Supplementary Appendix

Transcription

1 Outcomes of adult patients with sickle cell disease admitted to the intensive care unit: a case series. Jérôme Cecchini, MD 1, François Lionnet, MD 2, Michel Djibré, MD 1, Antoine Parrot, MD 1, Katia Stankovic Stojanovic, MD 2, Robert Girot, MD PhD 3, and Muriel Fartoukh MD PhD 1. Supplementary Appendix

2 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)

3 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 controlledanalgesia. 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 catheter or 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.

4 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 NCT ). 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.

5 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).

6 Table E1. Severity scoring system described by Hebbel et al.[1] and modified by Lee et al. [7] Clinical manifestations Severe painful crisis defined as acute painful event requiring hospital admission and morphine administration Central nervous system damage documented by MRI or MRA (and conventional arteriography) Proliferative retinopathy Leg ulceration Aseptic necrosis of bones documented by X-Ray and/or MRI Renal hemorrhage secondary to papillary necrosis ACS diagnosed on the basis of the association of thoracic pain, dyspnea, and pulmonary infiltrates on Chest-X-Ray Priapism Scoring 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 No lesion: 0 point Diagnosis of overt stroke, silent stroke, or cerebral vasculopathy: 2 points No lesion: 0 point Current or previous lesion: 1 point No lesion: 0 point Current or previous history of leg ulceration: 2 points No bone lesion: 0 point Aseptic necrosis: 2 points per lesion No episode: 0 point History of renal hemorrhage: 1 point No episode: 0 point History of documented ACS: 2 points per episode No history of priapism: 0 point History of stuttering or acute priapism: 1 point

7 Table E2. Within-group changes during the preceding 48 hours of ICU admission. Changes in clinical characteristics Uncomplicated Outcome, n=110 Values [median (IQR)] within the preceding 48 hrs of ICU admission P1 value Complicated Outcome, n=28 Values [median (IQR)] within the preceding 48 hrs of ICU admission P2 value All episodes, n=138 P3 value Heart rate (per min) 106 (93-120) / 98 (86-115) ( ) / 113 ( ) Systolic blood pressure (mm Hg) 120 ( ) / 122 ( ) ( ) / 120 ( ) Diastolic blood pressure (mm Hg) 69 (60-77) / 70 (60-80) (55-75) / 61 (58-75) Respiratory rate (per min) 28 (22-35) / 24 (18-30) (30-40) / 32 (24-40) Visual analog scale for pain (points) a 8 (7-10) / 6 (4-8) (7-9) / 4 (2-7) Temperature ( C) 38.5 ( ) / 37.8 ( ) ( ) / 37.9 ( ) Changes in laboratory values Hemoglobin (g/dl) 8.1 ( ) / 7.9 ( ) ( ) / 7.2 ( ) White cell count (10 9 /L) 16.7 ( ) / 16.2 ( ) ( ) / 16.4 ( ) Platelet count (10 9 /L) 319 ( ) / 295 ( ) ( ) / 210 ( ) Lactate dehydrogenase (IU/L) 557 ( ) / 563 ( ) ( ) / 914 ( ) Total bilirubin ( mol/l) 58 (36-91) / 51 (30-88) (36-105) / 76 (34-105) ASAT (IU/L) 56 (38-82) / 59 (37-94) (54-110) / 85 (49-267) ALAT (IU/L) 38 (26-53) / 37 (25-59) (22-56) / 40 (26-63) Prothrombin ratio (%) 80 (69-91) / 81 (66-89) (59-90) / 68 (46-89) Serum creatinine ( mol/l) 61 (48-71) / 57 (47-69) (53-111) / 68 (52-162) 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). a pain was assessed using a visual analog scale ranging from 0 (no pain) to 10 (extremely severe pain).

8 Table E3. Site of infection and pathogens involved in microbiologically documented episodes. Site of infection Pathogen No (%) Klebsiella pneumoniae 1 Candida albicans 1 Blood a Aeromonas caviae 1 Staphylococcus aureus 1 All 4 Streptococcus pneumoniae 5 Streptococcus anginosus (pleural effusion) 1 Klebsiella pneumoniae 2 Staphylococcus aureus 1 Gram-negative bacillus 1 Lower respiratory tract Stomatococcus mucilaginosus 1 Pseudomonas aeruginosa 2 Mucormycosis 1 Pneumocystis jirovecii 1 Influenza A virus 2 All 17 Escherichia coli 3 Urinary tract Klebsiella pneumoniae 2 Enterococcus faecalis 1 All 6 Streptococcus pneumoniae (meningitis) 1 Parvovirus B19 infection 2 Miscellaneous Cytomegalovirus infection 2 Cholecystitis 1 Klebsiella pneumoniae (sinusitis) 1 All 7 Values are indicating number (%). a including 1 catheter-related infection.

9 Table E4. Characteristics of episodes with AKI on ICU admission. All AKI episodes, n=14 No RRT, n=8 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/1,73m 2, 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 ( ) 160 ( ) 200 ( ) 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. a AKI 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 %. stage 2: serum creatinine increase from baseline > %. 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. RRT, n=6

10 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).

11 References 1. Hebbel R.P., Boogaerts M.A., Eaton J.W., et al. Erythrocyte adherence to endothelium in sickle-cell anemia. A possible determinant of disease severity. N Engl J Med, 1980, 302, p Adams R.J. Stroke prevention and treatment in sickle cell disease. Arch Neurol, 2001, 58, p Ballas S.K., Lieff S., Benjamin L.J., et al. Definitions of the phenotypic manifestations of sickle cell disease. Am J Hematol, 2010, 85, p Ohene-Frempong K., Weiner S.J., Sleeper L.A., et al. Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood, 1998, 91, p Petz L.D., Calhoun L., Shulman I.A., et al. The sickle cell hemolytic transfusion reaction syndrome. Transfusion, 1997, 37, p Lionnet F., Arlet J.B., Bartolucci P., et al. [Guidelines for management of adult sickle cell disease.]. Rev Med Interne, 2009, 30 Suppl 3, p.s Lee K., Gane P., Roudot-Thoraval F., et al. The nonexpression of CD36 on reticulocytes and mature red blood cells does not modify the clinical course of patients with sickle cell anemia. Blood, 2001, 98, p Mehta R.L., Kellum J.A., Shah S.V., et al. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care, 2007, 11, p.r31