Intensive Care in Patients With HIV Infection in the Era of Highly Active Antiretroviral Therapy

Intensive Care in Patients With HIV Infection in the Era of Highly Active Antiretroviral Therapy* Mangala Narasimhan, DO; Adam J. Posner, MD; Vera A. DePalo, MD, FCCP; Paul H. Mayo, MD, FCCP; and Mark J. Rosen, MD, FCCP

Study objectives: The use of highly active antiretroviral therapy (HAART) has dramatically improved morbidity and mortality in patients with HIV infection. The types of critical illness and their outcomes in HIV-infected patients in recent years is unknown. Design: We reviewed the medical records of all patients admitted to the Medical ICU of Beth Israel Medical Center, NY, from January to June 2001 and compared their characteristics with patients admitted to the same unit from November 1991 to October 1992. Results: Of 441 admissions in the first half of 2001, 63 admissions (14%) were in 53 HIVseropositive patients. There were 65 admissions to the Medical ICU during the 1-year period spanning 1991 to 1992. Compared with the earlier period, the 2001 patients were more likely to be black (52% vs 26%, respectively; p < 0.01) and injection drug users (75% vs 48%, respectively; p < 0.01), and were less likely to be white (11% vs 23%, respectively; difference not significant) and homosexual men (6% vs 26%, respectively; p < 0.01). In 2001, patients were less likely to be admitted with respiratory failure (22% vs 54%, respectively; p < 0.01) and with Pneumocystis jiroveci pneumonia (formerly referred to as Pneumocystis carinii) [3% vs 34%, respectively; p < 0.001], and were more likely to be admitted with non-HIV–related diseases (67% vs 12%, respectively; p < 0.001). Overall survival was much higher in the later period (71% vs 49%, respectively; p < 0.01). Conclusions: In the era of HAART, more patients with HIV infection were admitted to the ICU over a 12-month period than were 10 years previously. Patients were more likely to be injection drug users and were more likely to be admitted to the ICU because of non-HIV–associated conditions. (CHEST 2004; 125:1800 –1804) Key words: highly active antiretroviral therapy; HIV; intensive care; outcomes; respiratory failure Abbreviations: HAART ⫽ highly active antiretroviral therapy; PCP ⫽ Pneumocystis carinii pneumonia; SFGH ⫽ San Francisco General Hospital

use of highly active antiretroviral therapy T he(HAART) has led to a dramatically improved prognosis for people infected with HIV. Advances in the treatment of HIV infection and improving survival gives reason for optimism that HIV disease is controllable in many patients, a hope reflected in the estimated 362,827 persons living with AIDS in the

United States at the end of 2001.1 However, thousands still acquire life-threatening complications of HIV infection, and almost 9,000 people with AIDS died in the United States in 2001. With the introduction of HAART, the number of hospital admissions for HIV-associated disorders have declined in For editorial comment see page 1602

*From the Division of Pulmonary and Critical Care Medicine (Drs. Narasimhan, Posner, Mayo, and Rosen), Beth Israel Medical Center, Albert Einstein College of Medicine, New York, NY; and Brown University Medical School (Dr. DePalo), Providence, RI. Supported by a grant from the Alan & Barbara Mirken Pulmonary Fund. Manuscript received May 5, 2003; revision accepted November 4, 2003. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: [email protected]). Correspondence to: Mark J. Rosen, MD, FCCP, Beth Israel Medical Center, First Ave at 16th St, New York, NY 10003; e-mail: [email protected] 1800

the United States and Europe, but the impact of new treatments on admissions to ICUs is not known. In the only published study2 to date that addresses the impact of HAART on ICU utilization and outcomes, it seemed that admission rates were unchanged but that mortality rates were improved compared with those in earlier years of the AIDS epidemic. To study the impact of HAART on ICU admission rates, and the reasons for admission and their outcomes, we compared the characteristics of HIV-infected persons admitted to the Clinical Investigations in Critical Care

ICU of an urban hospital over 6 months in 2001, with those of HIV-infected patients who were admitted to the same unit over a 1-year period during 1991 and 1992. We hypothesized that ICU admission rates would have declined due to the benefits of HAART, that patients admitted to the ICU in 2001 may not know their HIV serostatus and therefore may not be using HAART or anti-Pneumocystis carinii pneumonia (PCP) prophylaxis, and that patients would have similar AIDS-related diagnoses on admission to the ICU as the patients studied in the pre-HAART era. Materials and Methods This study was approved by the Beth Israel Medical Center Institutional Review Board. All patients admitted to the Medical ICU were studied prospectively from January through June 2001 (ie, the post-HAART era), and their characteristics were compared with those of patients admitted to the same unit from November 1991 through October 1992 (ie, the pre-HAART era), which were published previously.3 Beth Israel Medical Center is an 847-bed, urban, acute care hospital and has been a designated AIDS treatment center for the past 15 years. There is an affiliated outpatient HIV clinic and an AIDS Clinical Trials Unit. In this study, patients were enrolled if they had HIV infection documented before or during that hospitalization and had been admitted to the ICU for any reason. The Medical ICU has always been a 16-bed unit, which consistently admits around 900 patients annually. Decisions for admission to the ICU and subsequent management always have been made by the full-time staff of the Division of Pulmonary and Critical Care Medicine, and there were no substantive changes in admission and discharge criteria over the 10-year study period. Data were collected on the following: gender; race; age; HIV transmission category; medical history (including opportunistic infections); CD4⫹ lymphocyte count; HIV load; intubation history; CBC count; serum chemistry measurements; microbiological study findings; medications prior to ICU admission, including HAART (defined as any combination antiretroviral therapy) and prophylaxis for Pneumocystis jiroveci and Mycobacterium avium complex infection; hospital course; length of stay; and survival. HIV-associated disorders are defined as AIDSdefining illnesses, as well as bacterial pneumonia. All other illnesses, including hepatitis C, were classified as non-HIV– associated. All statistical analyses were performed using an online calculator (the Online Chi-Square calculator; http://www. georgetown.edu/faculty/ballc/webtools/web_chi.html).

Results During the 6-month study period, there were 441 admissions to the ICU. In all, 96 patients with HIV were admitted to the ICU over a 1-year period, starting October 2000. In the 6-month period of intensive prospective review, 53 HIV-seropositive patients had a total of 63 ICU admissions (14% of all admissions). This group was compared to 65 different patients admitted to the same ICU during the same 1-year period approximately 10 years earlier. The characteristics of the patients admitted to the ICU in both periods are shown in Table 1. In the www.chestjournal.org

Table 1—Demographic Data 1991 to 1992 Compared to 2001* Clinical Data Mean age, yr Gender Male Female Race/ethnicity Black Hispanic White Asian Transmission category Injection drug user Heterosexual contact Unknown Homosexual men Transfusion Perinatal Hemophilia and injection drug use

1991–1992 (n ⫽ 65)

2001 (n ⫽ 53)

p Value

39

42

44 (68) 21 (32)

33 (62) 20 (38)

17 (26) 32 (49) 15 (23) 1 (2)

28 (53) 19 (36) 6 (11) 0

⬍ 0.01

31 (48) 7 (11) 7 (11) 17 (26) 2 (3) 0 1 (2)

40 (75) 4 (8) 4 (8) 3 (6) 1 (2) 1 (2) 0

⬍ 0.01 ⬍ 0.001

*Values given as No. (%), unless otherwise indicated.

post-HAART period, the mean age was 42 years, and 33 patients (62%) were men. Twenty-eight patients (52%) were black, 19 patients (36%) were Hispanic, and 6 patients (11%) were white. Most patients (n ⫽ 40 [75%]) acquired HIV infection by injection drug use, 3 patients (6%) acquired HIV by homosexual transmission, 4 patients (8%) acquired it by heterosexual transmission, 4 patients (8%) had an unknown transmission category, 1 patient acquired it by transmission from blood transfusion, and 1 patient acquired it by perinatal transmission. Compared with the earlier period, patients admitted to the ICU were more likely to be injection drug users (p ⬍ 0.01), while they were significantly less likely to be homosexual men (p ⬍ 0.01). Twenty-eight patients (52%) received HAART at some time before admission to the ICU. Of the 25 patients who never received HAART, 15 patients (60%) fulfilled the criteria for receiving this treatment (CD4⫹ lymphocyte count, ⬍ 200 cells/␮L) or fulfilled the criteria for AIDS-defining illness.4 In comparison, in 1991 to 1992 only 22 patients had received any antiretroviral therapy, and 15 patients received anti-PCP treatment. There was no difference in the outcomes of patients receiving these medications and those who were not. The principal diagnostic categories for ICU admission are listed in Table 2. Patients were admitted to the ICU for respiratory failure, sepsis syndrome, and neurologic, GI, renal, metabolic and cardiovascular disorders. The most common reason for ICU admission in both periods was respiratory failure, but the relative frequency of respiratory failure was lower in CHEST / 125 / 5 / MAY, 2004

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Table 2—ICU Admission Diagnosis and Outcomes (2001 vs 1991–1992)* Diagnosis Category

Admissions 2001

Survival to Hospital Discharge 2001

Admissions 1991–1992

Survival 1991–1992

Total Respiratory failure (all causes) P jiroveci pneumonia Bacterial pneumonia Pulmonary tuberculosis ARDS Kaposi sarcoma Hemoptysis Lung cancer Asthma Unknown Sepsis syndrome Neurologic disease Drug overdose Cardiac Hypotension GI Renal Metabolic Angioedema Pulmonary hypertension Dislodged endotracheal tube Unknown

63 (100) 14 (22)† 2 (3)† 6 (10) 0 1 (2) 1 (2) 1 (2) 1 (2) 2 (3) 0 10 (16) 6 (10)‡ 7 (11) 2 (3) 0 7 (11)§ 8 (13)§ 3 (5) 2 (3) 2 (3) 1 (2) 1 (2)

45 (71) 8 (57) 0 5 (83) 0 1 (100) 0 0 0 2 (100) 0 6 (60) 4 (67) 7 (100) 1 (50) 0 4 (57) 7 (88) 3 (100) 2 (100) 1 (50) 1 (100) 1 (100)

65 (100) 35 (54) 22 (34) 6 (9) 3 (5) 2 (3) 1 (2) 0 0 0 1 (2) 10 (15) 8 (12) 5 (8) 4 (6) 3 (5) 0 0 0 0 0 0 0

32 (49) 13 (37) 8 (36) 4 (67) 1 (33) 0 0 0 0 0 0 5 (50) 5 (63) 3 (60) 3 (75) 3 (100) 0 0 0 0 0 0 0

*Values given as No. (%). †p ⬍ 0.001 (compared to 1991–1992). ‡p ⬍ 0.05 (compared to 1991–1992). §p ⬍ 0.01 (compared to 1991–1992).

2001 (22% vs 54%, respectively; p ⬍ 0.001). Of the patients with respiratory failure, the incidence of Pneumocystis pneumonia was much lower in 2001. Also, no patient had tuberculosis in 2001, compared to three patients in the previous study. Patients were more likely to be admitted to the ICU for reasons other than respiratory failure in the later period, and two thirds of all patients were admitted to the ICU for disorders unrelated to HIV infection, compared with only eight patients (12%) in the pre-HAART period. Overall survival to hospital discharge was significantly higher in the post-HAART era (71% vs 49%, respectively; p ⬍ 0.01). Patients admitted to the ICU for a diagnosis unrelated to HIV infection were as likely to require mechanical ventilation as were those admitted for HIV-associated disorders (48% vs 55%, respectively; difference not significant), and there was no difference in survival rate (67% vs 70%, respectively; difference not significant). Also, there was no association between the use of HAART and mortality. CD4⫹ lymphocyte count was obtained in 49 patients (92%) during the hospital admission associated with the ICU admission, and there was no significant relationship between the degree of reduction in CD4⫹ count and survival (p ⬎ 0.20) [Table 1802

3]. Also, the mode of HIV transmission, sex, ethnicity, and HIV load did not influence mortality. The only laboratory measurement that had a statistically significant inverse correlation with survival was serum albumin level (p ⬍ 0.01). Discussion Before HAART became the standard of care, most patients with HIV infection had progressive immune compromise and eventually succumbed to opportunistic infection, AIDS-associated malignancy, or HIV-associated dementia and wasting. Questions about whether to provide intensive care were inevitable, and the medical literature described the inci-

Table 3—Patients and Mortality by CD4ⴙ Lymphocyte Count, 2001 CD4⫹, cells/␮L ⬎ 200 100–199 50–99 0–49 Unknown

Patients, No.

Mortality Rate, %

19 9 4 17 4

16 33 25 29 50

Clinical Investigations in Critical Care

dences and outcomes of the critical illnesses that HIV-infected persons developed. With the use of HAART, HIV-infected persons enjoyed a reduced risk of immune suppression and the development of AIDS, a reduced incidence of opportunistic infections, and improved survival.5–7 The full impact of HAART on ICU utilization and outcomes has not yet been described. We speculated that the reduced incidence of progression to AIDS and opportunistic infections in the general population would be reflected in the reduced utilization of ICU services, that patients who were admitted to the ICU were likely either to not know their HIV serostatus or to not have used HAART, and that the reasons for ICU admission would be similar to those from earlier in the AIDS epidemic. In this analysis, all of these hypotheses were shown to be incorrect. In fact, intensive care utilization increased over the 10 years, all patients knew they were HIV seropositive, most had used HAART, and the types of disorders they developed and their outcomes were quite different than those seen earlier in the epidemic. Despite ample evidence of favorable outcomes associated with the use of HAART, we saw the same number of ICU admissions in the first half of 2001 as in an entire year approximately 10 years previously.3 This cannot be explained by lack of the use of HAART in our patients, as HIV testing and treatment is accessible through public health programs, all of our patients knew their HIV status, and most reported using HAART at some time. The possibility that increased ICU admissions reflect changes in ICU personnel and policies is unlikely, as the staff is almost identical to that of 10 years ago and the policies have not changed. Rather, the increase in ICU admissions probably reflects the constantly growing population of persons living with HIV infection1 and the emergence of non-HIV–associated conditions as causes of critical illness. Also, our finding of increased numbers of admissions of HIVinfected persons over 10 years differs from the experience at San Francisco General Hospital (SFGH), where ICU admissions declined in the post-HAART era. The impact of HAART on ICU utilization has important implications for health policy and planning, and warrants further study. We found that patients in 2001 were more likely to be injection drug users and black, with a corresponding reduction in the number of ICU admissions of homosexual men and non-black patients. This reflects the demographics of the AIDS epidemic in the United States, where AIDS prevalence, morbidity and mortality have also increased among injection drug users and blacks.1 Race, ethnicity, and mode of HIV transmission also may play a role in the differences in reasons for ICU admission, as black persons may be www.chestjournal.org

less likely to acquire PCP than whites,8 and injection drug users are more likely than other HIV-infected persons to acquire bacterial pneumonia.9 Throughout the AIDS epidemic, respiratory failure has been the most common reason for ICU admission.10 This still seems to be true in the era of HAART. In the current series, 14 patients (22%) were admitted to the ICU because of respiratory failure, and they comprised the largest diagnostic group. In the only other published series2 describing a large number of patients with HIV infection treated in the ICU after the introduction of HAART, investigators at SFGH reported that respiratory failure accounted for approximately 40% of their ICU admissions. However, while they reported that 10.7% of their ICU admissions were for PCP, only two of our ICU admissions (3% [the same patient was admitted twice]) had PCP. We also found that two thirds of our ICU admissions were for nonAIDS–associated diagnoses. This reflects surveys11 indicating that these diagnoses (especially complications of hepatitis C) are now the most common causes of death in HIV-infected persons. In 2001, the overall rate of survival to hospital discharge after ICU admission in HIV-infected patients was 71%, which is much improved from the 49% rate of 10 years earlier. This is identical to the survival rate reported at SFGH in the post-HAART era.2 In 2001, more patients received mechanical ventilation (27 patients vs 23 patients, respectively), but the survival rate was significantly improved (67% vs 21%, respectively), perhaps because a larger proportion of patients received mechanical ventilation for problems other than respiratory failure. Despite the lower incidence of PCP, the prognosis did not improve over time. The one patient with PCP died in 2001, compared with 64% in the earlier study. As in other studies, we found that survival was not influenced by demographic characteristics or CD4⫹ lymphocyte count. In addition, patients with nonAIDS–associated diagnoses were equally likely to survive. In contrast with the SFGH investigators, who found that patients receiving HAART had better ICU outcomes than those who did not, we found no survival advantage in patients using HAART. However, it was not possible to reliably assess adherence to treatment, so we cannot assess the impact of HAART on survival with certainty. As not all patients admitted to the ICU were tested for HIV, their numbers may have been underestimated in both eras. The design of this study inherently limits the applicability of our conclusions to other institutions. Conducted at a single center, these conclusions reflect the hospital admission and discharge policies, and the practice patterns of our staff. In addition, the CHEST / 125 / 5 / MAY, 2004

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patient population at each institution probably has unique characteristics and treatment preferences that influence the types of diseases they acquire and their outcomes. Prospective multicenter studies would be the best way to determine the impact of changing demographics and treatments on critical illness in patients with HIV infection.12 We conclude that, in our institution, ICU admissions in patients with HIV infection have not declined in the era of HAART, and that most patients with critical illness know that they are HIV infected and have used this therapy. The majority of ICU admissions are now for non-HIV–associated disorders. Overall ICU mortality and mortality related to respiratory failure have improved. As earlier studies show, immunocompromise itself (as assessed by CD4⫹ lymphocyte count) does not predict higher mortality rates. Rather, the nature of each patient’s acute illness and physiologic reserve are probably the most important determinants of outcome. References 1 Centers for Disease Control and Prevention. HIV/AIDS surveillance report. MMWR Morb Mortal Wkly Rep 2001; 13:1– 48 2 Morris A, Creasman J, Turner J, et al. Intensive care of human immunodeficiency virus-infected patients during the era of highly active antiretroviral therapy. Am J Respir Crit Care Med 2001; 166:262–267 3 DePalo VA, Millstein B, Mayo P, et al. Outcome of inten-

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sive care in patients with HIV infection. Chest 1995; 107: 506 –510 Panel on Clinical Practices for Treatment of HIV Infection. Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. Available at: http://www.hivatis.org. Accessed April 6, 2004 Palella FJ, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection: the HIV Outpatient Study Investigators. N Engl J Med 1998; 338:853– 860 Valdez H, Chowdhry TK, Asaad R, et al. Changing spectrum of mortality due to human immunodeficiency virus: analysis of 260 deaths during 1995–1999. Clin Infect Dis 2001; 32:1487–1493 Murphy EL, Collier AC, Kalisch LA, et al. Highly active antiretroviral therapy decreases mortality morbidity in patients with advanced HIV disease. Ann Intern Med 2001; 135:17–26 Stansell JD, Osmond DH, Charlebois E, et al. Predictors of Pneumocystis carinii pneumonia in HIV-infected persons: Pulmonary Complications of HIV Infection Study Group. Am J Respir Crit Care Med 1997; 155:60 – 66 Hirschtick RE, Glassroth J, Jordan MC, et al. Bacterial pneumonia in patients with HIV infection: Pulmonary Complications of HIV Infection Study Group. N Engl J Med 1995; 333:845– 851 Rosen MJ, De Palo VA. Outcome of intensive care for patients with AIDS. Crit Care Clin 1993; 9:107–114 Monga HK, Rodriguez-Barrada MC, Breaux K, et al. Hepatitis C infection-related morbidity and mortality among patients with human immunodeficiency virus infection. Clin Infect Dis 2001; 33:240 –247 Beck JM, Rosen MJ, Peavy HH. Pulmonary complications of HIV infection: Report of the Fourth NHLBI Workshop. Am J Respir Crit Care Med 2001; 164:2120 –2126

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