Crit ical Care of theHematopoietic StemCell TransplantRecipient

Bekele Afessa, MDa,*, Elie Azoulay, MD, PhDb

KEYWORDS

� Bone marrow transplantation � Intensive care units� Mechanical ventilation � Mortality � Multiple organ failure� Prognosis

An estimated 50,000 to 60,000 patients undergo hematopoietic stem cell transplanta-tion (HSCT) worldwide annually.1 Peripheral blood is the source of more than 95% ofautologous transplantation in adults. The most common indications for HSCT aremultiple myeloma and lymphoma, accounting for 56%. Multiple myeloma and acuteleukemia are the most common indications for autologous and allogeneic transplan-tation, respectively. Among adults, 44% of allogeneic transplants are from unrelateddonors, and bone marrow accounted for 28% of unrelated donor transplants between2003 and 2006 compared with 66% between 1999 and 2000.1 Very few adults receiveumbilical-cord–blood transplants.

Because their innate and acquired immune systems are impaired, HSCT recipientsfrequently have infectious and noninfectious complications. The post-transplantrecovery of the immune system depends on the underlying disorder, conditioningregimen, stem cell source, and on complications, such as graft-versus-host disease(GVHD). The post-transplant complications follow characteristic time patterns. Thepretransplant conditioning regimen virtually eliminates all preexisting innate andacquired immunity.2 After HSCT, the immune system recovers along predictablepatterns depending on the underlying disorder, stem cell source, and complicationssuch as GVHD. Recovery occurs faster in autologous recipients, in those who receiveperipheral blood stem cell grafts, and after nonmyeloablative conditioning regimen.

The post-transplant period is divided into 3 phases: pre-engraftment, early post-transplant, and late post-transplant. The pre-engraftment phase (0 to 30 days) is

Grant support: None.a Division of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine, 200 FirstStreet SW, Rochester, MN 55905, USAb Service de R�eanimation M�edicale, Hopital Saint-Louis, 1 Avenue Claude Vellefaux, Paris75010, France* Corresponding author.E-mail address: afessa.bekele@mayo.edu (B. Afessa).

Crit Care Clin 26 (2010) 133–150doi:10.1016/j.ccc.2009.09.001 criticalcare.theclinics.com0749-0704/09/$ – see front matter ª 2010 Elsevier Inc. All rights reserved.

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characterized by neutropenia and breaks in the mucocutaneous barriers. During thisphase, the most prevalent pathogens are bacteria and Candida species and, if neutro-penia persists, Aspergillus species. During the period of neutropenia, there is no signif-icant difference in the type of infection between allogeneic and autologous HSCTrecipients.3 The early post-engraftment phase (30 to 100 days) is dominated byimpaired cell-mediated immunity. The effect of this cell-mediated defect is determinedby the development of GVHD and the immunosuppressant medications used to treatit. Cytomegalovirus (CMV), Pneumocystis jiroveci and Aspergillus species are thepredominant pathogens during this phase. The late post-transplant phase (>100days) is characterized by defects in cell-mediated and humoral immunity and infunction of the reticuloendothelial system in allogeneic transplant recipients. Duringthis phase, allogeneic HSCT recipients are at risk of viral infection and infection byencapsulated bacteria such as Haemophilus influenzae and Streptococcuspneumoniae. In endemic areas of the world, pulmonary tuberculosis occurs duringthe late post-transplant phase. After neutrophil engraftment, infections occur morefrequently in allogeneic HSCT recipients.3

Some of the post-transplant complications may be life-threatening and requiretreatment in the intensive care unit (ICU). A recent publication has provided anexcellent review of the critical care outcome of adult and pediatric HSCT recipients.4

This article reviews the critical care support of adult HSCT recipients.

RATE AND REASONS OF ICU ADMISSION

The reported numbers of HSCT recipients admitted to the ICU range from less than5% to more than 55%, with an overall rate of 15.7%.5–15 In the studies of patientstreated before 1995,5–7,12,14,16 272 of 1412 HSCT recipients (19.3%) were admittedto the ICU compared with 371 of 3037 patients (12.2%) after 19959,11,15,17,18

(P<.001). In one study that included only autologous HSCT recipients, less than 6%of them were admitted to the ICU.15 In the only study of adult umbilical-cord–bloodrecipients, 57% of them were admitted to the ICU.11

The most common reason for ICU admission is respiratory (Box 1).5–8,10,11,18,19

Among 844 HSCT recipients admitted to the ICU, the primary reason for admissionwas respiratory in 492 (58.3%).6–8,12,14,15,17–21 Pneumonia and sepsis-induced acutelung injury (ALI)/ARDS are common causes of hypoxemic respiratory failure in HSCTrecipients.22 Airway compromise due to mucositis may also lead to ICU admissionduring the pre-engraftment period.7,8,21 Several noninfectious pulmonary complica-tions can lead to respiratory failure in HSCT patients leading to ICU admission. Amongthese complications, pulmonary edema, DAH, and PERDS usually occur during the first30 days following transplant and IPS can occur at any time following transplant.23–25

Hemodynamic instability in HSCT recipients can be precipitated by hypovolemiaand sepsis. Poor oral intake associated with mucositis and gastrointestinal bleedingassociated with mucositis and thrombocytopenia can lead to hypovolemic shockwith multiple organ dysfunction requiring ICU admission. Autologous and allogeneicHSCT recipients are at increased risk of sepsis during the neutropenic, pre-engraft-ment period. In allogeneic HSCT recipients, GVHD and its treatment lead to prolongedimmunodeficiency with additional risk of sepsis. Hemodynamic compromisesecondary to sepsis was the primary reason for ICU admission in 101 of 548 HSCTrecipients (18.4%) described in the literature.7,12,14,15,18–21 Some studies havedescribed cardiac dysrhythmias to be the primary reason for admission to the ICUin 8% to 17% of HSCT recipients.18,19,21 Thrombocytopenia and GVHD predisposeHSCT recipients to hemorrhagic complications.26 Intracranial bleeding is reported in

Box 1

Main reasons for intensive care unit (ICU) admissions of HSCT recipients

Respiratory system

Airway

Pneumonia

Pulmonary edema

Acute respiratory distress syndrome (ARDS)

Idiopathic pneumonia syndrome (IPS)

Diffuse alveolar hemorrhage (DAH)

Per-engraftment respiratory distress syndrome (PERDS)

Cardiovascular system

Septic shock

Hypovolemic shock (dehydration and bleeding)

Cardiogenic shock

Obstructive shock

Central nervous system

Seizure

Intracranial bleeding

Gastrointestinal system

Gastrointestinal bleeding

Hepatic failure

Neutropenic colitis

Renal failure

Critical Care in Blood and Marrow Transplant 135

2% to 5% of HSCT recipients.26,27 In one autopsy study of 180 HSCT recipients, intra-cranial hemorrhage was found in 32%.28 Seizure and other central nervous manifes-tations are reported to be the primary reason for ICU admission in approximately 11%of HSCT recipients.11,12,15,17–19,21 Although hemostatic complications leading tobleeding and thromboembolic events are common in HSCT recipients,26 gastrointes-tinal bleeding has been reported to be the reason for ICU admission in only 15 of 326(4.6%) patients.7,11,12,15,21 Neutropenic colitis and acute intestinal GVHD can lead toICU admission for perforation and bleeding.7,11,12,15,21,29 Although acute renal failureis common in critically ill HSCT recipients,10 it is reported to be the primary reason forICU admission in less than 5%.11,19,21

ICU COURSE AND COMPLICATIONS

The ICU course of HSCT recipients is complicated with multiorgan dysfunction. Someof the organ dysfunctions occur at ICU admission whereas others develop during theICU course. Single or multiorgan failure has been reported in 64% to 94% and multi-organ failure in 22% to 81% of HSCT recipients admitted to the ICU.15,18,19,30

However, because of variations in organ failure definitions and incomplete reports, itis difficult to determine specific organ failure rates. Respiratory failure is the mostcommon organ failure and develops in most patients. Afessa and colleagues19

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reported ARDS in 62% of their patients. ARDS and interstitial pneumonia were themost common cause of death in the study by Jackson and colleagues.7 Naeem andcolleagues11 reported acute renal failure in 20 (80%) and hepatic failure in 13 (52%)of their 25 umbilical blood transplant recipients admitted to the ICU. A similarly highrate of acute renal failure, in 43 of 57 HSCT recipients (73.7%), was reported byLetourneau and colleagues.10 However, other studies have reported these rates tobe less than 20%.13,21

DIAGNOSTIC INTERVENTIONS

Various diagnostic and therapeutic procedures are performed in HSCT recipientsadmitted to the ICU. An earlier study had reported pulmonary artery catheterizationto be performed in most HSCT recipients admitted to the ICU.5 There are limitedrandomized clinical trials aimed at defining the role of pulmonary artery catheterizationin the critically ill. A review by the Cochrane Collaboration group showed pulmonaryartery catheterization to have no effect on patient outcome, including mortality andlength of stay.31 Most of the recent studies of critically ill HSCT recipients do notmention pulmonary artery catheterization or report a lower use rate.13 The authorsbelieve that the pulmonary artery catheter use rate in the critically ill HSCT recipientmay have declined since the 1996 publication of a retrospective study showing poten-tial harm associated with it.32

The patient’s immune system dysfunction, post-transplant timing, epidemiologichistory, noninvasively obtained microbiological and other laboratory values, and thepattern and rapidity of development of chest radiographic findings often help tonarrow the differential diagnosis and initiate empiric therapy in the critically ill HSCTrecipient presenting with pulmonary infiltrates. However, the atypical presentationsof some common diagnoses, the occurrence of unusual diagnoses, the coexistenceof multiple conditions responsible for the infiltrates, and the detrimental effect ofmissed diagnosis often lead to invasive diagnostic interventions, such as bronchos-copy, and rarely, surgical lung biopsy.33–38 Unfortunately, such invasive proceduresare not without complications in the critically ill HSCT recipient. In a study by Jacksonand colleagues,7 11 patients had invasive mechanical ventilation (MV) initiatedfollowing bronchoscopy or open lung biopsy and 9 of them died.

Recently, Azoulay and colleagues39 have described the role of diagnostic bronchos-copy in hematology and oncology patients, including HSCT recipients with acuterespiratory failure. In this observational, prospective, multicenter study, bronchoscopyprovided the only conclusive result in 33.7% of the patients who underwent the proce-dure.39 However, the bronchoscopy was associated with respiratory deterioration in22 of 45 (49%) patients who were not intubated during the procedure, leading to endo-tracheal intubation for MV support in 16 of them (36%). The noninvasive diagnosticstrategies for evaluation of pulmonary conditions include blood cultures; serologyfor Aspergillus antigen; examination of spontaneously expectorated sputum forbacteria, Aspergillus, and other fungi; induced sputum for P jiroveci; urine antigenfor Legionella pneumophila, and S pneumoniae; CMV circulating antigen; nasopharyn-geal aspirations; and echocardiography.39 Azoulay and colleagues39 included 148patients from 14 medical centers in their prospective, observational study; 141(95.3%) had at least 1 noninvasive evaluation and 101 (68.2%) underwent bronchos-copy. The noninvasive diagnostic strategy led to 105 diagnoses in 94 (66.7%) patientsand the bronchoscopy led to 58 diagnoses in 51 (50.5%) patients. Among the 148diagnoses established in the study, 88 (60.3%) were made only by noninvasive tests,41 (28.1%) only by bronchoscopy, and 17 (11.6%) by both types. There were no

Critical Care in Blood and Marrow Transplant 137

statistically significant difference in mortality between the bronchoscopy andnoninvasive groups. This study highlights that the diagnosis of pulmonary infiltratesin hematology and oncology patients, including HSCT recipients with acute respira-tory failure, can be established by following a noninvasive strategy. However,bronchoscopy plays a complementary role in selected patients.

ORGAN SUPPORT

Almost all critically ill HSCT recipients develop single or multiorgan failure. Pancyto-penia is an expected consequence of the conditioning regimen in HSCT recipients.Neutropenia is a major risk factor for bacterial and fungal infections. Despiteprophylaxis, preemptive and therapeutic use of antibiotics, and administration ofcolony-stimulating factors, infections are common in neutropenic HSCT recipients.The rate of infection depends on the degree and duration of neutropenia. Somerecommend that certain minimal criteria be met before the initiation of granulocytetransfusion: an absolute neutrophil count lower than 500/mL and infection unrespon-siveness to antibiotic therapy for at least 48 hours.40 However, a retrospective,case-control feasibility study of candidates and recipients of HSCT showed no benefitassociated with granulocyte transfusion.41 Similarly, a Cochrane meta-analysis of 8randomized clinical trials concluded that the available evidence was insufficient toeither support or refute the generalized use of granulocyte transfusion therapy inmost neutropenic patients, including HSCT recipients.42

Moreover, granulocyte transfusion is associated with multiple complicationsincluding fever and chills, respiratory failure due to sequestration of cells in the pulmo-nary vasculature, transfusion-associated GVHD, human leukocyte antigen (HLA)alloimmunization, and infection. There are limited data to guide clinicians on whento transfuse platelets to HSCT recipients. In a retrospective study of HSCT recipientsthat excluded patients at high risk of bleeding, an increased risk of bleeding could beestablished only if the platelet count dropped to less than 13,000/mL.43 The AmericanSociety of Clinical Oncology clinical practice guidelines recommend a plateletthreshold of 10,000/mL for transfusion.44 However, platelet transfusion at higher levelsmay be necessary if there is active bleeding, rapid fall in platelet count, or coagulationabnormalities. In the absence of hemodynamic instability, active bleeding, orcomorbidities, red blood cell transfusion is rarely needed if the hemoglobin is greaterthan 7 g/dL.45 To minimize the complications that may arise from leukocyte contam-ination, leukoreduced red blood cells are used for transfusion. To avoid the occur-rence of GVHD, red blood cells must be subjected to irradiation before transfusion.CMV-negative blood components should be administered to CMV seronegativeHSCT recipients.

Vasopressor-requiring shock is a common occurrence in critically ill HSCT recipi-ents. Of 499 HSCT recipients included in 6 studies, 236 (47.3%) required vasopressorsupport.7,8,11,17,19,21 The most common reason for vasopressor administration isseptic shock.19 Shock and other factors predispose the critically ill HSCT recipientto acute renal failure.10 Renal replacement therapy was instituted in 118 of 829HSCT recipients (14.2%) included in 3 studies.7,13,17

MECHANICAL VENTILATION

Most HSCT recipients are admitted to the ICU for respiratory failure and some moredevelop respiratory failure after ICU admission. Older age, active malignancy attime of transplantation, and donor-recipient marrow HLA mismatch are independentrisks for assisted MV after marrow transplantation.46 Among HSCT recipients

Table 1Rate of invasive MV and associated mortality in HSCT recipients admitted to the ICU

Study Years Total Invasive MVMortality ofInvasive MV

Torrecilla14 1981–1987 25 16 (64%) 15 (94%)

Denardo6 1979–1984 50 44 (88%) 40 (91%)

Faber-Langendoen48 1978–1990 191 173 (91%)

Afessa5 1982–1990 35 27 (77%) 25 (93%)

Crawford46 1986–1990 348 333 (96%)

Paz12 1984–1991 36 28 (78%) 27 (96%)

Epler47 1985–1991 71 64 (90%)

Paz16 1984–1993 25 24 (96%)

Jackson7 1988–1993 116 92 (79%) 76 (83%)

Huaringa49 1992–1993 60 55 (92%)

Kress51 1993–1996 20 11 (55%)

Price21 1994–1996 115 48 (42%) 39 (81%)

Khassawneh30 1991–1999 78 58 (74%)

Afessa19 1996–2000 112 62 (55%) 32 (52%)

Kew8 1992–2001 37 25 (68%) 20 (80%)

Soubani18 1998–2001 85 51 (60%) 41 (80%)

Scales13 1992–2002 504 258 (51%) 224 (87%)

Naeem11 1998–2003 25 12 (48%) 10 (83%)

Pene17 1997–2003 209 122 (58%) 103 (84%)

Trinkaus15 2001–2006 34 20 (59%) 11 (55%)

Total 805/1383 (58.2%) 1381/1598 (86.4%)

Abbreviation: MV, mechanical ventilation.

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admitted to ICU, 42% to 88% receive invasive MV (Table 1).5–8,11–15,17–19,21 Themortality rate associated with invasive MV exceeded 80% in most of the reportedstudies, with an overall survival rate of only 13.6% (see Table 1).5–8,11–19,21,30,46–51

There are conflicting data regarding the factors that influence the outcome of HSCTrecipients receiving MV. Price and colleagues21 reported peripheral blood stem cellsource to be associated with lower mortality. However, this was not confirmed inthe study by Afessa and colleagues.19 The cause of the respiratory failure is likely toinfluence the prognosis of MV in HSCT recipients. Survival is better for patientsintubated for DAH or pulmonary edema.7,49 In the study by Huaringa and colleagues,49

5 of 26 patients with DAH, 4 of 33 patients with pneumonia, and all 4 patients whoexperienced congestive heart failure/pulmonary edema survived. However, of the 7patients with idiopathic pneumonia syndrome, bronchiolitis obliterans organizingpneumonia, multisystem organ failure, or recurrent malignancy, none survived. Themortality rate was 100% in the patients who had CMV pneumonitis (n 5 9), aspergil-losis (n 5 5), and respiratory syncytial virus (n 5 4).49

Two studies had shown MV duration of more than 4 and 7 days to be associatedwith 100% mortality.6,14 However, this was not confirmed by later findings.7,18 In thestudy by Scales and colleagues,13 7% of the patients intubated for 10 days or moresurvived. In the study by Faber-Langendoen and colleagues,48 7 of the 16 30-daysurvivors received MV for 30 days or more and 2 for 3 months or more. Despite thehigh short-term mortality rate associated with invasive MV, some patients survive

Critical Care in Blood and Marrow Transplant 139

long-term. Two large transplant centers with 539 patients in total, each reporteda 6-month survival rate of 3%.46,48 In the study by Jackson and colleagues,7 9 of 92patients (10%) were alive at a median of 55 months postextubation. In the study byHuaringa and colleagues,49 5% were alive at 6 months. In the study by Khassawnehand colleagues,30 13 of 78 (17%) were alive at 6 months. In the study by Scales andcolleagues,13 the 1-year mortality of MV recipients was 87%. In the study by Peneand colleagues,17 6-month and 1-year survival was 14% and 10.6%, respectively.

NONINVASIVE POSITIVE PRESSURE VENTILATION

Despite some improvement, the prognosis of HSCT recipients requiring endotrachealintubation and MV has remained dismal. The use of noninvasive positive pressureventilation (NPPV) in patients with hematologic malignancy and acute respiratoryfailure improves gas exchange and reduces tachypnea.52 A randomized clinical trialof 52 immunocompromised patients, including 17 HSCT recipients with pulmonaryinfiltrates had shown that NPPV reduces endotracheal intubation and serious compli-cation rates, and it reduces mortality.53 The success of NPPV requires its earlyapplication and experienced staff with dedicated time. In a study of 237 mechanicallyventilated patients with cancer, including 42 HSCT recipients admitted to the ICU,Azoulay and colleagues54 have documented improvement in mortality in recent years.Using multiple logistic regression analysis, they showed that NPPV was partly respon-sible for the improved survival. Selected HSCT recipients with quickly reversible acuterespiratory failure are likely to benefit from NPPV. However, the available data arescarce. Afessa and colleagues19 reported on 71 patients treated with positive-pres-sure MV: NPPV only in 9 (13%), invasive only in 47 (66%), and combined invasiveand NPPV in 15 (21%). In the study by Pene and colleagues,17 66 patients (32%)were initially treated with NPPV for a median of 2 days, of whom 44 (66%) subse-quently received invasive MV. The hospital mortality of the 22 patients treated onlywith NPPV was 55% compared with 82% receiving invasive MV.17

THE IMPORTANCE OF RECENT CLINICAL TRIALS IN CRITICAL CARE

After decades of failure and negative results, recent clinical trials in critical care haverevealed that some interventions improve the outcome of the critically ill. In a random-ized clinical trial, Van de Berghe and colleagues55 showed intensive insulin therapyaimed at achieving blood glucose levels between 80 and 110 mg/dL reduces themortality rate of critically ill surgical patients, a significant number of them receivingparenteral nutrition. However, the result could not be confirmed in other groups ofpatients.56,57 Moreover, intensive insulin therapy may predispose critically ill septicpatients to hypoglycemia-related adverse effects.58

The ARDS Network group has shown that tidal volume of 6 (vs 12) mL/kg ofpredicted weight is associated with reduced mortality and duration of MV in patientswith ALI and ARDS.59

In a randomized clinical trial of patients with septic shock refractory to vasopres-sors, Annane and colleagues60 showed that a 7-day treatment with low-dosehydrocortisone and fludrocortisone reduces mortality in a subgroup of patients withrelative adrenal insufficiency. However, the finding was not confirmed by a later trialthat used different inclusion criteria and treatment.61 In a randomized clinical trial of1690 patients with severe sepsis and septic shock, treatment with recombinanthuman activated protein C reduced mortality.62 However, the potentially life-threat-ening complication of recombinant human activated protein C and the prematuretermination of subsequent studies have led to controversies and its limited use in

Afessa & Azoulay140

clinical practice.63 In the randomized clinical trial by Rivers and colleagues,64 earlygoal-directed therapy reduced the mortality rate of patients with severe sepsis andseptic shock from 46.5% to 30.5%. Although there may not be clarity about whichcomponent of the therapy is responsible for the mortality reduction, its applicationin clinical practice has led to significant reduction of sepsis-associated mortalityworldwide.65

The International Surviving Sepsis Campaign Guidelines make several recommen-dations for the management of the critically ill, based on the Grades of Recommen-dation, Assessment, Development and Evaluation (GRADE) system to rate theavailable evidence and the strength of recommendation.66 We have listed some ofthese recommendations in Table 2. However, we advise caution when applyingthese recommendations to the critically ill HSCT recipient. Although the SurvivingSepsis Campaign recommendations were based on the available clinical trials,HSCT recipients were inadequately represented or actively excluded from most ofthese trials. The authors believe that early goal-directed therapy for severe sepsisand septic shock and a lung protective strategy with low tidal volume for ALI/ARDS are likely to benefit critically ill HSCT recipients. It is advisable to avoid hypo-glycemia and hyperglycemia. However, the available conflicting data do not providestrong support to make specific recommendations about the target glucose level forcritically ill HSCT recipients. Although the role of short-term, low-dose corticosteroidfor septic shock has not been specifically studied in HSCT recipients, the authorsbelieve it is unlikely to have significant adverse effect. HSCT recipients were activelyexcluded from the original clinical trial evaluating the role of recombinant humanactivated protein C.62 An open-label, multicenter, single-arm clinical trial to investi-gate the safety and efficacy of recombinant human activated protein C in HSCTrecipients with severe sepsis was prematurely terminated due to low enrollment: 7patients at 3 of the 15 sites.67 Among 6 of the 7 patients who completed the

Table 2Recommendations for the management of severe sepsis based on the 2008 InternationalSurviving Sepsis Campaign Guidelines66

Recommendation Level of Evidence

Fluid resuscitation targeting central venous pressure of 8 (12 ifpositive-pressure ventilation) mm Hg

1C

Vasopressors to maintain mean arterial pressure of 65 mm Hg 1C

If central venous oxygen saturation <70% or mixed venous oxygensaturation <65% despite fluid, and hematocrit <30%, consider redblood cell transfusion

2C

If central venous oxygen saturation <70% or mixed venous oxygensaturation <65% despite fluid and hematocrit R30%, considerdobutamine

2C

Consider low dose intravenous hydrocortisone for septic shock poorlyresponsive to fluid and vasopressors

2C

Consider recombinant human activated protein C for sepsis inducedorgan dysfunction with APACHE II score R25

2B

Target a tidal volume of 6 mL/kilogram of predicted weight whenventilating patients with ALI/ARDS

1B

Use intravenous insulin to control hyperglycemia in patients withsevere sepsis

1B

Abbreviation: APACHE, Acute Physiology And Chronic Health Evaluation.

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drug infusion, 2 experienced serious bleeding, a nonfatal DAH, and a fatal intracra-nial hemorrhage. The available evidence does not justify the use of recombinanthuman activated protein C in HSCT recipients.

MORTALITY

Several studies have reported the short-term mortality rate of HSCT recipientsadmitted to the ICU (Table 3).5–8,12,14–21,68–70 Overall, 772 of 1193 (65%) patientsdied in the hospital or within 30 days of ICU discharge (see Table 3). Limited dataare available with regard to long-term mortality rate. The 6- to 12-month mortality ratesrange between 67% and 96%, with overall rate 74% (see Table 3). The outcome ofHSCT recipients admitted to the ICU has improved over the years. Of 267 patientstreated in the ICU before 1995,5–7,12,14,16 212 (79.4%) died compared with 327 of502 patients (62.9%) treated after 19958,11,15,17–19,69 (P<.001). This improvement ofsurvival over time may be due to selection bias. The earlier literature reported a veryhigh mortality rate. This may have led health care providers to refuse admission ofselected critically ill HSCT recipients to the ICU and also caused reluctance amongHSCT recipients to be admitted there.48,71 Other possible explanations for theimproved outcome include wider use of colony-stimulating factors for neutropenia,more frequent use of autologous transplant, use of peripheral blood stem cell trans-plantation, use of corticosteroids for respiratory failure due to DAH and PERDS, earlierapplication of noninvasive ventilation, lung protective strategies for acute lung injury,and early goal-directed therapy for severe sepsis.

Table 3The mortality of HSCT recipients admitted to the ICU

Study Year TotalHospital and30-Day Death (%)

6-Month to 1-YearDeath (%)

Denardo6 1979–1984 52 43 (83) 50 (96)

Torrecilla14 1981–1987 23 22 (96)

Afessa5 1982–1990 35 27 (77)

Paz 112 1984–1991 36 24 (67)

Paz 216 1991–1993 10 7 (70)

Jackson7 1988–1993 111 89 (80)

Price21 1994–1996 115 62 (54)

Groeger68 1994 253 141 (56)

Staudinger70 38 30 (79) 36 (95)

Afessa 219 1996–2000 112 58 (52)

Kim69 1999–2001 18 17 (94)

Kew8 1992–2001 37 23 (62) 29 (84)

Soubani18 1998–2001 85 50 (59) 55/76 (72)

Scales13 1992–2002 504 340 (67)

Naeem11 1998–2003 25 18 (72)

Pene17 1997–2003 209 141 (67) 165 (79)

Trinkaus15 2001–2006 34 20 (59)

Overall mortality 772/1193 (65) 675/916 (74)

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PROGNOSTIC FACTORS

There are several prognostic factors that may influence the outcome of HSCTrecipients admitted to the ICU (Box 2). Advanced age, coexisting comorbidities,and lower functional status have an adverse effect on survival. Allogeneic HSCT hashigher 100-day mortality than autologous HSCT.1 The 100-day post-transplantmortality of autologous HSCT recipients with multiple myeloma is less than 5%,whereas it exceeds 10% in acute leukemia not in remission.1 In allogeneic transplantrecipients with leukemia not in remission, the 100-day mortality exceeds 20%.1 Inautologous HSCT recipients, the most common cause of death is underlying diseaserelapse (70%), followed by infection (8%) and organ toxicity (6%).1 In allogeneic HSCTrecipients from HLA-identical sibling donors, the most common cause of death isunderlying disease relapse (41%), followed by infection (17%), GVHD (13%), andorgan toxicity (10%). In allogeneic HSCT recipients from unrelated donors, the mostcommon cause of death is underlying disease relapse (34%), followed by infection(20%), GVHD (14%), and organ toxicity (10%). Except in patients with active disease,patients receiving allogeneic transplants after reduced-intensity conditioning havelower early mortality.1

In the studies that reported the type of transplant, the mortality rate of allogeneicHSCT recipients admitted to ICU was 70.0% (604 of 867) compared with 58.3%(319 of 588) of autologous HSCT recipients (P<.001).5–8,11–13,15,18,19,68–70,72,73 GVHDis also a poor prognostic factor in the critically ill HSCT recipient.17,49 The availabledata do not show clear association between ICU mortality and source of stem cell.In the study by Price and colleagues,21 there was no significant difference in overallmortality between peripheral blood stem cell and bone marrow transplant recipients.However, in patients receiving MV, the mortality rate was lower in peripheral bloodstem cell recipients. Subsequent studies have not found an association betweenstem cell source and ICU mortality.17,19 There are limited data with regard to umbilical

Box 2

Prognostic factors influencing the outcome of the critically ill HSCT recipient

Pretransplant

Age

Functional status

Underlying diagnosis

Transplant-related

Disease status at transplant

Conditioning regimen

Transplant type

Source of stem cell

ICU-related

Reason for ICU

Admission

Organ failure

Severity of critical illness

Critical Care in Blood and Marrow Transplant 143

cord blood transplantation and ICU outcome. In one study that included only umbilicalcord blood stem cell recipients, the short-term mortality rate was 72%, which iscomparable to other sources.11 Among the 209 allogeneic HSCT recipients reportedby Pene and colleagues,17 the stem cell source was bone marrow in 67%, peripheralblood in 28%, and umbilical cord blood in 5%. The stem cell source had no effect onmortality.

The reason for ICU admission and the timing of the admission may influenceoutcome. Some studies have shown the presence of pneumonia,11 gram-negativeinfection,15 and infection or gastrointestinal bleeding21 at ICU admission to be associ-ated with increased mortality. There are conflicting data addressing the effect of thetiming of ICU admission after transplant on mortality. Some studies have shownthat ICU admission during an earlier period following HSCT is associated with highermortality rate,21,48,74 whereas others have found to the contrary.17,21 Several otherstudies have not found statistically significant association between timing of ICUadmission and mortality.7,19,49,71

The authors have described earlier the dismal prognosis of respiratory failurerequiring invasive MV. The development of nonrespiratory organ failure also correlateswith increased mortality.7,8,11,13–15,17,19,21 Jackson and colleagues7 reported 100%mortality for patients admitted to ICU with multiorgan failure. In the study by Scalesand colleagues,13 the 1-year mortality rate of HSCT recipients who received hemodi-alysis in the ICU was 94%. In a study by Soubani and colleagues,18 no patient withserum lactate of more than 6 survived.

ARDS and severe sepsis are frequent complications of critically ill HSCT recipients.In a study by Afessa and colleagues,19 the 30-day mortality rate of patients with ARDSwas 74% compared with 35% of those without ARDS, and the mortality rate ofpatients with sepsis was 70% compared with 23% of those without sepsis.

MORTALITY PREDICTION

The clinical decision-making process regarding the critically ill often requires theactive participation of health care providers and patients and surrogates. This processis facilitated by knowledge of the patient’s prognosis. Although they have no role inindividual patient decision-making, there are several adult ICU prognostic modelsdeveloped and validated to predict the probability of hospital death.75 The adult ICUprognostic models are derived from age, comorbidities, lead time bias, ICU admissiondiagnosis and admission source, and physiologic variables. The latest versions of theadult ICU prognostic models are Simplified Acute Physiology Score (SAPS) 3,76,77

Acute Physiology and Chronic Health Evaluation (APACHE) IV78 and Mortality Predic-tion Model (MPM) III.79 The pertinent comorbidities included in these models areimmunosuppression/hematologic malignancy in APACHE IV,78 hematological malig-nancies in SAPS 3,76,77 and metastatic neoplasm in MPM III.79 There are no data eval-uating the performance of these new models in predicting the prognosis of thecritically ill HSCT recipient. Although these models were based on data from tensand hundreds of thousands of patients, critically ill HSCT patients were not adequatelyrepresented. Among the older generation adult ICU prognostic models, APACHE II80

and III,81 SAPS II,82 and MPM II83 have been studied in the critically ill HSCT recipient.Several studies have shown nonsurvivors to have higher APACHE II7,12,15,18,21 andAPACHE III19 scores, and MPM II predicted probability of death18,21 compared withsurvivors. APACHE II, SAPS II, and MPM II models underestimate the mortality rateof the HSCT patient admitted to the ICU.5,7,21 In the study by Jackson andcolleagues,7 mortality was 100% when APACHE II score exceeded 45. In a study of

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414 patients with cancer, including 38 HSCT recipients admitted to the ICU, allpatients with APACHE III score exceeding 80 died in the ICU.70 Most of the studiesaddressing the role of the adult ICU prognostic models in HSCT recipients did notdescribe the discrimination and calibration of the models. In the study by Afessaand colleagues,19 the observed and APACHE III-predicted hospital mortality rateswere 46% and 42%, respectively, and the area under the receiver operating charac-teristic curve was 0.704 with good calibration (Hosmer-Lemeshow statistic 6.563,P 5 .564).

Accurate estimation of the risk of death is important in clinical trials, epidemiologicstudies, and most importantly, in clinical practice. Because of the high human andfinancial costs, the accurate estimation of risk is most important in ICU patients.Because prediction models, including the adult ICU ones based on data from thegeneral population, are unlikely to give us accurate estimation for the risk of HSCTrecipient death, some have tried to develop disease-specific models. Parimon andcolleagues84 had reported a model for predicting the 2-year risk of death followingallogeneic HSCT. However, this model is not specific for HSCT patients admitted tothe ICU. Groeger and colleagues68 developed and validated a model for predictingmortality of patients with cancer, including 253 HSCT recipients admitted to theICU. The study included 1713 patients from 4 large cancer centers. The modelincluded 16 predictor variables: PaO2/FIO2 ratio, platelet count, respiratory rate,systolic blood pressure, pre-ICU hospital days, intracranial mass effect, allogeneicbone marrow transplantation, recurrent or progressive cancer, albumin less than2.5 g/dL, bilirubin 2 mg/dL or more, Glasgow Coma Scale score less than 6,prothrombin time more than 15 seconds, blood urea nitrogen more than 50 mg/dL,endotracheal intubation, performance status before hospitalization, and cardiopulmo-nary resuscitation.68 The calibration was good for the development and validationmodels. The areas under the receiver operating characteristic curves were 0.812and 0.802 for the development and validation models, respectively. Although otherstudies have also reported multiple logistic regression models based on variablesobtained in HSCT recipients admitted to the ICU,7,19,21 they are not as well describedand validated as the model by Groeger and colleagues.68

TRIAGE FOR ICU ADMISSION

Intensivists and hematologists/oncologists often face the question of whether or not totransfer a clinically deteriorating HSCT recipient to the ICU. Because most of the inten-sivists do not participate in the pre- and post- ICU care of HSCT recipients, they arefamiliar only with the tip of the iceberg. Thiery and colleagues85 reported that intensiv-ists and hematologists/oncologists disagree 15% of the time on ICU admission triagedecisions for patients with cancer. Appropriate triage for ICU admission is extremelyimportant, especially in institutions with limited critical care resources, and it requiresthe active participation of intensivists, hematologists/oncologists, and patients andtheir surrogates for health care. There is a consensus in principle that patients toowell or too sick to benefit from ICU support should be denied ICU admission. However,the intensivists’ judgement in determining who is sick enough to benefit from ICUadmission is far from perfect. In a prospective study of 206 patients with cancer consid-ered for ICU admission, the intensivists considered 47 patients (22.8%) too well and 54patients (26.2%) too sick to benefit from ICU admission.85 Of the 47 patients consideredtoo well, 13 (28%) were subsequently admitted to ICU. The 30-day mortality rate of the54 patients considered too sick was 74%. One of the authors’ institutions hasimplemented a triage policy for ICU admission of patients with cancer.86 According

Fig. 1. Suggested approach in triaging hematopoietic stem cell recipients for ICU admission.

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to the policy, patients with cancer who have previously untreated malignancy, acutetumor lysis syndrome, or a bulky or infiltrating tumor at the earliest phase of treatment,and patients in complete remission are admitted to the ICU for full, unlimited support.Bedridden patients and patients with palliative care as the only treatment option andthose who refuse ICU admission are not admitted. All other groups of patients areadmitted to ICU on a trial basis, with full ICU support for 4 days and reevaluation onday 5 for the appropriate level of care. In a prospective study, called the ICU Trial, Le-cuyer and colleagues86 reported their experience with such a policy. Among 188patients (including 24 autologous HSCT recipients) admitted for ICU Trial, 85 (45.2%)died within the first 4 ICU days. Among the 103 5-day survivors, 14 had received and31 were scheduled to receive autologous HSCT; all those who received MV, vasopres-sors, or dialysis beyond the third ICU day died.86 With improving critical care support,there are several reports of HSCT recipients who survive 3 days of MV and other ICUorgan support. Based on the available data, the authors recommend saying ‘‘yes’’more often than ‘‘no’’ in considering HSCT recipients for ICU admission (Fig. 1).87

Lowering the level of care after ICU trial is not an uncommon practice. In the study byDeNardo and colleagues,6 do-not-resuscitate (DNR) orders were written in 26 of 50HSCT recipients (52%) at a mean of 10 days after ICU admission. Similarly, in 2 studiesfrom Mayo Clinic, DNR orders were written in 24 of 35 (68%) and 40 of 112 (36%) HSCTrecipients.5,19 In the study by Soubani and colleagues,18 22 of 33 ICU deaths followedlife support withdrawal.

SUMMARY

HSCT recipients often develop life-threatening complications following transplant forlethal conditions. Although the mortality rate of HSCT recipients admitted to the ICUhas declined over the last 2 decades, it still exceeds 80% in those receiving MV.With improvement in transplantation and critical care, we expect the prognosis ofthe critically ill to get better. Researchers need to continue their efforts to find bettertreatment modalities and describe the effect of the modalities on patient outcome.For appropriate use of limited ICU resources, reliable prognostication models needto be developed. When triaging HSCT recipients for ICU admission, the status ofthe patients’ underlying disease, short- and long-term prognostic factors, and thepatients’ wishes should be incorporated into the decision-making process.

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