Editorials
Conversely, anti-factor Xa levels measure a drug concentration not an effect. Neither assay is testing the action of UFH or LMWH, respectively, which is primarily the inhibition of thrombin generation. With thrombin generation assays, it can be noted that at a relatively low aPTT of 40–50 seconds, thrombin generation can be inhibited by up to 80% (7). The variability of individual thrombin generation potential is extremely broad, as is the response to fixed doses of anticoagulants (8). It is possible, therefore, that we could evaluate more relevant variables, such as thrombin generation assays, as VTE risk has been shown to increase in patients who generate more thrombin (9). Thrombin generation assays also predict bleeding episodes in congenital coagulation factor deficiencies (10), suggesting that the individual milieu of pro- and anticoagulant factors also contributes to bleeding phenotypes. Unfortunately, thrombin generation assays remain a research tool at present, but currently available thromboelastometric techniques are able to detect variations in thrombin generation, fibrinogen, and platelet count. Although promising, clinical studies in this area are still rudimentary. For example, Kashuk et al (11) identified an independent association between the degree of thromboelastometric hypercoagulability and subsequent development of thromboembolism in surgical patients, even after adjusting for use of pharmacological thromboprophylaxis. In the complex ICU patient, evaluating this variable could potentially guide customization of thromboprophylaxis regimens, including combinations of mechanical interventions with pharmacological anticoagulant and antiplatelet agents. In summary, focusing efforts on safely achieving effective antithrombotic levels using novel regimens and/or monitoring techniques, and evaluating combined thromboprophylactic modalities, are essential components of strategies to prevent VTE in the critically ill. One size is unlikely to fit all.
REFERENCES
1. Cook D, Meade M, Guyatt G, et al: Dalteparin versus unfractionated heparin in critically ill patients. N Engl J Med 2011; 364:1305–1314 2. Gould MK, Garcia DA, Wren SM, et al; American College of Chest Physicians: Prevention of VTE in nonorthopedic surgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e227S–e277S 3. Kahn SR, Lim W, Dunn AS, et al; American College of Chest Physicians: Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e195S–e226S 4. Lim W, Meade M, Lauzier F, et al; for the PROphylaxis for ThromboEmbolism in Critical care Trial Investigators, the Canadian Critical Care Trials Group, and the Australian and New Zealand Intensive Care Society Clinical Trials Group: Failure of Anticoagulant Thromboprophylaxis: Risk Factors in Medical-Surgical Critically Ill Patients. Crit Care Med 2015; 43:401–410 5. Kakkos SK, Caprini JA, Geroulakos G, et al: Combined intermittent pneumatic leg compression and pharmacological prophylaxis for prevention of venous thromboembolism in high-risk patients. Cochrane Database Syst Rev 2008; 4:CD005258 6. Robinson S, Zincuk A, Larsen UL, et al: A comparative study of varying doses of enoxaparin for thromboprophylaxis in critically ill patients: A double-blinded, randomised controlled trial. Crit Care 2013; 17:R75 7. al Dieri R, Alban S, Béguin S, et al: Thrombin generation for the control of heparin treatment, comparison with the activated partial thromboplastin time. J Thromb Haemost 2004; 2:1395–1401 8. Bloemen S, Hemker HC, Al Dieri R: Large inter-individual variation of the pharmacodynamic effect of anticoagulant drugs on thrombin generation. Haematologica 2013; 98:549–554 9. Ay C, Dunkler D, Simanek R, et al: Prediction of venous thromboembolism in patients with cancer by measuring thrombin generation: Results from the Vienna Cancer and Thrombosis Study. J Clin Oncol 2011; 29:2099–2103 10. Al Dieri R, Peyvandi F, Santagostino E, et al: The thrombogram in rare inherited coagulation disorders: Its relation to clinical bleeding. Thromb Haemost 2002; 88:576–582 11. Kashuk JL, Moore EE, Sabel A, et al: Rapid thrombelastography (r-TEG) identifies hypercoagulability and predicts thromboembolic events in surgical patients. Surgery 2009; 146:764–772; discussion 772–764
Sepsis: A Persistent Threat Following Hematopoietic Stem Cell Transplantation* W. Conrad Liles, MD, PhD Department of Medicine University of Washington Seattle, WA
S
epsis and sepsis-related complications—including septic shock, acute lung injury/acute respiratory distress syndrome, and multiple organ dysfunction syndrome
*See also p. 411. Key Words: bone marrow graft; endothelial activation/dysfunction; hemato poietic stem cell transplantation; mobilized peripheral blood stem cell graft; sepsis Dr. Liles’ institution received grant support from the National Institutes of Health. Copyright © 2015 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM.0000000000000781
Critical Care Medicine
(MODS)—are leading causes of morbidity and mortality in critically ill patients both in the United States and globally. The development of effective therapeutic agents for targeted treatment of clinical sepsis has remained elusive, despite decades of investigation (1). Individuals who have undergone hematopoietic stem cell transplantation (HSCT) are considered to be a population at greater risk for infections that could lead to sepsis because of their overall immunocompromised status, resulting from the underlying disease requiring HSCT, the conditioning regimen required for HSCT, and/or immunosuppressive medications used to prevent graft rejection and/or prevent/ treat graft-versus-host-disease (GVHD). However, most randomized controlled clinical trials for the treatment of sepsis have specifically excluded HSCT patients from enrollment. In this issue of Critical Care Medicine, Kumar et al (2) report that severe sepsis is more common and more likely to be fatal www.ccmjournal.org
501
Editorials
in individuals following HSCT than in non-HSCT patients. In HSCT recipients in whom sepsis develops, clinical outcomes were reported to be more favorable in individuals who received autologous versus allogeneic HSCT and in individuals who did not develop GVHD. Although many may find these results to be not surprising (if not entirely expected), the current study is important in documenting and defining the widespread burden and significant impact of severe sepsis in the HSCT patient population at the time of HSCT (termed “engraftment admission” in the article) and following HSCT (subsequent admission). In contrast to previous epidemiological studies representing primarily single tertiary care center experiences, the study by Kumar et al (2) utilized a large national (United States) administrative database (namely, the Healthcare Cost and Utilization Project—Nationwide Inpatient Sample [NIS] database from 2000 to 2008), yielding nearly 300,000 hospital discharges of HSCT patients, to determine sepsis-related outcomes at a nation-wide level. In this HSCT cohort, 7.5% of individuals were reported to develop severe sepsis. This frequency was five-fold greater than in the non-HSCT cohort. In general, the rates of end-organ failure (pulmonary, renal, and hepatic dysfunction/failure) were higher in allogeneic HSCT recipients compared with autologous HSCT and non-HSCT patients. Curiously, the risk of sepsis-related cardiac failure during the engraftment admission was reported to be lower in allogeneic HSCT patients compared with the observed rates in autologous HSCT and non-HSCT patients. Interestingly and somewhat surprisingly, the study failed to find an association of specific microbial pathogen (i.e., methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, Clostridium difficile, Candida species, Aspergillus species) with increased sepsis-related mortality in HSCT patients (2). It should be noted that retrospective analyses using administrative databases, such as performed in the current study, have inherent limitations and potential pitfalls. For example, it is well recognized that the timely administration of appropriate antimicrobial therapy is an important factor in improving clinical outcomes in sepsis (3–6). Also, administration of prophylactic antimicrobial therapy can certainly influence the risk for infections caused by specific pathogens. Unfortunately, given the administrative features and lack of coding in the NIS database, the authors were unable to address these important points plus the conditioning regimen employed prior to HSCT, duration and severity of associated neutropenia, and whether or not total body irradiation was administered. Investigation of the relative importance of these potential risk factors for severe sepsis in HSCT will require alternative research approaches. Another important issue not addressed in the current study is the relative risk for severe sepsis and MODS in HSCT patients stratified according to the type of HSCT graft received. By far, the vast majority of HSCT recipients undergo transplantation with either conventional bone marrow (BMT) or mobilized peripheral blood stem cells (PBSCT). Controversy persists regarding the appropriate stem cell source for HSCT (7–10). Therefore, it would be of considerable interest to determine whether the risk for severe sepsis and poor sepsis-related 502
www.ccmjournal.org
clinical outcomes varies between BMT and PBSCT in patients undergoing allogeneic HSCT. Finally, it will be important in subsequent studies to define effective strategies discrimination of HSCT patients at risk for progression to severe sepsis and MODS upon presentation with suspected infection. In this context, discovery and validation of clinically informative prognostic biomarkers would be an important clinical advance. Biomarkers of endothelial activation/dysfunction are promising candidates in this regard (10), given the increasing evidence that endothelial cell activation/dysfunction, with consequential microvascular leak, plays a critical mechanistic role in the pathogenesis of sepsis and MODS (11, 12). A recent National Heart, Lung and Blood Institute consensus panel on sepsis (https://www.nhlbi.nih.gov/ research/reports/2010-bsrts.htm) concluded that sepsis represents a syndrome of severe endothelial dysfunction that causes multiple organ failure in response to intravascular or extravascular infection. The angiopoietin-1/2 system has received considerable attention for its role in the regulation of microvascular endothelial function during sepsis (13). Dysregulation of the angiopoietin-1/2 system (low angiopoietin-1/high angiopoietin-2 in peripheral blood) has been associated prognostically with clinical outcomes in critically ill patients with severe sepsis (14). Furthermore, in the context of HSCT, angiopoietin-1/2 dysregulation was recently reported to be associated with a high risk of septic shock in patients with chemotherapy-associated febrile neutropenia (15). In summary, the study by Kumar et al (2) has established that sepsis remains a formidable challenge in HSCT (2). Subsequent studies should be designed to delineate specific risk factors for severe sepsis and sepsis-related complications in HSCT, in an effort to develop strategies to mitigate these risks and improve clinical outcomes in this vulnerable patient population.
REFERENCES
1. Angus DC, van der Poll T: Severe sepsis and septic shock. N Engl J Med 2013; 369:2063 2. Kumar G, Ahmad S, Taneja A, et al; the Milwaukee Initiative in Critical Care Outcomes Research Group of Investigators: Severe Sepsis in Hematopoietic Stem Cell Transplant Recipients. Crit Care Med 2015; 43:411–421 3. Dellinger RP, Levy MM, Rhodes A, et al: Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013; 41:580–637 4. Dellinger RP, Levy MM, Rhodes A, et al: Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med 2013; 39:165–228 5. Funk DJ, Kumar A: Antimicrobial therapy for life-threatening infections: Speed is life. Crit Care Clin 2011; 27:53–76 6. Kumar A: An alternate pathophysiologic paradigm of sepsis and septic shock: Implications for optimizing antimicrobial therapy. Virulence 2014; 5:80–97 7. Bensinger WI, Martin PJ, Storer B, et al: Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers. N Engl J Med 2001; 344:175–181 8. Bensinger WI: Allogeneic transplantation: Peripheral blood vs. bone marrow. Curr Opin Oncol 2012; 24:191–196 9. Holtick U, Albrecht M, Chemnitz JM, et al: Bone marrow versus peripheral blood allogeneic haematopoietic stem cell transplantation for haematological malignancies in adults. Cochrane Database Syst Rev 2014; 4:CD010189 February 2015 • Volume 43 • Number 2
Editorials 10. Xing K, Murthy S, Liles WC, et al: Clinical utility of biomarkers of endothelial activation in sepsis—A systematic review. Crit Care 2012; 16:R7 11. Lee WL, Liles WC: Endothelial activation, dysfunction and permeability during severe infections. Curr Opin Hematol 2011; 18:191–196 12. Goldenberg NM, Steinberg BE, Slutsky AS, et al: Broken barriers: A new take on sepsis pathogenesis. Sci Transl Med 2011; 3:88ps25
13. Parikh SM: Dysregulation of the angiopoietin-Tie-2 axis in sepsis and ARDS. Virulence 2013; 4:517–524 14. Ricciuto DR, dos Santos CC, Hawkes M, et al: Angiopoietin-1 and angiopoietin-2 as clinically informative prognostic biomarkers of morbidity and mortality in severe sepsis. Crit Care Med 2011; 39:702–710 15. Luz Fiusa MM, Costa-Lima C, de Souza GR, et al: A high angiopoietin-2/angiopoietin-1 ratio is associated with a high risk of septic shock in patients with febrile neutropenia. Crit Care 2013; 17:R169
Prediction of Mortality From Out-of-Hospital Cardiac Arrest Is Key to Decrease Morbidity and Mortality From Cardiac, Neurologic, and Other Major Organ Damage* Elsa Grace Garza, DNP Department of Internal Medicine University of Chicago Chicago, IL Mark J. Rumbak, MB, BCh Department of Internal Medicine Division of Pulmonary, Critical Care, Sleep Medicine Morsani College of Medicine University of South Florida Tampa, FL
I
n this issue of Critical Care Medicine, the article by Geri et al (1) is a very important one as it documents that copeptin levels drawn on days 1 and 3 may predict 1-year mortality from out-of-hospital cardiac arrest (OHCA). They prospectively studied 298 patients admitted to their ICU post OHCA and measured copeptin levels, the C-terminal fragment of the provasopressin peptide. This is released in equimolar ratio to arginine vasopressin (AVP). Copeptin is a surrogate for AVP, which is too short lived to be measured (1). They found that high copeptin levels on admission independently were associated with 1-year mortality. They also found that the levels of copeptin on day 3 were more robust and that the higher the levels the worse the prognosis (1). The strengths of the study were that it was prospective with good follow-up for mortality. The copeptin levels seem easy to measure and could be easily available. The weaknesses were, first, that so many patients were excluded. Although 510 patients were screened and only 298 patients were enrolled (because of inadequate blood samples), the mortality characteristics were found to
*See also p. 422. Key Words: acute coronary syndrome; cardiac arrest; copeptin; longterm follow-up; out-of-hospital The authors have disclosed that they do not have any potential conflicts of interest. Copyright © 2015 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM.0000000000000829
Critical Care Medicine
be the same in the study group and the excluded group. Second, it was an observational study. This shows that high copeptin levels are associated with mortality. Third, the follow-up was only performed for mortality from public registry and did not include documented specific cause of death. Fourth, not all patients underwent a cardiac catheterization, which would have revealed how many cardiac arrests were due to primary cardiac disease versus other illnesses. The copeptin levels in the patients with OHCA were significantly higher than those who suffered only from acute myocardial infarction, shock, and cardiac surgery (1, 2). Although these were not the same studies, this may reflect additional brain injury in addition to myocardial damage. In fact, the primary reason to elect a hypothermia therapy for people post– cardiac arrest is to prevent brain injury, not cardiac damage (3). Copeptin levels before and after cooling may show that cooling may in fact decrease level of brain damage. Counter regulatory hormones (steroids, glucagon, epinephrine, and AVP) go up in both cardiac and brain damage (4). Prolactin levels also increase post seizures reflecting brain damage (5). Measuring these hormones may help distinguish between cardiac and brain events. Serum sodium levels may reflect AVP increases and may be predictive as they are in subdural hemorrhage (6). Therefore, if patients were successfully cooled, would the copeptin levels be lower to predict a better outcome?
REFERENCES
1. Geri G, Dumas F, Chenevier-Gobeaux C, et al: Is Copeptin Level Associated With 1-Year Mortality After Out-of-Hospital Cardiac Arrest? Insights From the Paris Registry. Crit Care Med 2015; 43:422–429 2. Kelly D, Squire IB, Khan SQ, et al: C-terminal provasopressin (copeptin) is associated with left ventricular dysfunction, remodeling, and clinical heart failure in survivors of myocardial infarction. J Card Fail 2008; 14:739–745 3. Jessica E. Havnic M, Rittenberger, Jon C. Therapeutic Hypothermia After Cardiac Arrest. AJN 2012; 112:38–44 4. Saramma P, Girish Menon R, Srivastava A: Hyponatremia after aneurysmal subarachnoid hemorrhage: Implications and outcomes. J Neurosci Rural Pract 2013; 4:24–28 5. Chen DK, So YT, Fisher RS: Use of serum prolactin in diagnosing epileptic seizures: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2005; 65;668–675 www.ccmjournal.org
503
Copyright of Critical Care Medicine is the property of Lippincott Williams & Wilkins and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Conversely, anti-factor Xa levels measure a drug concentration not an effect. Neither assay is testing the action of UFH or LMWH, respectively, which is primarily the inhibition of thrombin generation. With thrombin generation assays, it can be noted that at a relatively low aPTT of 40–50 seconds, thrombin generation can be inhibited by up to 80% (7). The variability of individual thrombin generation potential is extremely broad, as is the response to fixed doses of anticoagulants (8). It is possible, therefore, that we could evaluate more relevant variables, such as thrombin generation assays, as VTE risk has been shown to increase in patients who generate more thrombin (9). Thrombin generation assays also predict bleeding episodes in congenital coagulation factor deficiencies (10), suggesting that the individual milieu of pro- and anticoagulant factors also contributes to bleeding phenotypes. Unfortunately, thrombin generation assays remain a research tool at present, but currently available thromboelastometric techniques are able to detect variations in thrombin generation, fibrinogen, and platelet count. Although promising, clinical studies in this area are still rudimentary. For example, Kashuk et al (11) identified an independent association between the degree of thromboelastometric hypercoagulability and subsequent development of thromboembolism in surgical patients, even after adjusting for use of pharmacological thromboprophylaxis. In the complex ICU patient, evaluating this variable could potentially guide customization of thromboprophylaxis regimens, including combinations of mechanical interventions with pharmacological anticoagulant and antiplatelet agents. In summary, focusing efforts on safely achieving effective antithrombotic levels using novel regimens and/or monitoring techniques, and evaluating combined thromboprophylactic modalities, are essential components of strategies to prevent VTE in the critically ill. One size is unlikely to fit all.
REFERENCES
1. Cook D, Meade M, Guyatt G, et al: Dalteparin versus unfractionated heparin in critically ill patients. N Engl J Med 2011; 364:1305–1314 2. Gould MK, Garcia DA, Wren SM, et al; American College of Chest Physicians: Prevention of VTE in nonorthopedic surgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e227S–e277S 3. Kahn SR, Lim W, Dunn AS, et al; American College of Chest Physicians: Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e195S–e226S 4. Lim W, Meade M, Lauzier F, et al; for the PROphylaxis for ThromboEmbolism in Critical care Trial Investigators, the Canadian Critical Care Trials Group, and the Australian and New Zealand Intensive Care Society Clinical Trials Group: Failure of Anticoagulant Thromboprophylaxis: Risk Factors in Medical-Surgical Critically Ill Patients. Crit Care Med 2015; 43:401–410 5. Kakkos SK, Caprini JA, Geroulakos G, et al: Combined intermittent pneumatic leg compression and pharmacological prophylaxis for prevention of venous thromboembolism in high-risk patients. Cochrane Database Syst Rev 2008; 4:CD005258 6. Robinson S, Zincuk A, Larsen UL, et al: A comparative study of varying doses of enoxaparin for thromboprophylaxis in critically ill patients: A double-blinded, randomised controlled trial. Crit Care 2013; 17:R75 7. al Dieri R, Alban S, Béguin S, et al: Thrombin generation for the control of heparin treatment, comparison with the activated partial thromboplastin time. J Thromb Haemost 2004; 2:1395–1401 8. Bloemen S, Hemker HC, Al Dieri R: Large inter-individual variation of the pharmacodynamic effect of anticoagulant drugs on thrombin generation. Haematologica 2013; 98:549–554 9. Ay C, Dunkler D, Simanek R, et al: Prediction of venous thromboembolism in patients with cancer by measuring thrombin generation: Results from the Vienna Cancer and Thrombosis Study. J Clin Oncol 2011; 29:2099–2103 10. Al Dieri R, Peyvandi F, Santagostino E, et al: The thrombogram in rare inherited coagulation disorders: Its relation to clinical bleeding. Thromb Haemost 2002; 88:576–582 11. Kashuk JL, Moore EE, Sabel A, et al: Rapid thrombelastography (r-TEG) identifies hypercoagulability and predicts thromboembolic events in surgical patients. Surgery 2009; 146:764–772; discussion 772–764
Sepsis: A Persistent Threat Following Hematopoietic Stem Cell Transplantation* W. Conrad Liles, MD, PhD Department of Medicine University of Washington Seattle, WA
S
epsis and sepsis-related complications—including septic shock, acute lung injury/acute respiratory distress syndrome, and multiple organ dysfunction syndrome
*See also p. 411. Key Words: bone marrow graft; endothelial activation/dysfunction; hemato poietic stem cell transplantation; mobilized peripheral blood stem cell graft; sepsis Dr. Liles’ institution received grant support from the National Institutes of Health. Copyright © 2015 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM.0000000000000781
Critical Care Medicine
(MODS)—are leading causes of morbidity and mortality in critically ill patients both in the United States and globally. The development of effective therapeutic agents for targeted treatment of clinical sepsis has remained elusive, despite decades of investigation (1). Individuals who have undergone hematopoietic stem cell transplantation (HSCT) are considered to be a population at greater risk for infections that could lead to sepsis because of their overall immunocompromised status, resulting from the underlying disease requiring HSCT, the conditioning regimen required for HSCT, and/or immunosuppressive medications used to prevent graft rejection and/or prevent/ treat graft-versus-host-disease (GVHD). However, most randomized controlled clinical trials for the treatment of sepsis have specifically excluded HSCT patients from enrollment. In this issue of Critical Care Medicine, Kumar et al (2) report that severe sepsis is more common and more likely to be fatal www.ccmjournal.org
501
Editorials
in individuals following HSCT than in non-HSCT patients. In HSCT recipients in whom sepsis develops, clinical outcomes were reported to be more favorable in individuals who received autologous versus allogeneic HSCT and in individuals who did not develop GVHD. Although many may find these results to be not surprising (if not entirely expected), the current study is important in documenting and defining the widespread burden and significant impact of severe sepsis in the HSCT patient population at the time of HSCT (termed “engraftment admission” in the article) and following HSCT (subsequent admission). In contrast to previous epidemiological studies representing primarily single tertiary care center experiences, the study by Kumar et al (2) utilized a large national (United States) administrative database (namely, the Healthcare Cost and Utilization Project—Nationwide Inpatient Sample [NIS] database from 2000 to 2008), yielding nearly 300,000 hospital discharges of HSCT patients, to determine sepsis-related outcomes at a nation-wide level. In this HSCT cohort, 7.5% of individuals were reported to develop severe sepsis. This frequency was five-fold greater than in the non-HSCT cohort. In general, the rates of end-organ failure (pulmonary, renal, and hepatic dysfunction/failure) were higher in allogeneic HSCT recipients compared with autologous HSCT and non-HSCT patients. Curiously, the risk of sepsis-related cardiac failure during the engraftment admission was reported to be lower in allogeneic HSCT patients compared with the observed rates in autologous HSCT and non-HSCT patients. Interestingly and somewhat surprisingly, the study failed to find an association of specific microbial pathogen (i.e., methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, Clostridium difficile, Candida species, Aspergillus species) with increased sepsis-related mortality in HSCT patients (2). It should be noted that retrospective analyses using administrative databases, such as performed in the current study, have inherent limitations and potential pitfalls. For example, it is well recognized that the timely administration of appropriate antimicrobial therapy is an important factor in improving clinical outcomes in sepsis (3–6). Also, administration of prophylactic antimicrobial therapy can certainly influence the risk for infections caused by specific pathogens. Unfortunately, given the administrative features and lack of coding in the NIS database, the authors were unable to address these important points plus the conditioning regimen employed prior to HSCT, duration and severity of associated neutropenia, and whether or not total body irradiation was administered. Investigation of the relative importance of these potential risk factors for severe sepsis in HSCT will require alternative research approaches. Another important issue not addressed in the current study is the relative risk for severe sepsis and MODS in HSCT patients stratified according to the type of HSCT graft received. By far, the vast majority of HSCT recipients undergo transplantation with either conventional bone marrow (BMT) or mobilized peripheral blood stem cells (PBSCT). Controversy persists regarding the appropriate stem cell source for HSCT (7–10). Therefore, it would be of considerable interest to determine whether the risk for severe sepsis and poor sepsis-related 502
www.ccmjournal.org
clinical outcomes varies between BMT and PBSCT in patients undergoing allogeneic HSCT. Finally, it will be important in subsequent studies to define effective strategies discrimination of HSCT patients at risk for progression to severe sepsis and MODS upon presentation with suspected infection. In this context, discovery and validation of clinically informative prognostic biomarkers would be an important clinical advance. Biomarkers of endothelial activation/dysfunction are promising candidates in this regard (10), given the increasing evidence that endothelial cell activation/dysfunction, with consequential microvascular leak, plays a critical mechanistic role in the pathogenesis of sepsis and MODS (11, 12). A recent National Heart, Lung and Blood Institute consensus panel on sepsis (https://www.nhlbi.nih.gov/ research/reports/2010-bsrts.htm) concluded that sepsis represents a syndrome of severe endothelial dysfunction that causes multiple organ failure in response to intravascular or extravascular infection. The angiopoietin-1/2 system has received considerable attention for its role in the regulation of microvascular endothelial function during sepsis (13). Dysregulation of the angiopoietin-1/2 system (low angiopoietin-1/high angiopoietin-2 in peripheral blood) has been associated prognostically with clinical outcomes in critically ill patients with severe sepsis (14). Furthermore, in the context of HSCT, angiopoietin-1/2 dysregulation was recently reported to be associated with a high risk of septic shock in patients with chemotherapy-associated febrile neutropenia (15). In summary, the study by Kumar et al (2) has established that sepsis remains a formidable challenge in HSCT (2). Subsequent studies should be designed to delineate specific risk factors for severe sepsis and sepsis-related complications in HSCT, in an effort to develop strategies to mitigate these risks and improve clinical outcomes in this vulnerable patient population.
REFERENCES
1. Angus DC, van der Poll T: Severe sepsis and septic shock. N Engl J Med 2013; 369:2063 2. Kumar G, Ahmad S, Taneja A, et al; the Milwaukee Initiative in Critical Care Outcomes Research Group of Investigators: Severe Sepsis in Hematopoietic Stem Cell Transplant Recipients. Crit Care Med 2015; 43:411–421 3. Dellinger RP, Levy MM, Rhodes A, et al: Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013; 41:580–637 4. Dellinger RP, Levy MM, Rhodes A, et al: Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med 2013; 39:165–228 5. Funk DJ, Kumar A: Antimicrobial therapy for life-threatening infections: Speed is life. Crit Care Clin 2011; 27:53–76 6. Kumar A: An alternate pathophysiologic paradigm of sepsis and septic shock: Implications for optimizing antimicrobial therapy. Virulence 2014; 5:80–97 7. Bensinger WI, Martin PJ, Storer B, et al: Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers. N Engl J Med 2001; 344:175–181 8. Bensinger WI: Allogeneic transplantation: Peripheral blood vs. bone marrow. Curr Opin Oncol 2012; 24:191–196 9. Holtick U, Albrecht M, Chemnitz JM, et al: Bone marrow versus peripheral blood allogeneic haematopoietic stem cell transplantation for haematological malignancies in adults. Cochrane Database Syst Rev 2014; 4:CD010189 February 2015 • Volume 43 • Number 2
Editorials 10. Xing K, Murthy S, Liles WC, et al: Clinical utility of biomarkers of endothelial activation in sepsis—A systematic review. Crit Care 2012; 16:R7 11. Lee WL, Liles WC: Endothelial activation, dysfunction and permeability during severe infections. Curr Opin Hematol 2011; 18:191–196 12. Goldenberg NM, Steinberg BE, Slutsky AS, et al: Broken barriers: A new take on sepsis pathogenesis. Sci Transl Med 2011; 3:88ps25
13. Parikh SM: Dysregulation of the angiopoietin-Tie-2 axis in sepsis and ARDS. Virulence 2013; 4:517–524 14. Ricciuto DR, dos Santos CC, Hawkes M, et al: Angiopoietin-1 and angiopoietin-2 as clinically informative prognostic biomarkers of morbidity and mortality in severe sepsis. Crit Care Med 2011; 39:702–710 15. Luz Fiusa MM, Costa-Lima C, de Souza GR, et al: A high angiopoietin-2/angiopoietin-1 ratio is associated with a high risk of septic shock in patients with febrile neutropenia. Crit Care 2013; 17:R169
Prediction of Mortality From Out-of-Hospital Cardiac Arrest Is Key to Decrease Morbidity and Mortality From Cardiac, Neurologic, and Other Major Organ Damage* Elsa Grace Garza, DNP Department of Internal Medicine University of Chicago Chicago, IL Mark J. Rumbak, MB, BCh Department of Internal Medicine Division of Pulmonary, Critical Care, Sleep Medicine Morsani College of Medicine University of South Florida Tampa, FL
I
n this issue of Critical Care Medicine, the article by Geri et al (1) is a very important one as it documents that copeptin levels drawn on days 1 and 3 may predict 1-year mortality from out-of-hospital cardiac arrest (OHCA). They prospectively studied 298 patients admitted to their ICU post OHCA and measured copeptin levels, the C-terminal fragment of the provasopressin peptide. This is released in equimolar ratio to arginine vasopressin (AVP). Copeptin is a surrogate for AVP, which is too short lived to be measured (1). They found that high copeptin levels on admission independently were associated with 1-year mortality. They also found that the levels of copeptin on day 3 were more robust and that the higher the levels the worse the prognosis (1). The strengths of the study were that it was prospective with good follow-up for mortality. The copeptin levels seem easy to measure and could be easily available. The weaknesses were, first, that so many patients were excluded. Although 510 patients were screened and only 298 patients were enrolled (because of inadequate blood samples), the mortality characteristics were found to
*See also p. 422. Key Words: acute coronary syndrome; cardiac arrest; copeptin; longterm follow-up; out-of-hospital The authors have disclosed that they do not have any potential conflicts of interest. Copyright © 2015 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM.0000000000000829
Critical Care Medicine
be the same in the study group and the excluded group. Second, it was an observational study. This shows that high copeptin levels are associated with mortality. Third, the follow-up was only performed for mortality from public registry and did not include documented specific cause of death. Fourth, not all patients underwent a cardiac catheterization, which would have revealed how many cardiac arrests were due to primary cardiac disease versus other illnesses. The copeptin levels in the patients with OHCA were significantly higher than those who suffered only from acute myocardial infarction, shock, and cardiac surgery (1, 2). Although these were not the same studies, this may reflect additional brain injury in addition to myocardial damage. In fact, the primary reason to elect a hypothermia therapy for people post– cardiac arrest is to prevent brain injury, not cardiac damage (3). Copeptin levels before and after cooling may show that cooling may in fact decrease level of brain damage. Counter regulatory hormones (steroids, glucagon, epinephrine, and AVP) go up in both cardiac and brain damage (4). Prolactin levels also increase post seizures reflecting brain damage (5). Measuring these hormones may help distinguish between cardiac and brain events. Serum sodium levels may reflect AVP increases and may be predictive as they are in subdural hemorrhage (6). Therefore, if patients were successfully cooled, would the copeptin levels be lower to predict a better outcome?
REFERENCES
1. Geri G, Dumas F, Chenevier-Gobeaux C, et al: Is Copeptin Level Associated With 1-Year Mortality After Out-of-Hospital Cardiac Arrest? Insights From the Paris Registry. Crit Care Med 2015; 43:422–429 2. Kelly D, Squire IB, Khan SQ, et al: C-terminal provasopressin (copeptin) is associated with left ventricular dysfunction, remodeling, and clinical heart failure in survivors of myocardial infarction. J Card Fail 2008; 14:739–745 3. Jessica E. Havnic M, Rittenberger, Jon C. Therapeutic Hypothermia After Cardiac Arrest. AJN 2012; 112:38–44 4. Saramma P, Girish Menon R, Srivastava A: Hyponatremia after aneurysmal subarachnoid hemorrhage: Implications and outcomes. J Neurosci Rural Pract 2013; 4:24–28 5. Chen DK, So YT, Fisher RS: Use of serum prolactin in diagnosing epileptic seizures: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2005; 65;668–675 www.ccmjournal.org
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