Outcomes of adult patients with sickle cell disease admitted to the intensive care unit: a case series.
Jérôme Cecchini, MD1, François Lionnet, MD2, Michel Djibré, MD1, Antoine Parrot, MD1, Katia Stankovic Stojanovic, MD2, Robert Girot, MD PhD3, and Muriel Fartoukh MD PhD1.
Supplementary Appendix
Data Collection
Demographics, anamnestic data, and baseline characteristics
Age, sex, body mass index, and dates of hospital and ICU admission were recorded. Baseline characteristics included the type of hemoglobinopathy (homozygous HbSS; compound heterozygous; co-existence of -thalassemia) and the steady-state laboratory values [hemoglobin (Hb), fetal hemoglobin (HbF), lactate dehydrogenase (LDH), serum creatinine and the estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease (MDRD)]. This information were obtained during routine visits distant by at least 1 month from an acute clinical event, and 3 months from a blood product transfusion, except for patients included in a blood transfusion program.
The SCD-related organ damages recorded included retinopathy, cerebral vasculopathy, leg ulcer, priapism, avascular necrosis, cholelithiasis, microalbuminuria or proteinuria. History and frequency of painful crisis and ACS requiring hospitalization were recorded. The clinical severity of SCD was assessed on the clinical severity scoring system described by Hebbel et al. [1] (Table E1). Long-term treatments with folate supplementation, hydroxycarbamide, blood transfusion program, erythropoietin, or iron chelator were recorded.
ICU and hospital stay
Vital parameters, including heart and respiratory rates, blood pressure, pulse oximetry value and pain, were recorded on ICU admission. Pain was assessed using a visual analog scale ranging from 0 (no pain) to 10 (extremely severe pain). The worst values of the 48 hours preceding ICU admission were also recorded. Laboratory values on ICU admission and within the preceding 48 hours included white blood cell and platelet counts, hemoglobin value and its change from baseline, LDH, total bilirubin, aspartate (ASAT) and alanine (ALAT)
aminotransferase, prothrombin ratio and serum creatinine. The lowest value of HbS obtained after transfusion was recorded for homozygous SCD patients.
Life-threatening events present on or developing during ICU admission included acute respiratory failure, shock, acute kidney injury (AKI), and MOF. The reasons for ICU admission and the associated organ failures were separated into SCD-related and unrelated events.
SCD-related events included vaso-occlusive crisis (VOC), ACS, hyperhemolytic transfusion reaction, opioid overdose, and cerebro vascular events (stroke or seizure) [2-5].
Management
Standard care included bed rest, supplemental oxygen, intravenous hydration (30 ml/kg/day), folate supplementation, analgesics and blood products transfusion, as needed [6]. Opioid analgesics administration consisted in intravenous morphine patient controlled-
analgesia. Blood transfusions were more likely administered alone when anemia was pronounced, and combined with phlebotomy when hemoglobin level did not drop enough while the clinical condition worsened, with the correspondence of 300 ml of blood exsanguinated for 1 pack of blood product transfused. Antibiotics were administered anytime an infection was clinically suspected or confirmed. A definite diagnosis of infection was retained when bacteria, fungi or viruses were evidenced in blood, lower respiratory or urinary tracts samplings, or any normally sterile site. Routine microbiological samples included blood and urine samples if core temperature was > 38.5°C. Sputum, blinded protected telescoping catheteror bronchoalveolar lavage samples and urinary antigen tests for Legionella pneumophila and Streptococcus pneumoniae were obtained in case of ACS.
Other microbiological samples were clinically guided.
Inhaled nitric oxide (iNO) was used in case of severe ACS, or as part of enrolment in the iNOSTA study, a randomised controlled trial testing the efficacy and safety of iNO in patients with mild ACS (ClinicalTrials.gov Identifier NCT00748423).
Results
Of the 167 episodes referred to the ICU and the affiliated step-down unit, 29 were excluded from the analysis, because of missing data (n=3), organizational reasons (n=17) or planned postpartum monitoring (n=9). Altogether, 138 admissions were analyzed in 119 patients (Figure 1).
Characteristics in the preceding 48 hours and on ICU admission
The therapeutic management was similar between the 2 groups before ICU admission, consisting in pain control with morphine (83%), non-steroidal anti-inflammatory drugs (26%), steroids (4%), administration of antibiotics (66%), and venous thrombo-embolism prophylaxis (32%). Acute respiratory failure (n=68; 49%), shock (n=10; 7%), and AKI (n=14;
10%) were diagnosed in 74 episodes (54%) on ICU admission. ACS was the most frequent diagnosis on ICU admission (n=99; 72%), whereas it accounted for 20% of the initial diagnoses (Table 3). There were only 8 episodes unrelated to SCD, including postpartum haemorrhage (n=1), skin and soft tissue infection (n=1), influenza A(H1N1)v infection (n=1), Pneumocystis jirovecii pneumonia (n=1), vaginal bleeding (n=1), bronchospasm (n=1), and
parapneumonic pleural effusion (n=2) (Table 3). An infection was microbiologically documented in 29 episodes (21%), more often in the CO group (n=10; 34%) than in the UCO group (n=18; 17%) (p=0.03). The most common infected sites were lung, blood and urines.
The three major pathogens were Streptococcus pneumoniae, Klebsiella pneumoniae and Escherichia coli (Table E3).
Management and outcome
Management and outcome (Table 4)
Mechanical ventilation was administered to 25 episodes (18%), including 21 episodes with a diagnosis of ACS on ICU admission and 23 episodes with a final diagnosis of ACS (Figure E1).
Vaso-active drugs were administered to 10 episodes (7%). Acute kidney injury (AKI) was diagnosed in 14 episodes (10%) on ICU admission, 10 of which required a renal replacement therapy (Table E4).
Table E1. Severity scoring system described by Hebbel et al.[1] and modified by Lee et al. [7]
Clinical manifestations Scoring
Severe painful crisis defined as acute painful event requiring hospital admission and morphine administration
Less than 1 per year: 0 point 1 to 2 per year: 1 point 3 to 5 per year: 2 points More than 5 per year: 3 points Central nervous system damage
documented by MRI or MRA (and conventional arteriography)
No lesion: 0 point
Diagnosis of overt stroke, silent stroke, or cerebral vasculopathy: 2 points
Proliferative retinopathy No lesion: 0 point
Current or previous lesion: 1 point Leg ulceration
No lesion: 0 point
Current or previous history of leg ulceration: 2 points
Aseptic necrosis of bones documented by X-Ray and/or MRI
No bone lesion: 0 point
Aseptic necrosis: 2 points per lesion Renal hemorrhage secondary to papillary
necrosis
No episode: 0 point
History of renal hemorrhage: 1 point ACS diagnosed on the basis of the
association of thoracic pain, dyspnea, and pulmonary infiltrates on Chest-X-Ray
No episode: 0 point
History of documented ACS: 2 points per episode
Priapism
No history of priapism: 0 point
History of stuttering or acute priapism: 1 point
Table E2. Within-group changes during the preceding 48 hours of ICU admission.
Uncomplicated Outcome, n=110
Complicated Outcome, n=28
All episodes, n=138 Changes in clinical characteristics
Values [median (IQR)] within
the preceding 48 hrs of ICU admission P1 value Values [median (IQR)] within
the preceding 48 hrs of ICU admission P2 value P3 value
Heart rate (per min) 106 (93-120) / 98 (86-115) 0.5 114 (100-133) / 113 (100-126) 0.8 0.5
Systolic blood pressure (mm Hg) 120 (107-135) / 122 (114-138) 0.1 108 (100-131) / 120 (108-137) 0.05 0.03 Diastolic blood pressure (mm Hg) 69 (60-77) / 70 (60-80) 0.5 60 (55-75) / 61 (58-75) 0.1 0.2 Respiratory rate (per min) 28 (22-35) / 24 (18-30) 0.002 35 (30-40) / 32 (24-40) 0.08 0.0003 Visual analog scale for pain (points)a 8 (7-10) / 6 (4-8) 0.0001 8 (7-9) / 4 (2-7) 0.02 0.00001 Temperature (°C) 38.5 (37.7-39) / 37.8 (37.2-38.6) 0.004 39.0 (38.5-39.4) / 37.9 (37.4-38.4) 0.006 0.0001 Changes in laboratory values
Hemoglobin (g/dL) 8.1 (6.8-9.3) / 7.9 (7.1-8.9) 0.02 7.4 (5.8-8.1) / 7.2 (5.4-7.7) 0.2 0.007 White cell count (109/L) 16.7 (12.7-19.9) / 16.2 (12.8-20.8) 0.5 16.8 (14.0-19.1) / 16.4 (12.0-23.9) 0.5 0.8 Platelet count (109/L) 319 (223-454) / 295 (226-404) 0.0001 267 (166-338) / 210 (128-299) 0.03 0.00001 Lactate dehydrogenase (IU/L) 557 (390-992) / 563 (377-1102) 0.9 862 (428-1331) / 914 (452-1511) 0.6 0.9
Total bilirubin (mol/L) 58 (36-91) / 51 (30-88) 0.7 44 (36-105) / 76 (34-105) 0.3 0.4
ASAT (IU/L) 56 (38-82) / 59 (37-94) 0.6 68 (54-110) / 85 (49-267) 0.4 0.9
ALAT (IU/L) 38 (26-53) / 37 (25-59) 0.7 34 (22-56) / 40 (26-63) 0.2 0.8
Prothrombin ratio (%) 80 (69-91) / 81 (66-89) 0.3 76 (59-90) / 68 (46-89) 0.5 0.2
Serum creatinine (mol/L) 61 (48-71) / 57 (47-69) 0.02 63 (53-111) / 68 (52-162) 0.9 0.03
Values are indicating median (inter-quartile range). P values refer to within-group paired changes (P1: within Uncomplicated Outcome group;
P2: within Complicated Outcome group) and overall changes (P3).
apain was assessed using a visual analog scale ranging from 0 (no pain) to 10 (extremely severe pain).
Table E3. Site of infection and pathogens involved in microbiologically documented episodes.
Site of infection Pathogen No (%)
Blooda
Klebsiella pneumoniae 1
Candida albicans 1
Aeromonas caviae 1
Staphylococcus aureus 1
All 4
Lower respiratory tract
Streptococcus pneumoniae 5
Streptococcus anginosus (pleural effusion) 1
Klebsiella pneumoniae 2
Staphylococcus aureus 1
Gram-negative bacillus 1
Stomatococcus mucilaginosus 1
Pseudomonas aeruginosa 2
Mucormycosis 1
Pneumocystis jirovecii 1
Influenza A virus 2
All 17
Urinary tract
Escherichia coli 3
Klebsiella pneumoniae 2
Enterococcus faecalis 1
All 6
Miscellaneous
Streptococcus pneumoniae (meningitis) 1
Parvovirus B19 infection 2
Cytomegalovirus infection 2
Cholecystitis 1
Klebsiella pneumoniae (sinusitis) 1
All 7
Values are indicating number (%).
aincluding 1 catheter-related infection.
Table E4. Characteristics of episodes with AKI on ICU admission.
All AKI episodes, n=14
No RRT, n=8
RRT, n=6 Preexisting renal abnormalities
Microalbuminuria or proteinuria, n (%) 10 (71) 6 (75) 4 (67)
Chronic renal insufficiency, n (%) 5 (36) 2 (25) 3 (50)
AKI stages, n (%)a
Baseline eGFR, mL/min/1,73m2 , median (quartile) 99 (58-141) 125 (86-149) 87 (43-99)
Stage 1 10 (71) 7 (88) 3 (50)
Stage 2 2 (14) 0 (0) 2 (33)
Stage 3 2 (14) 1 (13) 1 (17)
Increase in serum creatinine, %b 160 (150-210) 160 (150-170) 200 (170-260) Complicated outcome
No (%) 10 (71) 4 (50) 6 (100)
Need for organ support other than RRT, n (%) 8 (57) 4 (50) 4 (67)
NSAIDs before ICU admission
No (%) 3 (21) 2 (25) 1 (17)
Values are indicating median (inter-quartile range) or number (%).
Definition of abbreviations: AKI = acute kidney injury; eGFR = estimated glomerular filtration rate; ICU = intensive care unit; NSAIDs = non-steroid anti-inflammatory drugs; RRT = renal replacement therapy.
aAKI stage based on serum creatinine on ICU admission and defined as [8]
stage 1: serum creatinine increase ≥ 26.4 µmol/L or serum creatinine increase from baseline ≥ 150-200%.
stage 2: serum creatinine increase from baseline > 200-300%.
stage 3: serum creatinine increase from baseline > 300% or serum creatinine ≥ 354 µmol/L with an acute increase of at least 44 µmol/L.
b as compared with baseline serum creatinine value.
Figure E1. Respiratory management of Acute Chest Syndrome in the intensive care unit.
Abreviations: NIV, Non-invasive ventilation.
Non-invasive ventilation was first administered to 20 episodes during ICU stay, 9 of which were secondarily intubated. NIV failure and success correspond to the need or not for subsequent tracheal intubation, respectively. Altogether, invasive ventilation was administered to 12 episodes (12%) for a median duration of 8 days (1-10).
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