Editorials
has been observed to be associated with increased cost and blood loss (11). In summary, data generated in RCT refer to low-risk bleeding patients and probably explain that no difference in the incidence of bleeding was found by Gattas et al (10). Experience with the potential comparative benefits and drawbacks of CBA in actively bleeding or high-risk patients with severe thrombocytopenia or coagulation abnormalities is therefore lacking. Other subgroups, like patients in septic states, in which heparin-based anticoagulation is less effective, and patients with suboptimal vascular access, in whom clotting is a frequent complication, need to be addressed in future CBA clinical research. Current Kidney Disease Improving Global Outcome guidelines consider CBA to be the method of choice for CRRT anticoagulation, if no contraindications for citrate infusion exist (12). With 212 randomized patients and 857 circuits, the trial by Gattas et al (10) is the largest multicenter RCT published so far in the field of CBA. The data generated have significant external validity because of the pragmatic design accepting variability inherent to clinical practice. Also, the main study results are highly significant and lend support to the recommendations. Based on the data given in Gattas et al (10) and other recent studies (5, 6), if no contraindications for citrate infusion exist, CBA should be considered a safer and cheaper option than conventional heparin-based anticoagulation and no longer be reserved for patients at high risk of bleeding.
REFERENCES
1. Wu MY, Hsu YH, Bai CH, et al: Regional citrate versus heparin anticoagulation for continuous renal replacement therapy: A meta-analysis of randomized controlled trials. Am J Kidney Dis 2012; 59:810–818
2. Mehta RL, McDonald BR, Aguilar MM, et al: Regional citrate anticoagulation for continuous arteriovenous hemodialysis in critically ill patients. Kidney Int 1990; 38:976–981 3. Hofbauer R, Moser D, Frass M, et al: Effect of anticoagulation on blood membrane interactions during hemodialysis. Kidney Int 1999; 56:1578–1583 4. Morgera S, Scholle C, Voss G, et al: Metabolic complications during regional citrate anticoagulation in continuous venovenous hemodialysis: Single-center experience. Nephron Clin Pract 2004; 97:c131–c136 5. Stucker F, Ponte B, Tataw J, et al: Efficacy and safety of citrate-based anticoagulation compared to heparin in patients with acute kidney injury requiring continuous renal replacement therapy: A randomized controlled trial. Crit Care 2015; 19:822 6. Schilder L, Nurmohamed SA, Bosch FH, et al; CASH study group: Citrate anticoagulation versus systemic heparinisation in continuous venovenous hemofiltration in critically ill patients with acute kidney injury: A multi-center randomized clinical trial. Crit Care 2014; 18:472 7. Khadzhynov D, Schelter C, Lieker I, et al: Incidence and outcome of metabolic disarrangements consistent with citrate accumulation in critically ill patients undergoing continuous venovenous hemodialysis with regional citrate anticoagulation. J Crit Care 2014; 29:265–271 8. Schultheiß C, Saugel B, Phillip V, et al: Continuous venovenous hemodialysis with regional citrate anticoagulation in patients with liver failure: A prospective observational study. Crit Care 2012; 16:R162 9. Raimundo M, Crichton S, Lei K, et al: Maintaining normal levels of ionized calcium during citrate-based renal replacement therapy is associated with stable parathyroid hormone levels. Nephron Clin Pract 2013; 124:124–131 10. Gattas DJ, Rajbhandari D, Bradford C, et al: A Randomized Controlled Trial of Regional Citrate Versus Regional Heparin Anticoagulation for Continuous Renal Replacement Therapy in Critically Ill Adults. Crit Care Med 2015; 43:1622–1629 11. Oudemans-van Straaten HM, Bosman RJ, Koopmans M, et al: Citrate anticoagulation for continuous venovenous hemofiltration. Crit Care Med 2009; 37:545–552 12. Lameire N, Kellum JA; KDIGO AKI Guideline Work Group: Contrastinduced acute kidney injury and renal support for acute kidney injury: A KDIGO summary (Part 2). Crit Care 2013; 17:205
HIV Infection and Severe Sepsis: A Bitter Pill to Swallow* Matthew R. Gingo, MD, MS Department of Medicine University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center Pittsburgh, PA
*See also p. 1638. Key Words: human immunodeficiency virus; intensive care; sepsis The authors received support for article research from the National Institutes of Health. Copyright © 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved. DOI: 10.1097/CCM.0000000000001053
Critical Care Medicine
Alison Morris, MD, MS Department of Medicine University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center; and Department of Immunology University of Pittsburgh School of Medicine Pittsburgh, PA
I
nfection with HIV affects over 1.3 million people in the United States and over 35 million people worldwide (1). Despite improvements in treatment, HIV is still associated with increased morbidity and mortality. Although infectious complications of HIV and AIDS have decreased, noncommunicable diseases such as cardiovascular disease, chronic obstructive pulmonary disease, end-stage renal disease, and diabetes are becoming more common in HIV-infected persons as they are living longer with highly active antiretroviral therapy (HAART) (2). www.ccmjournal.org
Copyright © 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
1779
Editorials
The impact of HAART has also been seen in the ICU in both the diagnoses seen and their prognoses. In the early AIDS era, mortality for HIV-infected persons admitted to the ICU was very high, and it was often seen as futile to admit these patients to the ICU (3, 4). HAART, in combination with HIV-specific improvements in care such as corticosteroids for Pneumocystis pneumonia and advances in general ICU care such as low tidal volume ventilation, has resulted in an overall improvement in survival of HIV-infected persons admitted to the ICU (5). Causes of ICU admission have also shifted with a decrease in AIDS-associated diagnoses such as Pneumocystis pneumonia; however, respiratory failure has remained the most common cause of ICU admission, and sepsis has increased (5–8). Additionally, with effective treatment, HIV-infected persons are living longer. In 2009, 36.2% of HIV-infected persons who received medical care were over 50 years old, and this estimate is expected to go over 50% in 2015 (9, 10). Diagnoses common in the ICU setting, such as sepsis, increase drastically with age (11). Sepsis is also independently associated with worse mortality in HIV-infected persons, even in the era of HAART (7, 12). Other comorbid conditions associated with aging with HIV such as cardiovascular disease might also impact mortality in this population. It is unclear if current survival of HIV-infected patients admitted to the ICU with sepsis is as good or worse than HIV-uninfected patients. In this issue of Critical Care Medicine, Cribbs et al (13) compare baseline characteristics and outcomes in HIV-infected and HIV-uninfected persons with severe sepsis admitted to three ICUs in Grady Memorial Hospital. HIV-infected patients were younger and had a lower body mass index, but they were more likely to have a history of chronic dialysis, pneumonia, infection requiring hospitalization, and sepsis. HIV-infected patients also have higher hospital mortality (50% vs 38%; p = 0.007). This association remained significant when controlling for baseline demographics, history of infections, and other predictors of mortality, including the Acute Physiology and Chronic Health Evaluation II score that was available in a subset of HIV-infected and HIV-uninfected persons. While the primary source of infection was most commonly respiratory in both HIV-infected and HIV-uninfected individuals, respiratory was more often the primary source in HIV-infected, 61% versus 48% (p = 0.002); and HIV-infected persons were less likely to have Gram-positive infections (39% vs 53%; p = 0.01), but more likely to have fungal infections such as Pneumocystis, Cryptococcus, and Candida as the primary cause of their sepsis. The difference in outcomes with HIV infection may be related to subtle immune defects even in treated HIV or other underlying factors that remain as unadjusted confounders. A striking finding of the study was that even in a major U.S. city, the population had a low prevalence of HAART use at the time of severe sepsis (22%), and most participants had a CD4 count less than or equal to 200 (79%). Only 11% of HIV-infected participants were new diagnoses of HIV. The distribution of CD4 count was low, even in those on HAART. It is hard to know how outcomes of severe sepsis in HIVinfected persons well controlled on HAART might differ from that found in this study, and caution should be taken 1780
www.ccmjournal.org
when applying results from this study to different ICU populations. Additionally, while HIV treatment is widely available in the Ponce de Leon Center in Atlanta, GA, where most HIV-infected participants in this cohort seek care, there is a disparity in healthcare coverage that likely confounds the relationship between HIV infection and in-hospital mortality in this study. The study also does not elucidate how long-term outcomes may differ between HIV-infected and HIV-uninfected persons after severe sepsis, which may be of even greater divergence considering the premorbid conditions and potential differences in access to care. Cribbs et al (13) show that outcomes in HIV-infected patients admitted to the ICU with severe sepsis are worse than outcomes in HIV-uninfected patients. These data point out the need to improve HIV care and care delivery, both in the acute ICU setting (awareness of the spectrum of infectious causes) and potentially in chronic HIV care delivery. The study has generated questions worth answering to determine why HIVinfected persons have worse outcomes from severe sepsis.
REFERENCES
1. UNAIDS: Global Report: UNAIDS Report on the Global AIDS Epidemic 2013. Available at: http://www.unaids.org/en/KnowledgeCentre/ HIVData/EpiUpdate/EpiUpdArchive/2009/default.asp. Accessed March 19, 2015 2. Kendall CE, Wong J, Taljaard M, et al: A cross-sectional, populationbased study measuring comorbidity among people living with HIV in Ontario. BMC Public Health 2014; 14:161 3. Schein RM, Fischl MA, Pitchenik AE, et al: ICU survival of patients with the acquired immunodeficiency syndrome. Crit Care Med 1986; 14:1026–1027 4. Wachter RM, Luce JM, Turner J, et al: Intensive care of patients with the acquired immunodeficiency syndrome. Outcome and changing patterns of utilization. Am Rev Respir Dis 1986; 134:891–896 5. Akgün KM, Pisani M, Crothers K: The changing epidemiology of HIVinfected patients in the intensive care unit. J Intensive Care Med 2011; 26:151–164 6. Casalino E, Wolff M, Ravaud P, et al: Impact of HAART advent on admission patterns and survival in HIV-infected patients admitted to an intensive care unit. AIDS 2004; 18:1429–1433 7. Greenberg JA, Lennox JL, Martin GS: Outcomes for critically ill patients with HIV and severe sepsis in the era of highly active antiretroviral therapy. J Crit Care 2012; 27:51–57 8. Palacios R, Hidalgo A, Reina C, et al: Effect of antiretroviral therapy on admissions of HIV-infected patients to an intensive care unit. HIV Med 2006; 7:193–196 9. Blair JM, Fagan JL, Frazier EL, et al: Behavioral and clinical characteristics of persons receiving medical care for HIV infection—Medical Monitoring Project, United States, 2009. MMWR Surveill Summ 2014; 63(Suppl 5):1–22 10. Effros RB, Fletcher CV, Gebo K, et al: Aging and infectious diseases: Workshop on HIV infection and aging: What is known and future research directions. Clin Infect Dis 2008; 47:542–553 11. Angus DC, Linde-Zwirble WT, Lidicker J, et al: Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001; 29:1303–1310 12. Rosenberg AL, Seneff MG, Atiyeh L, et al: The importance of bacterial sepsis in intensive care unit patients with acquired immunodeficiency syndrome: Implications for future care in the age of increasing antiretroviral resistance. Crit Care Med 2001; 29:548–556 13. Cribbs SK, Tse C, Andrews J, et al: Characteristics and Outcomes of HIV-Infected Patients With Severe Sepsis: Continued Risk in the Post–Highly Active Antiretroviral Therapy Era. Crit Care Med 2015; 43:1638–1645 August 2015 • Volume 43 • Number 8
Copyright © 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
has been observed to be associated with increased cost and blood loss (11). In summary, data generated in RCT refer to low-risk bleeding patients and probably explain that no difference in the incidence of bleeding was found by Gattas et al (10). Experience with the potential comparative benefits and drawbacks of CBA in actively bleeding or high-risk patients with severe thrombocytopenia or coagulation abnormalities is therefore lacking. Other subgroups, like patients in septic states, in which heparin-based anticoagulation is less effective, and patients with suboptimal vascular access, in whom clotting is a frequent complication, need to be addressed in future CBA clinical research. Current Kidney Disease Improving Global Outcome guidelines consider CBA to be the method of choice for CRRT anticoagulation, if no contraindications for citrate infusion exist (12). With 212 randomized patients and 857 circuits, the trial by Gattas et al (10) is the largest multicenter RCT published so far in the field of CBA. The data generated have significant external validity because of the pragmatic design accepting variability inherent to clinical practice. Also, the main study results are highly significant and lend support to the recommendations. Based on the data given in Gattas et al (10) and other recent studies (5, 6), if no contraindications for citrate infusion exist, CBA should be considered a safer and cheaper option than conventional heparin-based anticoagulation and no longer be reserved for patients at high risk of bleeding.
REFERENCES
1. Wu MY, Hsu YH, Bai CH, et al: Regional citrate versus heparin anticoagulation for continuous renal replacement therapy: A meta-analysis of randomized controlled trials. Am J Kidney Dis 2012; 59:810–818
2. Mehta RL, McDonald BR, Aguilar MM, et al: Regional citrate anticoagulation for continuous arteriovenous hemodialysis in critically ill patients. Kidney Int 1990; 38:976–981 3. Hofbauer R, Moser D, Frass M, et al: Effect of anticoagulation on blood membrane interactions during hemodialysis. Kidney Int 1999; 56:1578–1583 4. Morgera S, Scholle C, Voss G, et al: Metabolic complications during regional citrate anticoagulation in continuous venovenous hemodialysis: Single-center experience. Nephron Clin Pract 2004; 97:c131–c136 5. Stucker F, Ponte B, Tataw J, et al: Efficacy and safety of citrate-based anticoagulation compared to heparin in patients with acute kidney injury requiring continuous renal replacement therapy: A randomized controlled trial. Crit Care 2015; 19:822 6. Schilder L, Nurmohamed SA, Bosch FH, et al; CASH study group: Citrate anticoagulation versus systemic heparinisation in continuous venovenous hemofiltration in critically ill patients with acute kidney injury: A multi-center randomized clinical trial. Crit Care 2014; 18:472 7. Khadzhynov D, Schelter C, Lieker I, et al: Incidence and outcome of metabolic disarrangements consistent with citrate accumulation in critically ill patients undergoing continuous venovenous hemodialysis with regional citrate anticoagulation. J Crit Care 2014; 29:265–271 8. Schultheiß C, Saugel B, Phillip V, et al: Continuous venovenous hemodialysis with regional citrate anticoagulation in patients with liver failure: A prospective observational study. Crit Care 2012; 16:R162 9. Raimundo M, Crichton S, Lei K, et al: Maintaining normal levels of ionized calcium during citrate-based renal replacement therapy is associated with stable parathyroid hormone levels. Nephron Clin Pract 2013; 124:124–131 10. Gattas DJ, Rajbhandari D, Bradford C, et al: A Randomized Controlled Trial of Regional Citrate Versus Regional Heparin Anticoagulation for Continuous Renal Replacement Therapy in Critically Ill Adults. Crit Care Med 2015; 43:1622–1629 11. Oudemans-van Straaten HM, Bosman RJ, Koopmans M, et al: Citrate anticoagulation for continuous venovenous hemofiltration. Crit Care Med 2009; 37:545–552 12. Lameire N, Kellum JA; KDIGO AKI Guideline Work Group: Contrastinduced acute kidney injury and renal support for acute kidney injury: A KDIGO summary (Part 2). Crit Care 2013; 17:205
HIV Infection and Severe Sepsis: A Bitter Pill to Swallow* Matthew R. Gingo, MD, MS Department of Medicine University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center Pittsburgh, PA
*See also p. 1638. Key Words: human immunodeficiency virus; intensive care; sepsis The authors received support for article research from the National Institutes of Health. Copyright © 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved. DOI: 10.1097/CCM.0000000000001053
Critical Care Medicine
Alison Morris, MD, MS Department of Medicine University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center; and Department of Immunology University of Pittsburgh School of Medicine Pittsburgh, PA
I
nfection with HIV affects over 1.3 million people in the United States and over 35 million people worldwide (1). Despite improvements in treatment, HIV is still associated with increased morbidity and mortality. Although infectious complications of HIV and AIDS have decreased, noncommunicable diseases such as cardiovascular disease, chronic obstructive pulmonary disease, end-stage renal disease, and diabetes are becoming more common in HIV-infected persons as they are living longer with highly active antiretroviral therapy (HAART) (2). www.ccmjournal.org
Copyright © 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
1779
Editorials
The impact of HAART has also been seen in the ICU in both the diagnoses seen and their prognoses. In the early AIDS era, mortality for HIV-infected persons admitted to the ICU was very high, and it was often seen as futile to admit these patients to the ICU (3, 4). HAART, in combination with HIV-specific improvements in care such as corticosteroids for Pneumocystis pneumonia and advances in general ICU care such as low tidal volume ventilation, has resulted in an overall improvement in survival of HIV-infected persons admitted to the ICU (5). Causes of ICU admission have also shifted with a decrease in AIDS-associated diagnoses such as Pneumocystis pneumonia; however, respiratory failure has remained the most common cause of ICU admission, and sepsis has increased (5–8). Additionally, with effective treatment, HIV-infected persons are living longer. In 2009, 36.2% of HIV-infected persons who received medical care were over 50 years old, and this estimate is expected to go over 50% in 2015 (9, 10). Diagnoses common in the ICU setting, such as sepsis, increase drastically with age (11). Sepsis is also independently associated with worse mortality in HIV-infected persons, even in the era of HAART (7, 12). Other comorbid conditions associated with aging with HIV such as cardiovascular disease might also impact mortality in this population. It is unclear if current survival of HIV-infected patients admitted to the ICU with sepsis is as good or worse than HIV-uninfected patients. In this issue of Critical Care Medicine, Cribbs et al (13) compare baseline characteristics and outcomes in HIV-infected and HIV-uninfected persons with severe sepsis admitted to three ICUs in Grady Memorial Hospital. HIV-infected patients were younger and had a lower body mass index, but they were more likely to have a history of chronic dialysis, pneumonia, infection requiring hospitalization, and sepsis. HIV-infected patients also have higher hospital mortality (50% vs 38%; p = 0.007). This association remained significant when controlling for baseline demographics, history of infections, and other predictors of mortality, including the Acute Physiology and Chronic Health Evaluation II score that was available in a subset of HIV-infected and HIV-uninfected persons. While the primary source of infection was most commonly respiratory in both HIV-infected and HIV-uninfected individuals, respiratory was more often the primary source in HIV-infected, 61% versus 48% (p = 0.002); and HIV-infected persons were less likely to have Gram-positive infections (39% vs 53%; p = 0.01), but more likely to have fungal infections such as Pneumocystis, Cryptococcus, and Candida as the primary cause of their sepsis. The difference in outcomes with HIV infection may be related to subtle immune defects even in treated HIV or other underlying factors that remain as unadjusted confounders. A striking finding of the study was that even in a major U.S. city, the population had a low prevalence of HAART use at the time of severe sepsis (22%), and most participants had a CD4 count less than or equal to 200 (79%). Only 11% of HIV-infected participants were new diagnoses of HIV. The distribution of CD4 count was low, even in those on HAART. It is hard to know how outcomes of severe sepsis in HIVinfected persons well controlled on HAART might differ from that found in this study, and caution should be taken 1780
www.ccmjournal.org
when applying results from this study to different ICU populations. Additionally, while HIV treatment is widely available in the Ponce de Leon Center in Atlanta, GA, where most HIV-infected participants in this cohort seek care, there is a disparity in healthcare coverage that likely confounds the relationship between HIV infection and in-hospital mortality in this study. The study also does not elucidate how long-term outcomes may differ between HIV-infected and HIV-uninfected persons after severe sepsis, which may be of even greater divergence considering the premorbid conditions and potential differences in access to care. Cribbs et al (13) show that outcomes in HIV-infected patients admitted to the ICU with severe sepsis are worse than outcomes in HIV-uninfected patients. These data point out the need to improve HIV care and care delivery, both in the acute ICU setting (awareness of the spectrum of infectious causes) and potentially in chronic HIV care delivery. The study has generated questions worth answering to determine why HIVinfected persons have worse outcomes from severe sepsis.
REFERENCES
1. UNAIDS: Global Report: UNAIDS Report on the Global AIDS Epidemic 2013. Available at: http://www.unaids.org/en/KnowledgeCentre/ HIVData/EpiUpdate/EpiUpdArchive/2009/default.asp. Accessed March 19, 2015 2. Kendall CE, Wong J, Taljaard M, et al: A cross-sectional, populationbased study measuring comorbidity among people living with HIV in Ontario. BMC Public Health 2014; 14:161 3. Schein RM, Fischl MA, Pitchenik AE, et al: ICU survival of patients with the acquired immunodeficiency syndrome. Crit Care Med 1986; 14:1026–1027 4. Wachter RM, Luce JM, Turner J, et al: Intensive care of patients with the acquired immunodeficiency syndrome. Outcome and changing patterns of utilization. Am Rev Respir Dis 1986; 134:891–896 5. Akgün KM, Pisani M, Crothers K: The changing epidemiology of HIVinfected patients in the intensive care unit. J Intensive Care Med 2011; 26:151–164 6. Casalino E, Wolff M, Ravaud P, et al: Impact of HAART advent on admission patterns and survival in HIV-infected patients admitted to an intensive care unit. AIDS 2004; 18:1429–1433 7. Greenberg JA, Lennox JL, Martin GS: Outcomes for critically ill patients with HIV and severe sepsis in the era of highly active antiretroviral therapy. J Crit Care 2012; 27:51–57 8. Palacios R, Hidalgo A, Reina C, et al: Effect of antiretroviral therapy on admissions of HIV-infected patients to an intensive care unit. HIV Med 2006; 7:193–196 9. Blair JM, Fagan JL, Frazier EL, et al: Behavioral and clinical characteristics of persons receiving medical care for HIV infection—Medical Monitoring Project, United States, 2009. MMWR Surveill Summ 2014; 63(Suppl 5):1–22 10. Effros RB, Fletcher CV, Gebo K, et al: Aging and infectious diseases: Workshop on HIV infection and aging: What is known and future research directions. Clin Infect Dis 2008; 47:542–553 11. Angus DC, Linde-Zwirble WT, Lidicker J, et al: Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001; 29:1303–1310 12. Rosenberg AL, Seneff MG, Atiyeh L, et al: The importance of bacterial sepsis in intensive care unit patients with acquired immunodeficiency syndrome: Implications for future care in the age of increasing antiretroviral resistance. Crit Care Med 2001; 29:548–556 13. Cribbs SK, Tse C, Andrews J, et al: Characteristics and Outcomes of HIV-Infected Patients With Severe Sepsis: Continued Risk in the Post–Highly Active Antiretroviral Therapy Era. Crit Care Med 2015; 43:1638–1645 August 2015 • Volume 43 • Number 8
Copyright © 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
