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Length of Stay and Survival after Intensive Care for Severe Pneumocystis carinii Pneumonia
Length of Stay and Survival after Intensive Care for Severe Pneumocystis carinii Pneumonia* A Prospective Study Samuel A. Bozzette, M.D.; David Feigal, M.D., M.RH.; joseph Chiu, M.D.; Daniel Gluckstein, M.D.; Carol Kemper; M.D.; Fred Sattler; M.D.; and the California Collaborative Treatment Group Survival rates for persons reeervmg intensive care for PneumocyBtiB carina pneumonia have improved. However,
the utility of prolonged intensive care for patients who do
not show initial improvement remains unclear. We assessed
survival in a nested cohort study of patients receiving intensive care while participating in a randomized trial of early adjunctive corticosteroids for Pneumocystis pneumonia. Twenty-eight of 251 (II percent) participants were admitted to an intensive care unit. Fourteen (SO percent) of these were discharged alive from the intensive care unit and 11 (39 percent) were discharged alive from the hospital. Survivors and nonsurvivors were similar demographically
Recent studies have demonstrated improved survival rates for persons requiring intensive care for respiratory failure secondary to Pneumocystis carini; pneumonia. However, the utility of prolonged intensive care for these patients remains unclear. We therefore performed a prospective cohort study of patients receiving intensive care while participating in the California Collaborative Treatment Group trial of early adjunctive corticosteroids for Pneumocystis pneumonia." METHODS
At enrollment into the parent randomized adjunctive corticosteroid study, participants had received less than 36 h of intensive care for HIV-related Pneumocystis pneumonia and were not in respiratory failure as defined by the use of mechanical ventilation or a hypoxemia (PaO/estimated FIoJ ratio <75. 8 Participants in this study were those patients in the corticosteroid trial who were admitted to an intensive care unit for clinical deterioration after enrollment. Persons dying in the intensive care unit were compared with persons discharged alive from intensive care and those discharged alive from hospital using chi square tests or t tests as appropriate. A survival curve was generated using the KaplanMeier method and the daily conditional probability of survival (equal to the proportion of those patients still in the intensive care *From the Divisions of Infectious Diseases (Dr. Bozzette) and General Internal Medicine (Dr. Feigal), the University of California, San Diego; the Divisions of Infectious Diseases, the University of California, Irvine (Dr. Chiu), Kaiser-Permanente Medical Center, Los Angeles (Dr. Gluckstein), Santa Clara Valley Medical Center (Dr. Kemper), and the University of Southern California, Los Angeles (Dr. Sattler). This work was supported by the California University-wide AIDS Research Program through the California Collaborative Treatment Group. Manuscript received August 20; revision accepted November 19. Reprint requests: Dr. Bozzette, 2760 Fifth Avenue, San Diego 92103
1404
and with respect to treatment received but differed in the mean days of intensive care received {4.5 vs 8.6 (p=O.02]). The conditional probability surviving to hospital discharge after intensive care dropped steadily from 39 percent at intensive care unit admission to 17 percent after one week and to 0 percent after two weeks. (Cheat 1992; 101:1404-07) AIDS = acquired immunode6ciency syndrome; Flo. = forced inspiratory oxygen; HIV = human immunode6ciency virus; PaO. = arterial oxygen pressure
unit on each day who went on to survive) was calculated for each day of intensive care. RESULTS
Twenty-eight of 251 (11 percent) patients with Pneumocystis pneumonia enrolled in the adjunctive corticosteroid trial were admitted to an intensive care unit between July 23, 1987, and May 29, 1989. Five (18 percent) of these patients were admitted to intensive care on study day 0, 10 (35 percent) on study day 1, and six (22 percent) on study day 2. Twenty-two (79 percent) received mechanical ventilation. Fourteen (50 percent) patients were discharged alive from the intensive care unit and 11 (39 percent) survived the acute episode while three died in the hospital after intensive care unit discharge. Six of the 17 nonsurvivors (35 percent) had care withdrawn and expired on days 4, 4, 7, 9, 11 and 13, while 11 of 17 (65 percent) expired despite continued medical care on days 2, 3, 3, 4, 6, 7, 7, 13, 13, 19 and 21. All 11 (39 percent) patients surviving the acute episode also survived the 12 weeks to the final follow-up visit. The 11 survivors and 17 nonsurvivors of the acute episode were similar with respect to mean age (35 vs 37 years), race (9 [82 percent] vs 14 [82 percent] were white), HIV risk factor (9 [82 percent] vs 12 [71 percent] were homosexual), mean hypoxemia ratio at intensive care unit admission (249 vs 229), mean hospital day at intensive care unit admission (2.5 vs 2.8), mean days since the study opened that the patient enrolled (345 vs 321), and early use of corticosteroids (3 [27 percent] vs 5 [29 percent]), "rescue" corticosteSurvival after Intensive Care for Sewmt pcp (8ozzette et 81)
l .~
en :::J
'5 ~
I Q.
1.0
0.8
0.6 0.4 0.2 0.0
_
--L.IL..L..L.L~....L.IL..L-.LL""'
2 4 6 8 10 12 14 16 18 20
Days in
leu
FIGURE 1. Kaplan-Meier cumulative probability of intensive care unit survival (line) and conditional probability of survival (bars) given that the patient remains in intensive care unit on that day. Patients having care withdrawn because offailure to improve expired on days 4,4, 7, 9, 11 and 13, while patients dying despite continued full care expired on days 2, 3, 3, 4, 6, 7, 7, 13, 13, 19 and 21.
roids (8 [73 percent] vs 13 [77 percent]), or both early and "rescue" corticosteroids (2 [18 percent] vs 3 [18 percent]). For all comparisons, the probability value was >0.2. Survivors and nonsurvivors of the acute episode differed in the mean days of intensive care received (4.5 vs 8.6 [p=0.02]) and there was a trend toward a difference in mean hypoxemia ratio at hospital admission (289 vs 240 [p=0.10]). The survival curve for all patients and conditional probability of surviving after each day in the intensive care unit are shown in Figure
1.
These findings persisted when considering survival to intensive care unit discharge and when excluding the six patients who did not receive mechanical ventilation or the six nonsurvivors in whom respiratory support was withdrawn because offailure to improve. DISCUSSION
This study has prospectively validated other recent retrospective reports of improved outcomes in patients receiving intensive care for Pneumocystis-associated respiratory failure.>" Additionally, an association was demonstrated between length of intensive care unit stay and outcome. The clinical significance of this association is evident in Figure 1 which shows the conditional probability of survival dropping steadily from 39 percent at intensive care unit admission to 17 percent for patients still in the intensive care unit after one week and to 0 percent after two weeks. This result is in contrast to the increasing probability of survival with increasing stay for many other conditions requiring intensive care such as myocardial infarction. 9
This study was limited by its small size and the fact that it included no patients who presented with respiratory failure. The latter probably presents only a mild risk to validity because 75 percent of patients were enrolled within 72 h of presentation. The former undoubtedly caused a poor power to detect additional poor prognostic factors beyond prolonged intensive care unit stay and the trend toward an association between worse oxygenation at presentation and poor outeome.v' However, despite the small size of the study, the association between length of stay and outcome was surprisingly robust in that it persisted even after excluding patients who never received mechanical ventilation or who expired after having ventilatory support withdrawn. Decisions regarding the provision of intensive care to persons in the advanced stages of a fatal illness often are difficult. 10 However, this and other reports indicate that patients receiving intensive care for Pneumocystis pneumonia-associated respiratory failure have a good probability of being discharged alive from the intensive care unit and of surviving the acute episode."? Furthermore, all survivors of the acute episode were alive at a 12-week follow-up and may thus share in the improved prognosis seen in other AIDS patients with a history of Pneumocystis pneumonia." Decisions regarding discontinuation of intensive care for patients who remain critically ill are even more difficult." In this study, the probability of being discharged alive decreased dramatically with increasing length of intensive care unit stay and survival was observed after two weeks of intensive care. Although such findings must be continually reassessed, the prognosis for recovery from P carinii pneumonia after two weeks of intensive care appears to be poor. ACKNOWLEDGMENTS: Other participants in this work at the institutions of the California Colfaborative Treatment Group included: University of California, San Diego- J. A. McCutchan, M.D.; A. W Wu, M.D.; 'I: C. Meng, M.D., D. D. Richman, M.D.; R. Spragg, M.D.; J. Coffman, R.N.; University of Southern California, Los Angeles-J. Leedom, M.D.; T. Boylan, M.D.; B. Alai; M. D. C. Hughlett, R.N.; University of California, IrvineJ. TIDes, M.D.; R. Loya, ~A.; Kaiser Permanente Hospital, Los Angeles-D. Nielsen, M.D.; Santa Clara Valley Medical CenterS. Deresinski, M.D.; O. Lang, R.N. Angie Bartok, M.~H., served as data manager, with Ben Freeman and Jeannie Niosi. The authors wish to thank Dr. Charles van der Horst for his assistance in the development of the ideas which led to this study and Dr. Boger Spragg for his helpful suggestions. REFERENCES
1 Wachter RM, Luce JM, Turner J, Volberding E Hopewell PC. Intensive care of patients with the acquired immunodeficiency syndrome. Am Rev Respir Dis 1986; 134:891-96 2 Brenner M, Ognibene F~ Lack EE, et al. Prognostic factors and life expectancy of patients with acquired immunodeficiency syndrome and Pneumocystis carinU pneumonia. Am Rev Respir Dis 1987; 136:1199-1206 3 El-Sadr ~ Simberfoff MS. Survival and prognostic factors in severe Pneumocystis carinU pneumonia requiring mechanical ventilation. Am Rev Respir Dis 1988; 137:1264-67 CHEST I 101 I 5 I MA~
1992
1405
4 Garay SM, Greene J. Prognostic indicators in the initial presentation of Pneumocystis carin" pneumonia. Chest 1989; 95:76972 5 Friedman Y, Franklin C, Rackow EC, Weil MH. Improved survival in patients with AIDS, Pneumocystis carinii pneumonia, and severe respiratory failure. Chest 1989; 96:862-66 6 EtJeren LS, Nadarajah D, PaIat D. Survival following mechanical ventilation for Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome: a different perspective. Am J Med 1989; 87:401-04 7 Wachter RM, Russi MB, Bloch DA, Hopewell PC, Luce JM. Pneumocy8ti.t carinii pneumonia and respiratory failure in AIDS: improved outcomes and increased use of intensive care units. Am Rev Respir Dis 1991; 143:251-56 8 Bozzette SA, Sattler FR, Chiu J, Wu AW, Gluclcstein D, Kemper C, et ale A randomized trial of early adjunctive corticosteroids
1408
9
10
11
12
in Pneumocystis carinii pneumonia. N Engl J Med 1990; 323: 1451-57 McNeer JF, Wallace AG, Wagner GS, Starmer CF, Rosati RA. The course of acute myocardial infarction: feasibility of early discharge of the uncomplicated patient. Circulation 1975; 51:410-13 Ruark EJ, RafBn TA, and the Stanford University Medical Center Committee on Ethics. Initiating and withdrawing life support: principles and practices in adult medicine. N Engl J Med 1988; 318:25-30 Harris JE. Improved short-term survival of AIDS patients initially diagnosed with Pneumocystis carinii pneumonia, 1984 through 1987. JAMA 1990; 263:397-401 Schneiderman LJ, Spragg RC. Ethical decisions in discontinuing mechanical ventilation. N Engl J Moo 1990; 318:984-88
Survival after Intensive Carefor Sewr8 pcp (Bozzette et 81)
the utility of prolonged intensive care for patients who do
not show initial improvement remains unclear. We assessed
survival in a nested cohort study of patients receiving intensive care while participating in a randomized trial of early adjunctive corticosteroids for Pneumocystis pneumonia. Twenty-eight of 251 (II percent) participants were admitted to an intensive care unit. Fourteen (SO percent) of these were discharged alive from the intensive care unit and 11 (39 percent) were discharged alive from the hospital. Survivors and nonsurvivors were similar demographically
Recent studies have demonstrated improved survival rates for persons requiring intensive care for respiratory failure secondary to Pneumocystis carini; pneumonia. However, the utility of prolonged intensive care for these patients remains unclear. We therefore performed a prospective cohort study of patients receiving intensive care while participating in the California Collaborative Treatment Group trial of early adjunctive corticosteroids for Pneumocystis pneumonia." METHODS
At enrollment into the parent randomized adjunctive corticosteroid study, participants had received less than 36 h of intensive care for HIV-related Pneumocystis pneumonia and were not in respiratory failure as defined by the use of mechanical ventilation or a hypoxemia (PaO/estimated FIoJ ratio <75. 8 Participants in this study were those patients in the corticosteroid trial who were admitted to an intensive care unit for clinical deterioration after enrollment. Persons dying in the intensive care unit were compared with persons discharged alive from intensive care and those discharged alive from hospital using chi square tests or t tests as appropriate. A survival curve was generated using the KaplanMeier method and the daily conditional probability of survival (equal to the proportion of those patients still in the intensive care *From the Divisions of Infectious Diseases (Dr. Bozzette) and General Internal Medicine (Dr. Feigal), the University of California, San Diego; the Divisions of Infectious Diseases, the University of California, Irvine (Dr. Chiu), Kaiser-Permanente Medical Center, Los Angeles (Dr. Gluckstein), Santa Clara Valley Medical Center (Dr. Kemper), and the University of Southern California, Los Angeles (Dr. Sattler). This work was supported by the California University-wide AIDS Research Program through the California Collaborative Treatment Group. Manuscript received August 20; revision accepted November 19. Reprint requests: Dr. Bozzette, 2760 Fifth Avenue, San Diego 92103
1404
and with respect to treatment received but differed in the mean days of intensive care received {4.5 vs 8.6 (p=O.02]). The conditional probability surviving to hospital discharge after intensive care dropped steadily from 39 percent at intensive care unit admission to 17 percent after one week and to 0 percent after two weeks. (Cheat 1992; 101:1404-07) AIDS = acquired immunode6ciency syndrome; Flo. = forced inspiratory oxygen; HIV = human immunode6ciency virus; PaO. = arterial oxygen pressure
unit on each day who went on to survive) was calculated for each day of intensive care. RESULTS
Twenty-eight of 251 (11 percent) patients with Pneumocystis pneumonia enrolled in the adjunctive corticosteroid trial were admitted to an intensive care unit between July 23, 1987, and May 29, 1989. Five (18 percent) of these patients were admitted to intensive care on study day 0, 10 (35 percent) on study day 1, and six (22 percent) on study day 2. Twenty-two (79 percent) received mechanical ventilation. Fourteen (50 percent) patients were discharged alive from the intensive care unit and 11 (39 percent) survived the acute episode while three died in the hospital after intensive care unit discharge. Six of the 17 nonsurvivors (35 percent) had care withdrawn and expired on days 4, 4, 7, 9, 11 and 13, while 11 of 17 (65 percent) expired despite continued medical care on days 2, 3, 3, 4, 6, 7, 7, 13, 13, 19 and 21. All 11 (39 percent) patients surviving the acute episode also survived the 12 weeks to the final follow-up visit. The 11 survivors and 17 nonsurvivors of the acute episode were similar with respect to mean age (35 vs 37 years), race (9 [82 percent] vs 14 [82 percent] were white), HIV risk factor (9 [82 percent] vs 12 [71 percent] were homosexual), mean hypoxemia ratio at intensive care unit admission (249 vs 229), mean hospital day at intensive care unit admission (2.5 vs 2.8), mean days since the study opened that the patient enrolled (345 vs 321), and early use of corticosteroids (3 [27 percent] vs 5 [29 percent]), "rescue" corticosteSurvival after Intensive Care for Sewmt pcp (8ozzette et 81)
l .~
en :::J
'5 ~
I Q.
1.0
0.8
0.6 0.4 0.2 0.0
_
--L.IL..L..L.L~....L.IL..L-.LL""'
2 4 6 8 10 12 14 16 18 20
Days in
leu
FIGURE 1. Kaplan-Meier cumulative probability of intensive care unit survival (line) and conditional probability of survival (bars) given that the patient remains in intensive care unit on that day. Patients having care withdrawn because offailure to improve expired on days 4,4, 7, 9, 11 and 13, while patients dying despite continued full care expired on days 2, 3, 3, 4, 6, 7, 7, 13, 13, 19 and 21.
roids (8 [73 percent] vs 13 [77 percent]), or both early and "rescue" corticosteroids (2 [18 percent] vs 3 [18 percent]). For all comparisons, the probability value was >0.2. Survivors and nonsurvivors of the acute episode differed in the mean days of intensive care received (4.5 vs 8.6 [p=0.02]) and there was a trend toward a difference in mean hypoxemia ratio at hospital admission (289 vs 240 [p=0.10]). The survival curve for all patients and conditional probability of surviving after each day in the intensive care unit are shown in Figure
1.
These findings persisted when considering survival to intensive care unit discharge and when excluding the six patients who did not receive mechanical ventilation or the six nonsurvivors in whom respiratory support was withdrawn because offailure to improve. DISCUSSION
This study has prospectively validated other recent retrospective reports of improved outcomes in patients receiving intensive care for Pneumocystis-associated respiratory failure.>" Additionally, an association was demonstrated between length of intensive care unit stay and outcome. The clinical significance of this association is evident in Figure 1 which shows the conditional probability of survival dropping steadily from 39 percent at intensive care unit admission to 17 percent for patients still in the intensive care unit after one week and to 0 percent after two weeks. This result is in contrast to the increasing probability of survival with increasing stay for many other conditions requiring intensive care such as myocardial infarction. 9
This study was limited by its small size and the fact that it included no patients who presented with respiratory failure. The latter probably presents only a mild risk to validity because 75 percent of patients were enrolled within 72 h of presentation. The former undoubtedly caused a poor power to detect additional poor prognostic factors beyond prolonged intensive care unit stay and the trend toward an association between worse oxygenation at presentation and poor outeome.v' However, despite the small size of the study, the association between length of stay and outcome was surprisingly robust in that it persisted even after excluding patients who never received mechanical ventilation or who expired after having ventilatory support withdrawn. Decisions regarding the provision of intensive care to persons in the advanced stages of a fatal illness often are difficult. 10 However, this and other reports indicate that patients receiving intensive care for Pneumocystis pneumonia-associated respiratory failure have a good probability of being discharged alive from the intensive care unit and of surviving the acute episode."? Furthermore, all survivors of the acute episode were alive at a 12-week follow-up and may thus share in the improved prognosis seen in other AIDS patients with a history of Pneumocystis pneumonia." Decisions regarding discontinuation of intensive care for patients who remain critically ill are even more difficult." In this study, the probability of being discharged alive decreased dramatically with increasing length of intensive care unit stay and survival was observed after two weeks of intensive care. Although such findings must be continually reassessed, the prognosis for recovery from P carinii pneumonia after two weeks of intensive care appears to be poor. ACKNOWLEDGMENTS: Other participants in this work at the institutions of the California Colfaborative Treatment Group included: University of California, San Diego- J. A. McCutchan, M.D.; A. W Wu, M.D.; 'I: C. Meng, M.D., D. D. Richman, M.D.; R. Spragg, M.D.; J. Coffman, R.N.; University of Southern California, Los Angeles-J. Leedom, M.D.; T. Boylan, M.D.; B. Alai; M. D. C. Hughlett, R.N.; University of California, IrvineJ. TIDes, M.D.; R. Loya, ~A.; Kaiser Permanente Hospital, Los Angeles-D. Nielsen, M.D.; Santa Clara Valley Medical CenterS. Deresinski, M.D.; O. Lang, R.N. Angie Bartok, M.~H., served as data manager, with Ben Freeman and Jeannie Niosi. The authors wish to thank Dr. Charles van der Horst for his assistance in the development of the ideas which led to this study and Dr. Boger Spragg for his helpful suggestions. REFERENCES
1 Wachter RM, Luce JM, Turner J, Volberding E Hopewell PC. Intensive care of patients with the acquired immunodeficiency syndrome. Am Rev Respir Dis 1986; 134:891-96 2 Brenner M, Ognibene F~ Lack EE, et al. Prognostic factors and life expectancy of patients with acquired immunodeficiency syndrome and Pneumocystis carinU pneumonia. Am Rev Respir Dis 1987; 136:1199-1206 3 El-Sadr ~ Simberfoff MS. Survival and prognostic factors in severe Pneumocystis carinU pneumonia requiring mechanical ventilation. Am Rev Respir Dis 1988; 137:1264-67 CHEST I 101 I 5 I MA~
1992
1405
4 Garay SM, Greene J. Prognostic indicators in the initial presentation of Pneumocystis carin" pneumonia. Chest 1989; 95:76972 5 Friedman Y, Franklin C, Rackow EC, Weil MH. Improved survival in patients with AIDS, Pneumocystis carinii pneumonia, and severe respiratory failure. Chest 1989; 96:862-66 6 EtJeren LS, Nadarajah D, PaIat D. Survival following mechanical ventilation for Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome: a different perspective. Am J Med 1989; 87:401-04 7 Wachter RM, Russi MB, Bloch DA, Hopewell PC, Luce JM. Pneumocy8ti.t carinii pneumonia and respiratory failure in AIDS: improved outcomes and increased use of intensive care units. Am Rev Respir Dis 1991; 143:251-56 8 Bozzette SA, Sattler FR, Chiu J, Wu AW, Gluclcstein D, Kemper C, et ale A randomized trial of early adjunctive corticosteroids
1408
9
10
11
12
in Pneumocystis carinii pneumonia. N Engl J Med 1990; 323: 1451-57 McNeer JF, Wallace AG, Wagner GS, Starmer CF, Rosati RA. The course of acute myocardial infarction: feasibility of early discharge of the uncomplicated patient. Circulation 1975; 51:410-13 Ruark EJ, RafBn TA, and the Stanford University Medical Center Committee on Ethics. Initiating and withdrawing life support: principles and practices in adult medicine. N Engl J Med 1988; 318:25-30 Harris JE. Improved short-term survival of AIDS patients initially diagnosed with Pneumocystis carinii pneumonia, 1984 through 1987. JAMA 1990; 263:397-401 Schneiderman LJ, Spragg RC. Ethical decisions in discontinuing mechanical ventilation. N Engl J Moo 1990; 318:984-88
Survival after Intensive Carefor Sewr8 pcp (Bozzette et 81)