. Given the aim and scope of the Diagnostic Test Interpretation series, the discussion was focused predominantly on the differential for a persistently elevated lactate level in a patient who was not critically ill to highlight the various possible interpretations and limitations of this diagnostic test. Meng Chen, MD Tiffany Y. Kim, MD Antonio M. Pessegueiro, MD Author Affiliations: David Geffen School of Medicine, University of California, Los Angeles. Corresponding Author: Antonio M. Pessegueiro, MD, Department of Medicine, David Geffen School of Medicine, University of California, 757 Westwood Plaza, Los Angeles, CA 90095 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
Clinician Understanding of Cholesterol Treatment Guidelines To the Editor Dr Ganda’s Viewpoint1 focused on the similarities and differences among 4 major international cholesterol treatment guidelines. The review highlighted the complex nature of clinical practice guidelines and the challenges faced by clinicians in their interpretation. Physicians are often faced with the difficulty of reconciling conflicting information and managing conclusions from experts whose viewpoints may be nuanced by conflicts of interest.2 Given that 1 in 4 US adults takes cholesterol-lowering drugs, including more than 40% of adults aged 60 years or older,3 we were concerned when Ganda presented ezetimibe as a forthcoming treatment option for cholesterol lowering. The pre-
jama.com
(Reprinted) JAMA June 16, 2015 Volume 313, Number 23
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Carleton University User on 06/21/2015
2381
Letters
liminary results of the IMPROVE-IT trial were first presented at the American Heart Association’s scientific sessions in November 2014. As of this writing, the results have not yet appeared in a peer-reviewed publication. Therefore, it may not have been suitable to incorporate the results of this study in a review article, given the broad audience, the potential for rapid uptake, and the resulting farreaching treatment implications. Readers may assume the results are well established and have been appropriately critiqued. In fact, the initial results of the IMPROVE-IT trial are already being referenced in direct-to-physician educational mailings. We think it ought to have been made clear that a publication of the trial results was not yet available and that the results apply to a select secondary prevention population in patients co-treated with statins presenting with acute coronary syndrome. We are concerned about the risks of disseminating the findings prior to the due process of expert peer scrutiny.
hypothesis. Contrary to the data in clinical trials, a significant proportion of patients taking statin therapy are unable to intensify the statin dose to meet the current recommendations for high-risk patients.3 My Viewpoint addressed the clinical dilemma in such patients and presented the possibility of an alternative approach of combining ezetimibe with the highest tolerated statin dose. The full publication of the IMPROVE-IT trial may provide insight into this approach. Om P. Ganda, MD Author Affiliation: Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts. Corresponding Author: Om P. Ganda, MD, Joslin Diabetes Center, Harvard Medical School, 1 Joslin Pl, Boston, MA 02215 ([email protected]). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. IMPROVE-IT Study Team. Cholesterol-lowering drug with different action adds to statin’s reduction of cardiovascular risk. Abstract presented at: American Heart Association Scientific Sessions; November 15-19, 2014; Chicago, IL. Abstract LBCT.02.
Todd C. Lee, MD, MPH Emily G. McDonald, MD Author Affiliations: Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada. Corresponding Author: Emily G. McDonald, MD, Department of Medicine, McGill University Health Centre, Royal Victoria Hospital, 1001 Decarie Blvd, Montreal, QC H4A 3J1, Canada ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Ganda OP. Deciphering cholesterol treatment guidelines: a clinician’s perspective. JAMA. 2015;313(10):1009-1010.
2. Improved Reduction of Outcomes: Vytorin Efficacy International Trial: a multicenter, double-blind, randomized study to establish the clinical benefit and safety of Vytorin (ezetimibe/simvastatin tablet) vs simvastatin monotherapy in high-risk subjects presenting with acute coronary syndrome. http://my.americanheart.org/idc/groups/ahamah-public/@wcm/@sop/@scon /documents/downloadable/ucm_469669.pdf. Accessed March 10, 2015. 3. Stroes ES, Thompson PD, Corsini A, et al; European Atherosclerosis Society Consensus Panel. Statin-associated muscle symptoms: impact on statin therapy: European Atherosclerosis Society Consensus Panel statement on assessment, aetiology and management. Eur Heart J. 2015;36(17):1012-1022.
2. Graham R, Mancher M, Wolman DM, Greenfield S, Steinberg E. Clinical Practice Guidelines We Can Trust. Washington, DC: National Academies Press; 2011. 3. Gu Q, Paulose-Ram R, Burt VL, Kit BK. Prescription cholesterol-lowering medication use in adults aged 40 and over: United States, 2003-2012. December 2014. http://www.cdc.gov/nchs/data/databriefs/db177.pdf. Accessed April 30, 2015.
In Reply Drs Lee and McDonald reaffirm the need to provide a perspective for clinicians faced with the challenges in the interpretation of divergent guidelines in an important area of cholesterol management. In this context, they bring up an important point regarding the potential implications of commenting on the results of a clinical trial that have been presented in a scientific meeting but have only been published in an abstract form. I agree that the final interpretation of any clinical trial must await full peer review. The results of the IMPROVE-IT trial have been disseminated widely in both professional and lay media since their presentation at the American Heart Association’s annual scientific sessions in November 2014.1 A more accessible reference to the IMPROVE-IT trial results2 is now included in the online version of my Viewpoint. Ezetimibe is the first nonstatin drug that has been shown to have modest but significant benefits when combined with a statin in high-risk patients, thus supporting the cholesterol
2382
Guidelines for Letters Letters discussing a recent JAMA article should be submitted within 4 weeks of the article's publication in print. Letters received after 4 weeks will rarely be considered. Letters should not exceed 400 words of text and 5 references and may have no more than 3 authors. Letters reporting original research should not exceed 600 words of text and 6 references and may have no more than 7 authors. They may include up to 2 tables or figures but online supplementary material is not allowed. All letters should include a word count. Letters must not duplicate other material published or submitted for publication. Letters not meeting these specifications are generally not considered. Letters being considered for publication ordinarily will be sent to the authors of the JAMA article, who will be given the opportunity to reply. Letters will be published at the discretion of the editors and are subject to abridgement and editing. Further instructions can be found at http://jama.com/public /InstructionsForAuthors.aspx. A signed statement for authorship criteria and responsibility, financial disclosure, copyright transfer, and acknowledgment and the ICMJE Form for Disclosure of Potential Conflicts of Interest are required before publication. Letters should be submitted via the JAMA online submission and review system at http: //manuscripts.jama.com. For technical assistance, please contact [email protected]. Section Editor: Jody W. Zylke, MD, Deputy Editor.
JAMA June 16, 2015 Volume 313, Number 23 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Carleton University User on 06/21/2015
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