Early Intermittent Noninvasive Ventilation for Acute Chest Syndrome in Adults with Sickle Cell Disease.
A pilot study.
Muriel Fartoukh MD,1 Yannick Lefort MD,1 Anoosha Habibi MD,2 Dora Bachir MD,2 Frédéric Galacteros MD,2
Bertrand Godeau MD,2 Bernard Maitre MD,3 Laurent Brochard MD1
1
Medical Intensive Care Unit, 2Sickle Cell Disease Center, 3Pulmonology Unit; AP-HP, Albert Chenevier -
Henri Mondor Teaching Hospital, INSERM U 955, and Paris XII University; Créteil, France
Electronic Supplementary Material
1.
Online Resource 1
Standard care used in both groups
Standard care included bed rest, continuous supplemental oxygen, intravenous fluid [30 ml/kg of 5
percent glucose, up to 2000 ml/24 hrs], folate supplementation, and analgesics and blood products transfusion, as
needed. Amoxicillin (100 mg/kg/day) was given in patients anytime an infection could be suspected.
The management of pain was standardized whether patients were receiving oxygen alone or in
combination with NIV. Different analgesic agents were used to treat pain. The dosage was adjusted according to
the patient's comfort or tolerance. Pain severity was assessed every four hours using a visual analog scale
ranging from 0 (no pain) to 10 (extremely severe pain). Non-narcotics (paracetamol and propacetamol) given
intravenously every four hours were used first alone or in association with nefopam. If the pain score was greater
than 5/10, morphine was added and adjusted based on pain severity and tolerance of the drug. The time between
the non-narcotics administration and the pain severity assessment was 2 hours for indicating the supplementary
administration of morphine. A titration of morphine was performed to ensure pain relief; continuous infusion
was possibly administered, if necessary. Incentive spirometry was not used routinely, because difficulties were
experienced previously in our unit regarding the acceptance and implementation of the technique in patients with
established ACS.
The following situation indicated the need for blood transfusion possibly associated with
exsanguination: no improvement of thoracic or extrathoracic pain or dyspnea 48 to 72 hours after admission,
pain at new sites, new chest X-ray infiltrate 24 hours after admission, and/or severe anemia. The decision to
administer blood transfusions alone or combined with exsanguination was left to the discretion of the Sickle Cell
Disease Center medical staff, unaware of the treatment arm in which the patient had been assigned. Blood
transfusions alone were more likely administered when anemia was pronounced and the symptoms related to
ACS persisted or worsened. Otherwise, when hemoglobin level did not drop enough while the symptoms related
to ACS persisted or worsened, exsanguination was performed before blood products were administered, with the
correspondence of 300 ml of blood exsanguinated for 1 pack of blood product transfused.
2.
Online Resource 2
Patient characteristics at baseline
Table 1 compares the main baseline characteristics in the two treatment groups. Patients (37 females
and 30 males) were 28 (25-35) years of age. Homozygous sickle cell anemia was by far the most common
disease. Baseline between-group differences were noted for core temperature, respiratory rate, and the total pain
score; all these differences suggested a greater severity in the group randomly allocated to NIV (Table 1). The
main symptoms at admission are reported in Table 1. Hypoxemia was mild to moderate in most episodes;
however, PaO2 was lower than 65 mm Hg in one-third of episodes (12 in the oxygen group and 10 in the NIV
group). Hypercapnia, defined as PaCO2 greater than 45 mm Hg, was noted in 9 (25%) episodes in the oxygen
group and 7 (20%) in the NIV group. Laboratory markers for hemolysis were similar in the two groups.
Subgroups analyses have been performed in the patients with a baseline PaO2 ≤ 65 mm Hg (n = 22).
Baseline characteristics of those more hypoxemic patients are provided in the table E1. The two groups still
differed for the respiratory rate and the overall pain score; the patients allocated to NIV had a trend to a higher
PaCO2 at baseline; these entire differences still suggested a greater severity in the more hypoxemic patients
allocated to NIV. For a more comprehensive view, the spectrum of PaO2 (mm Hg) is shown in the Figure E1,
representing the distribution of the PaO2 values by intervals of 5 from the lowest to the highest value.
3.
Online Resource 3
1/ Main respiratory changes in subgroup of patients with a baseline Pa O2 ≤ 65 mm Hg (n = 22)
The proportions of patients whose PaO2 was greater than 80 mm Hg on day 3 was still not significantly
different between the two groups (2/10 [20%] with NIV and 3/12 [25%] with oxygen; P=1). However, there was
a trend to a significant difference in the (A-a)O2 values between the two groups on day 3 (Figure E2).
NIV was associated with significant decreases in respiratory rate from baseline to day 3 (Figure E3).
Significant improvements in PaO2 and (A-a)O2 from baseline to day 3 were also noted with NIV (Figure E2 and
E4).
Conversely, oxygen was not associated with significant decrease in respiratory rate from baseline to day
3 (Figure E3). Neither did the (A-a)O2 values decrease (Figure E2). Nevertheless, PaO2 increased from baseline to
day 3 (Figure E4).
Last, PaCO2 remained unchanged over the 3-day period in both groups.
2/ Blood transfusions, pain severity, and narcotic use in the subgroup of patients with a baseline Pa O2 ≤ 65
mm Hg (n = 22)
NIV was not significantly associated with less pain severity and narcotics use, suggesting again a
greater discomfort related to NIV, as compared with oxygen alone. However, blood transfusions were less
required with NIV, although the small number of patients may be questionable for drawing any conclusion
(Table E2).
3/ Lengths of stay in the step-down unit and hospital in the subgroup of patients with a baseline Pa O2 ≤ 65 mm
Hg (n = 22)
Length of stay was longer in the NIV group, both in the step-down unit and the hospital (Table E2).
4.
Online Resource 4
Patient satisfaction and compliance with the respiratory device
In the NIV group, 2 patients, each with one episode, refused to use the NIV device. They were included
in the NIV group for the intention-to-treat analysis. Median NIV duration was 4 hours per day, and median
number of NIV sequences per day was 3 on each of the first 3 days in the step-down unit. Patients receiving NIV
were less satisfied with the respiratory device than patients receiving oxygen on all 3 days (all P values <0.05)
(Figure E5). In keeping with this finding, compliance on day 3 was lower in the NIV group than in the oxygen
group (3 [2-3] vs. 3 [3-3]; P=0.003). The patients who were non-compliant with NIV were given oxygen. No
major complications associated with the oxygen or NIV mask were recorded. However, chest pain worsened in 4
patients in the NIV group and 1 patient in the oxygen group.
Legend for Figures.
Legend for Figure E2. Changes from baseline in the alveolar-arterial oxygen gradient ((A-a)O2) in each of
the two treatment groups of patients with a baseline PaO2 ≤ 65 mm Hg (n = 22).
The medians and the 10th, 25th, 75th, and 90th percentiles are shown as vertical boxes with error bars. (A-a)O2
significantly decreased with NIV from 35 mm Hg (34-38) to 18 mm Hg (14-21) (P=0.03), but not with oxygen
(from 37 mm Hg [35-45] to 34 mm Hg [22-42]; P=0.13). There was a trend to a significant difference in the (Aa)O2 values between the two groups on day 3 (18 mm Hg (14-21) with NIV and 34 mm Hg [22-42] with oxygen;
P=0.06).
Legend for Figure E3. Daily changes from baseline in the respiratory rate (RR) in each of the two
treatment groups of patients with a baseline PaO2 ≤ 65 mm Hg (n = 22).
The medians and the 10th, 25th, 75th, and 90th percentiles are shown as vertical boxes with error bars. NIV was
associated with significant decreases from baseline in respiratory rate, on day 1 (from 26 [24-28] to 20 [20-24];
P=0.016), day 2 (from 26 [24-28] to 22 [20-27]; P=0.04) and day 3 (from 26 [24-28] to 20 [19-24]; P=0.02).
Conversely, oxygen was not associated with significant decrease in respiratory rate from baseline to day 3 (from
24 [20-24] to 24 [20-27]; P=0.65).
Legend for Figure E4. Changes from baseline in the partial pressure of oxygen in arterial blood (PaO2) in
each of the two treatment groups of patients with a baseline PaO2 ≤ 65 mm Hg (n = 22).
The medians and the 10th, 25th, 75th, and 90th percentiles are shown as vertical boxes with error bars. PaO2
significantly increased from baseline to day 3 in both groups: PaO2 increased from 61 mm Hg (55-63) to 72 mm
Hg (70-78) (P=0.002) with NIV and from 60 mm Hg (54-62) to 68 mm Hg (59-75) (P=0.02) with oxygen.
However, the proportions of patients whose PaO2 was greater than 80 mm Hg on day 3 was not significantly
different between the two groups (2/10 [20%] with NIV and 3/12 [25%] with oxygen; P=1).
Legend for Figure E5. Patient satisfaction and compliance with the oxygen or NIV delivery system evaluated
on each of the first 3 days in the step-down unit.
Patients’ satisfaction was significantly lower in the NIV group than in the oxygen group on all the 3 days (all P
values <0.05). Nurses assessed patients’ compliance with oxygen or NIV, including comfort, tolerance and
willingness. Patients assigned to NIV were less compliant with the use of the mask on day 3, compared to
patients in the oxygen group (P=0.003). Both the satisfaction score and the compliance score could range from 0
to 3.
Figure E1. Spectrum of the partial pressure of oxygen in arterial blood (PaO2) values.
30
Episodes, n
25
20
15
10
5
0
40
45
50
55
60
65
70
PaO2, Day 0
75
80
85
mm Hg
Figure E2. Changes from baseline in the alveolar-arterial oxygen gradient ((A-a)O2) in each of the two treatment groups of patients with a baseline PaO2 ≤ 65 mm Hg (n = 22).
(A-a)O2, mm Hg
70
60
50
40
NIV
Oxygen
30
20
10
0
(A-a)O2, Day 0
(A-a)O2, Day 3
Figure E3. Daily changes from baseline in the respiratory rate (RR) in each of the two treatment groups of patients with a baseline PaO2 ≤ 65 mm Hg (n = 22).
Respiratory rate (RR), min
34
29
NIV
24
Oxygen
19
14
RR, Day 0
RR, Day 1
RR, Day 2
RR, Day3
Figure E4. Changes from baseline in the partial pressure of oxygen in arterial blood (PaO2) in each of the two treatment groups of patients with a baseline PaO2 ≤ 65 mm Hg (n
= 22).
90
PaO2, mm Hg
80
70
NIV
Oxygen
60
50
40
PaO2, Day 0
PaO2, Day 3
Figure E5. Patient satisfaction and compliance with the oxygen or NIV delivery system evaluated on each of the first 3 days in the step-down unit.
5
4
3
NIV
2
Oxygen
1
0
Satisfaction, Day 1
Day 2
Day 3
5
4
3
NIV
2
Oxygen
1
0
Compliance, Day 1
Day 2
Day 3
Table E1. Baseline characteristics of the subgroup of patients with a baseline PaO2 ≤ 65 mm Hg (n = 22).
Oxygen
NIV
12 episodes
10 episodes
5/7
4/6
1
Age, years
28 (21-34)
28 (25-33)
0.6
Heart rate, beats/min
98 (91-109)
90 (84-99)
0.3
120 (112-140)
121 (110-132)
0.7
37.7 (37.1-38.2)
37.5 (37.2-38)
0.7
Respiratory rate, breaths/min*
24 (20-24)
26 (24-28)
0.05
Chest pain, n (%)
11 (92%)
10 (100%)
1
Extrathoracic pain, n (%)
4 (33%)
4 (40%)
1
Pulmonary crackles, n (%)
10 (83%)
6 (60%)
0.5
New pulmonary infiltrates on chest X-ray, n (%)
12 (100%)
7 (70%)
0.4
Overall pain score on a 10-mm visual analog scale*
4 (2-5)
5 (5-7)
0.03
Multi-site pain score
3 (2-4)
5 (3-5)
0.1
Radiographic score*
3 (2-4)
2 (1-2)
0.009
PaO2, mm Hg
60 (54-62)
61 (55-63)
0.7
PaCO2, mm Hg
42 (35-44)
45 (42-48)
0.08
7.41 (7.39-7.44)
7.40 (7.37-7.41)
0.4
37 (35-45)
35 (34-38)
0.1
21.3 (18.9-25.1)
15.8 (13.2-19.2)
0.1
Hemoglobin, g/dl
8 (7-9)
9 (8-9)
0.4
Platelets, x 109/L
338 (272-461)
292 (213-327)
0.4
LDH, IU/L
425 (327-471)
486 (422-583)
0.2
51 (35-96)
54 (33-62)
0.7
Baseline variables
Females/males
Systolic blood pressure, mm Hg
Core temperature at admission, °C
PH
(A-a)O2, mm Hg
White cell count, x 109/L
Bilirubin (total), µmoles/L
P value
Results are expressed as medians and inter quartiles (25-75), unless otherwise stated. *Significant (P<0.05) difference between the two groups
Table E2. Treatments and outcomes in the patients with a baseline PaO2 ≤ 65 mm Hg (n = 22).
Oxygen
NIV
12 episodes
10 episodes
Overall pain score during the step-down unit stay
4 (2-5)
4 (3-6)
0.2
Overall multi-site pain score during the step-down unit stay
2 (1-3)
3 (2-7)
0.2
55 (15-100)
170 (27-304)
0.1
Cumulative paracetamol dosage, g
8 (2-16)
15 (6-18)
0.05
Cumulative nefopam dosage, mg
0 (0-40)
160 (0-210)
0.2
During the step-down unit stay
7 (60%)
2 (20%)
0.1
During the hospital stay
9 (75%)
4 (40%)
0.2
Step-down unit *
5 (4-6)
7 (5-9)
0.046
Hospital
9 (8-12)
10 (6-14)
Variables
P
value
Pain severity
Cumulative dosage, mg morphine equivalents
Blood transfusion, n (%)
Length of stay, days
0.9
Results are expressed as medians and inter quartiles (25-75), unless otherwise stated. *Significant (P<0.05)
difference between the two groups