Intensive Care Med (2010) 36:1355–1362 DOI 10.1007/s00134-010-1907-4
Muriel Fartoukh Yannick Lefort Anoosha Habibi Dora Bachir Fre´de´ric Galacteros Bertrand Godeau Bernard Maitre Laurent Brochard
Received: 11 July 2009 Accepted: 19 March 2010 Published online: 18 May 2010 Ó Copyright jointly held by Springer and ESICM 2010 Electronic supplementary material The online version of this article (doi:10.1007/s00134-010-1907-4) contains supplementary material, which is available to authorized users.
ORIGINAL
Early intermittent noninvasive ventilation for acute chest syndrome in adults with sickle cell disease: a pilot study
B. Maitre Pulmonology Unit, AP-HP, Albert Chenevier-Henri Mondor Teaching Hospital, INSERM U 955, Paris XII University, Cre´teil, France
Abstract Purpose: Alveolar hypoxia and hypoxic vasoconstriction lead to trapping of sickle cells within the pulmonary vasculature. Improving alveolar ventilation and oxygenation may improve the outcome of acute chest syndrome (ACS). Methods: Prospective randomized single-center open study from November 1998 to February 2002 to test whether noninvasive ventilation M. Fartoukh Y. Lefort L. Brochard ()) (NIV) was more effective than oxyMedical Intensive Care Unit, AP-HP, gen alone in improving oxygenation Albert Chenevier-Henri Mondor Teaching on day 3 in adults with ACS and to Hospital, INSERM U 955, Paris XII evaluate the effects on pain, transfuUniversity, 51 Avenue du Mare´chal De sion requirements, and length of stay. Lattre de Tassigny, 94010 Cre´teil, France Results: Seventy-one consecutive e-mail:
[email protected] ACS episodes in 67 patients were Tel.: ?33-1-49812545 Fax: ?33-1-42079943 randomly allocated to oxygen (n = 36) or NIV (n = 35) for 3 days A. Habibi D. Bachir F. Galacteros in a medical step-down unit. Baseline B. Godeau respiratory rate and pain score were Sickle Cell Disease Center, AP-HP, higher in the NIV group. NIV Albert Chenevier-Henri Mondor Teaching promptly lowered the respiratory rate, Hospital, INSERM U 955, raised PaO2 , and decreased alveolar– Paris XII University, Cre´teil, France
Introduction
arterial oxygen gradient ððA aÞO2 Þ, which remained unchanged with oxygen alone. PaCO2 significantly worsened only in the oxygen group. On day 3, the groups did not differ regarding the proportion of episodes with normal PaO2 (35% with NIV and 25% with oxygen; P = 0.5) or ððA aÞO2 Þ. Patient satisfaction and compliance were lower with NIV. No differences were noted in pain relief, transfusions, or length of stay. In the subgroup of patients with severe hypoxemia ðPaO2 65 mmHg), physiological variables also improved faster with NIV, the differences being slightly more pronounced. Conclusions: Respiratory rate and gas exchange improved faster with NIV. However, NIV failed to significantly reduce the number of patients remaining hypoxemic at day 3, and was associated with greater patient discomfort. Keywords Alveolar ventilation Hypoxemia Blood transfusions Sickle cell disease Acute chest syndrome
hypoxemia combined with various respiratory symptoms (chest pain, tachypnea, wheezing, or cough), a new pulAcute chest syndrome (ACS) is one of the most common monary infiltrate on the chest X-ray, and a fever [1, 2]. complications of sickle cell disease, with a frequency of Although ACS is usually self-limited, some episodes 10–15 episodes/100 patient-years. ACS is defined as progress rapidly to acute respiratory failure and cause
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substantial morbidity or death. Regional alveolar hypoxia and the resulting pulmonary vasoconstriction lead to the occlusion of pulmonary microvessels by sickle cells and to lung injury [3]. Regional alveolar hypoxia may result from pneumonia, emboli from blood clots or bone marrow, chest-wall splinting from rib infarctions, atelectasis, sedation from narcotic analgesics given to treat non-pulmonary crises, and alveolar hypoventilation. Therefore, improving alveolar oxygenation and augmenting alveolar ventilation may be key objectives of the treatment of ACS, in addition to ensuring pain relief and giving blood transfusions and antibiotics [4]. Sickle cell entrapment can be reversed by restoring normal blood oxygenation [3]. However, supplemental oxygen alone might fail to improve regional alveolar oxygenation, most notably at sites characterized by severe ventilation–perfusion mismatching [3–5]. In addition, established ACS is characterized by rapid shallow breathing [6] and blood gas measurements usually show normal or high partial pressures of carbon dioxide ðPaCO2 Þ indicating relative alveolar hypoventilation [4]. Incentive spirometry and positive expiratory pressure prevented pulmonary complications in patients at high risk for ACS [7–9], and bilevel positive airway pressure seemed effective in a retrospective study of children with established ACS [10]. However, there is no clinical information on the feasibility, efficacy, and safety of the administration of noninvasive mechanical ventilation (NIV) in adults with ACS. The objective of this pilot study was to evaluate the hypothesis that NIV reduces the number of patients remaining hypoxemic at day 3 when used in adults who have early-stage ACS.
hospital with early-stage ACS, as well as consecutive inpatients who developed ACS during their hospitalization. Patients could be included twice in the event of recurrent ACS, provided the first episode resolved completely and was followed by hospital discharge before the onset of the second episode. Included patients were allocated at random to either supplemental oxygen alone (oxygen group) or oxygen and NIV (NIV group). All patients in both groups received standard care for ACS, and remained in the step-down unit for at least 3 days. Standard care used in both groups Standard care included bed rest, continuous supplemental oxygen, intravenous fluid (30 mL/kg of 5% glucose, up to 2,000 mL/24 h), folate supplementation, analgesics and blood products transfusion, as needed. Amoxicillin [100 mg/(kg day)] was given in patients anytime an infection was suspected (see Online Resource 1 in the Electronic Supplementary Material). Study therapy
Oxygen given via a facial mask was titrated to maintain the pulse oximetry value ðSpO2 Þ C95% in both groups. Patients assigned to the NIV group received sequential pressure support ventilation, with sequences of 1 h every 4 h during the day, via an ONYX’O2 ventilator (Puritan Bennett, Tyco Healthcare France, Plaisir, France), using a facial mask with nasal protection. The mask was individually selected and adjusted, according to the facial morphology of the patient, the measurement of leaks, and Patients and methods the comfort. The settings were adjusted to obtain an expired tidal volume of at least 7 mL/kg, providing a Patients pressure support level averaging 12 cmH2O. The endThe study was conducted prospectively between Novem- expiratory pressure was set arbitrarily at 5 cmH2O. ber 1998 and February 2002 at the Henri Mondor Teaching Oxygen was administered between the NIV sequences, Hospital. Consecutive adults with sickle cell disease (SS, using the same procedure as in the oxygen group. SC, or Sb-thalassemia) and clinical symptoms suggesting early-stage ACS were eligible. Early-stage ACS was defined as acute hypoxemia [partial pressure of oxygen in Monitoring arterial blood ðPaO2 Þ\80 mmHg on room air] and at least one of the following criteria: thoracic or extrathoracic Pain severity was assessed every 4 h using a visual analog pain, pulmonary crackles by physical examination, new scale ranging from 0 (no pain) to 10 (extremely severe pulmonary infiltrate on the chest X-ray. Non-inclusion pain). The management of pain was standardized whether criteria were age less than 18 years, pregnancy, need for patients were receiving oxygen alone or in combination immediate blood transfusion or immediate endotracheal with NIV (see Online Resource 1 in the Electronic Supplementary Material). The total amount of narcotics was mechanical ventilation, and multiple organ failure. recorded in milligrams of morphine equivalent. In addition, the patients scored their pain during the clinical Study design round, at seven sites (chest, each of the 4 limbs, spine, and skull) each one being scored from 0 to 3; the overall siteWe included consecutive outpatients seen at the emer- specific scores were therefore summed from 0 (no pain at gency department or Sickle Cell Disease Center of our any site) to 21 (worst possible). Blood gas values,
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hemoglobin level, and markers for hemolysis were recorded daily. Arterial blood gases were performed on room air in both groups. Chest X-rays were performed at inclusion and at least on day 3, and analyzed by four quadrants, classified as: 0, no infiltrate; 1, mild-to-moderate infiltrate; and 2, alveolar opacity. The radiographic score could range from 0 to 8 (all quadrants showing alveolar opacity). The patients rated their satisfaction with oxygen or NIV, including mask/ventilator comfort and pain control, on a scale from 0 to 3 (satisfied). Nurses assessed patients’ compliance with oxygen or NIV, including comfort, tolerance, and willingness, using a scale from 0 to 3 (compliant). Outcome measures and statistical analysis The data generated by this prospective, randomized, single-center, open study were analyzed on an intention-totreat basis. A random allocation sequence was generated by using a random-number table. The investigators enrolled consecutive patients and used opaque, sealed, numbered envelopes to assign each patient to one of the groups. This method ensured concealment of the allocation sequence.
The primary outcome was the number of episodes free of hypoxemia at day 3 (i.e., PaO2 [80 mmHg on room air), assessed on PaO2 values on day 3 of the study. To estimate the sample size, we used the results of two previous studies. In a retrospective study by van Agtmael et al. [11] hypoxemia persisted on day 3 in 84% of 81 ACS episodes. In a prospective randomized trial by Bellet et al. [7] incentive spirometry significantly decreased pulmonary complications (1/19 vs. 8/19; P = 0.019) in patients with chest or back pain above the diaphragm and no baseline pulmonary infiltrates. We therefore assumed that 80% of episodes assigned to oxygen would be hypoxemic on day 3 and that NIV might decrease the proportion of episodes with hypoxemia on day 3 by at least 50%. With the a risk at 0.05 and the b risk at 0.1 (90% power), 35 episodes would be required in each group. Secondary outcomes included comparison of the alveolar–arterial oxygen gradient ðA aÞO2 when breathing room air, and pain relief, narcotic, and blood transfusion requirements, patient satisfaction and compliance with the respiratory device, and length of stay. Patients were usually discharged from the step-down unit when the following clinical criteria were met: the absence of pain or a very residual one, a temperature B37.8°C, a
Fig. 1 Consort flow chart. Dagger four patients were included twice. One patient was randomly allocated twice to NIV; another was randomly allocated twice to oxygen. The two other patients were subsequently allocated to NIV then to oxygen
80 episodes of ACS in 76 patients
9 patients (9 episodes) refused to participate
71 episodes in 67 patients allocated at random to oxygen or NIV †
35 episodes allocated to NIV
36 episodes allocated to oxygen
33 episodes received NIV
36 episodes received oxygen alone
35 episodes in the NIV group for the intention to treat analysis
36 episodes in the oxygen group for the intention to treat analysis
2 patients (2 episodes) refused to use the NIV device
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heart rate B100 beats/min, a respiratory rate B24 breaths/min, and oxygen saturation C90% or arterial oxygen partial pressure C60 mmHg. The return to baseline status indicated hospital discharge thereafter, although other social or psychological criteria might have been involved in the decision process leading to hospital discharge. Results are reported as medians and interquartiles (25–75). Demographics and clinical data were analyzed by using standard descriptive statistics. We used the chi-square test or Fisher’s exact test, as appropriate, for categorical data, and the nonparametric Mann–Whitney U test for continuous variables. Within-group changes were analyzed by using the nonparametric signed rank test and the McNemar’s test for continuous variables and categorical variables, respectively. P values \0.05 were considered statistically significant.
Mondor Teaching Hospital approved the study protocol. Written informed consent was obtained from all patients or their family or healthcare proxies prior to enrollment.
Results From November 1998 to February 2002, 76 consecutive patients with 80 episodes of ACS were eligible for inclusion. However, nine patients, each with a single episode, refused to participate in the study. The remaining 67 patients had 71 episodes (Fig. 1). Patient characteristics at baseline
Table 1 compares the main baseline characteristics in the two groups. Patients (37 females and 30 males) were 28 Ethical considerations (25–35) years of age. Homozygous sickle cell anemia was by far the most common disease. Baseline between-group The institutional review board (Comite´ de Protection des differences were noted for core temperature, respiratory Personnes dans la Recherche Biome´dicale) of the Henri rate, and the total pain score; all these differences Table 1 Baseline characteristics of episodes of acute chest syndrome allocated at random to oxygen or noninvasive ventilation (NIV) Baseline variables
Oxygen 36 episodes
NIV 35 episodes
P value
Females/males Age (years) Homozygous sickle cell disease, n (%) Sickle cell–hemoglobin C disease, n (%) Sickle cell–b-thalassemia disease, n (%) Heart rate (beats/min) Systolic blood pressure (mmHg) Core temperature at admission (°C)* Respiratory rate (breaths/min) Chest pain, n (%) Extrathoracic pain, n (%) Pulmonary crackles, n (%) New pulmonary infiltrates on chest X-ray, n (%) Overall pain score on a 10-mm visual analog scaleà Multi-site pain score§ Radiographic score PaO2 (mmHg) PaCO2 (mmHg) pH ðA aÞO2 (mmHg) White cell count (9109/L) Hemoglobin (g/dL) Platelets (9109/L) LDH (IU/L) Bilirubin (total) (lmol/L)
20/16 31 (25–35) 34 (94) 2 (6) 0 84 (73–98) 120 (112–140) 37.2 (36.7–37.9) 20 (20–24) 32 (89) 18 (50) 22 (61) 27 (75) 5 (3–6) 4 (2–5) 2 (1–3) 69 (62–76) 43 (39–45) 7.40 (7.38–7.44) 26 (20–36) 16.6 (12.75–21.05) 9 (8–9) 317 (270–432) 377 (256–447) 48 (33–68)
22/13 27 (25–34) 32 (91) 1 (3) 2 (6) 89 (83–104) 126 (110–132) 37.7 (37.2–38) 24 (20–28) 32 (91) 21 (60) 27 (77) 22 (63) 5 (5–7) 5 (3–8) 2 (1–3) 69 (64–75) 42 (40–44) 7.40 (7.38–7.43) 29 (23–34) 15.8 (12.15–19.3) 8 (7–9) 320 (291–424) 416 (256–503) 44 (31–61)
0.2 0.4 0.7 1 0.2 0.1 0.7 0.04 0.01 1 0.5 0.2 0.4 0.07 0.02 0.4 0.7 0.95 0.45 0.8 0.6 0.4 0.8 0.8 0.5
There were 71 episodes in 67 patients. Results are expressed as medians and interquartiles (25–75), unless otherwise stated PaO2 , partial pressure of oxygen in arterial blood; PaCO2 , partial pressure of carbon dioxide in arterial blood; ðA aÞO2 , alveolar– arterial oxygen partial pressure gradient measured when breathing room air and calculated as follows: ðA aÞO2 ¼ ð713 FiO2 Þ ðPaCO2 1:2Þ PaO2 , where FiO2 is the fraction of inspired oxygen
Four variables showed statistically significant differences between the two groups: core temperature (* P = 0.04), respiratory rate ( P = 0.012), overall pain score (àP = 0.07), and multi-site pain score (§P = 0.02)
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suggested a greater severity in the group 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 mmHg in onethird of episodes (12 in the oxygen group and 10 in the NIV group). Hypercapnia, defined as PaCO2 greater than 45 mmHg, was noted in nine (25%) episodes in the oxygen group and seven (20%) in the NIV group. Laboratory markers for hemolysis were similar in the two groups. Additional data are given in the Electronic Supplementary Material (Online Resource 2) for the distribution of the PaO2 values (Fig. E1) and the characteristics of the more hypoxemic patients (Table E1).
P = 0.02]. Similarly, significant improvements in PaO2 and ðA aÞO2 from baseline to day 3 were noted with NIV but not with oxygen (Table 2; Fig. 2). Finally, PaCO2 remained unchanged over the 3-day period in the NIV group but worsened significantly on day 1 in the oxygen group (Fig. 3). Subgroups analyses are available for the more hypoxemic patients (see Online Resource 3 and Figs. E2, E3, and E4 in the Electronic Supplementary Material). Invasive mechanical ventilation was not required for any of the ACS episodes included in the study. Changes in vital signs, physical findings, the radiological score, and laboratory variables are shown in Table 2. Blood transfusions, pain severity, and narcotic use Red blood cell transfusion requirements were not significantly different in the two groups. The multi-site pain score was higher during the step-down unit stay in the NIV group, whereas the overall pain scores were not different between the two groups. Neither was a difference in the cumulative amounts of narcotics given during the step-down unit stay between the two groups (Table 3).
Main respiratory changes in the oxygen and noninvasive ventilation groups
The proportion of patients whose PaO2 was greater than 80 mmHg on day 3 was not significantly different between the two groups [8/32 (25%) with oxygen and 11/31 (35%) with NIV; P = 0.5]. Neither were the ðA aÞO2 values different between the two groups on day 3 [24 mmHg (17–33) with oxygen and 21 mmHg (14–26) with NIV; Lengths of stay in the step-down unit and hospital P = 0.22] (Table 2). NIV, but not oxygen, was associated with significant decreases in respiratory rate on day 2 [20 (18–24) vs. 24 Length of stay in the step-down unit was significantly (20–28); P = 0.006] and day 3 [20 (18–22) vs. 24 (20–28); longer in the NIV group. However, hospital length of stay Table 2 Changes from baseline to day 3 in 71 episodes of acute chest syndrome (67 patients) allocated at random to oxygen or noninvasive ventilation (NIV) Variables
Heart rate (beats/min) Systolic blood pressure (mmHg) Core temperature (°C) Respiratory rate (breaths/min) Pulmonary crackles, n (%) Overall pain score on a 10-mm visual analog scale Multi-site pain score Radiographic score PaO2 (mmHg) ðA aÞO2 (mmHg) White cell count (9109/L) Hemoglobin (g/dL) Platelets (9109/L) LDH (IU/L) Bilirubin (total) (lmol/L)
Oxygen 36 episodes
NIV 35 episodes
Baseline
Day 3
Baseline
Day 3
84 (73–98) 120 (112–140) 37.2 (36.7–37.9)à 20 (20–24)à 22 (61) 5 (3–6)à 4 (2–5)à 2 (1–3) 69 (62–76) 26 (20–36) 16.6 (12.75–21.05) 9 (8–9) 317 (270–432) 377 (256–447) 48 (33–68)
90 (82–101) 120 (103–121)* 37.3 (36.6–37.6) 20 (20–24) 19 (63) 2 (0–4)* 1 (1–2)* 2 (1–3) 72 (62–80) 24 (17–33) 13.8 (11.25–18.25)* 8 (7–9) 320 (240–426) 306 (240–426)* 33 (22–53)*
89 (83–104) 126 (110–132) 37.7 (37.2–38)à 24 (20–28)à 27 (77) 5 (5–7)à 5 (3–8)à 2 (1–3) 69 (64–75) 29 (23–34) 15.8 (12.15–19.3) 8 (7–9) 320 (291–424) 416 (256–503) 44 (31–61)
88 (74–100) 120 (110–130) 37.1 (36.8–37.7) 20 (18–22) 21 (66) 2 (0–4) 3 (1–5) 2 (1–4) 73 (69–82) 21 (14–26) 11.9 (9.8–15.5) 8 (7–9) 369 (266–452) 277 (216–435) 30 (19–40)
Results are expressed as medians and interquartiles (25–75), unless otherwise stated PaO2 , partial pressure of oxygen in arterial blood; ðA aÞO2 , alveolar–arterial oxygen partial pressure gradient measured when breathing room air and calculated as follows: ðA aÞO2 ¼ ð713 FiO2 Þ ðPaCO2 1:2Þ PaO2 , where FiO2 is the fraction of inspired oxygen
LDH lactate dehydrogenase * Significant (P \ 0.05) changes in the oxygen group from baseline to day 3. Significant (P \ 0.05) changes in the NIV group from baseline to day 3. à Significant (P \ 0.05) baseline differences between the two groups
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NIV Oxygen
100
60
90
*
55
80
PaCO2, mm Hg
PaO2, mm Hg
NIV Oxygen
70 60
50 45 40
50 35 40
PaO2 Day 0
PaO2 Day 3
30
Day 0 70
NIV Oxygen
(A-a)O2, mm Hg
60 50 40
Day 1
Day 2
Day 3
Fig. 3 Changes in partial pressure of carbon dioxide in arterial blood ðPaCO2 Þ values in each of the two treatment groups. The medians and the 10th, 25th, 75th, and 90th percentiles are shown as vertical boxes with error bars. Asterisk there was a significant, but not sustained, initial worsening of the PaCO2 values in the oxygen group on day 1 (P = 0.004)
30
Table 3 Treatments and outcomes in 71 episodes of acute chest syndrome (67 patients) allocated at random to oxygen or noninvasive ventilation (NIV)
20 10
Variables
0
(A-a) O2 Day 0
(A-a) O2 Day 3
Pain severity Fig. 2 Changes from baseline in the partial pressure of oxygen in Overall pain score during arterial blood ðPaO2 Þ and the alveolar–arterial oxygen gradient the step-down unit stay ððA aÞO2 Þ measured in patients breathing room air in each of the Overall multi-site pain two treatment groups. The medians and the 10th, 25th, 75th, and score during the step90th percentiles are shown as vertical boxes with error bars. down unit stay* Significant improvements from baseline to day 3 were noted in the Cumulative dosage, mg NIV group for PaO2 [increase from 69 mmHg (64–75) to 73 mmHg morphine equivalents (69–82); P = 0.009] and for ðA aÞO2 [decrease from 29 mmHg Cumulative paracetamol (23–34) to 21 mmHg (14–26); P = 0.002]. In the oxygen group, no dosage (g) significant changes occurred from baseline to day 3 for PaO2 Cumulative nefopam [69 mmHg (62–76) and 72 mmHg (62–80), respectively; P = 0.05] dosage (mg) or ðA aÞO2 [26 mmHg (20–36) and 24 mmHg (17–33), respec- Blood transfusion, n (%) tively; P = 0.05] During the step-down unit stay During the hospital stay was not different between the two groups (Table 3). Length of stay (days) unit* Subgroup analyses for pain relief, narcotic, and blood Step-down Hospital
Oxygen 36 episodes
NIV 35 episodes
P value
4 (2–5)
4 (2–5)
0.3
2 (1–3)
4 (2–6)
0.009*
55 (9–119)
50 (8–203)
0.3
8 (4–13)
10 (3–15)
0.9
0 (0–85)
0 (0–160)
0.7
9 (25)
8 (23)
0.9
15 (42)
12 (34)
0.7
5 (4–6) 7 (4–11)
6 (5–7) 8 (6–11)
0.02* 0.3
transfusion requirements, and lengths of stay are available for the more hypoxemic patients (see Online Resource 3 Results are expressed as medians and interquartiles (25–75), unless and Table E2 in the Electronic Supplementary Material). otherwise stated * Significant (P \ 0.05) difference between the two groups
Patient satisfaction and compliance with the respiratory device
Discussion
The patients’ satisfaction and compliance with the respi- This prospective, randomized, single-center, open study ratory device are detailed in Online Resource 4 and was designed to evaluate whether NIV improved oxyFig. E5 in the Electronic Supplementary Material. genation faster than standard care and improved various
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outcomes, compared to supplemental oxygen alone, in adult patients with early ACS complicating sickle cell disease. NIV provided faster improvements in respiratory rate and gas exchange compared to oxygen alone but failed to significantly reduce the number of patients still hypoxemic at day 3. ACS is among the leading causes of admission and death in patients with sickle cell disease. The diagnosis of early-stage ACS may be difficult [1, 12] as the clinical presentation consists of nonspecific manifestations such as a fever, chest pain, tachypnea, wheezing, coughing, and/or a new pulmonary infiltrate [2, 4]. Hypoxemia is a feature in about 70% of episodes [13, 14]. In a prospective study of 671 ACS episodes requiring hospital admission in 538 patients, admission was for another reason (mainly pain) in half the episodes, with clinical and radiographic evidence of ACS developing within 3 days after admission [2]. Laboratory values worsened after the diagnosis of ACS despite aggressive treatment, highlighting the need for close monitoring. For our study, we defined early-stage ACS as mild hypoxemia ðPaO2 \80 mmHg) combined with suggestive clinical and radiographic manifestations or only extrarespiratory symptoms. At diagnosis, the most common clinical manifestations were chest pain, extrathoracic pain, and crackles in both lung fields. A new pulmonary infiltrate was common. Laboratory tests showed moderate-to-severe decreases in hemoglobin and increases in bilirubin and lactic dehydrogenase levels. Given that the precipitating factor of ACS usually remains unidentified, the optimal treatment for ACS is unclear. However, aggressive treatment is recommended, including hospitalization, analgesics, antibiotics, intravenous fluids, blood transfusions, and supplemental oxygen [2, 4, 15, 16]. Regional alveolar hypoxia and hypoxic vasoconstriction are two major mechanisms responsible for trapping of sickle cells within the small lung vessels [3]. Regional alveolar hypoxia promotes the adhesion of sickle cells to the pulmonary vascular endothelium, whereas regional hypoxic vasoconstriction promotes the mechanical entrapment of rigid sickle cells. Thus, regional alveolar hypoxia may initiate regional occlusion of the pulmonary microvessels. Evidence that correcting the hypoxia reverses sickle cell entrapment [3] suggests that supplemental oxygen should be given to patients with ACS. However, oxygen alone is probably insufficient to improve alveolar oxygenation in regions with marked ventilation–perfusion mismatching [3, 5]. Incentive spirometry alone or combined with intermittent positive endexpiratory pressure (PEEP) or bilevel positive airway pressure was effective in preventing ACS in patients with vaso-occlusive crisis [6–9] and in ensuring resolution of established ACS [10]. Patients with vaso-occlusive crisis and chest pain exhibited rapid shallow breathing with smaller tidal volumes and higher respiratory rates, but similar minute ventilation, compared to patients with pain
at other sites [6]. This finding suggested that using NIV to ensure intermittent positive airway pressure might help to reverse ACS by reducing the work of breathing and by increasing the functional residual capacity and lung compliance [17, 18]. In a retrospective study of 9 children with 25 episodes of ACS between 1994 and 2000, bilevel positive airway pressure combined with antibiotics, intravenous fluids, and blood transfusions induced significant improvements in oxygen requirements, heart rate, and respiratory rate [10]. Most of the patients received bilevel positive airway pressure continuously for 72 h then overnight only; mean maximum intermittent positive airway pressure was 12 cmH2O and mean maximum expiratory positive airway pressure 6 cmH2O. In our study, NIV was used intermittently for 3 days, for a median duration of 4 h/day. Oxygen was set to obtain SpO2 value C 95%, as pulse oximetry was found to be more accurate than calculated saturation in the presence of abnormal hemoglobin [19]. A significant decrease in respiratory rate versus baseline was noted as early as day 2 in the NIV group, despite higher baseline values, compared to the oxygen group. In addition, PaO2 increased versus baseline in the NIV group, suggesting improved gas exchange. Of note, PaCO2 remained unchanged over the 3-day period in the NIV group but worsened significantly on day 1 in the oxygen group. Conceivably, NIV induced alveolar recruitment, thereby improving oxygenation. However, NIV failed to improve the primary outcome measure (number of patients hypoxemic at day 3), and neither did NIV improve pain control, decrease blood transfusion requirements, or decrease length of stay. These results may be related to the limitations of our study. First, our inclusion criteria may have been too broad. Patients were required to have mild-to-moderate hypoxemia with a median PaO2 of 69 mmHg (64–75) on room air, and a normal chest X-ray did not prevent inclusion. A more severe hypoxemia, defined with a PaO2 65 mmHg, was present at baseline in 22 episodes. A more stringent criterion ðPaO2 60 mmHg) was present in only 11 episodes (6 in the oxygen group and 5 in the NIV group), a subgroup too small to allow a reliable statistical analysis. Whether NIV is effective in preventing respiratory failure in patients with greater disease severity deserves evaluation. Of note, in the subgroup of patients with severe hypoxemia ðPaO2 65 mmHg), physiological variables also improved faster in the NIV group, the differences being slightly more pronounced. Second, baseline differences occurred between the two groups determined by random allocation. These differences indicated a greater severity of ACS in the NIV group (higher core temperature, faster respiratory rate, and higher pain scores), and also, possibly, the longer length of stay. Therefore, they may have led to underestimation of the efficacy of NIV. Next, although the study was conducted in a quaternary referral center that has extensive experience with NIV, the median NIV duration was only 4 h/day, which was perhaps inadequate to ensure efficacy,
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especially in the more hypoxemic patients with hypercapnia. This might reflect at least in part the difficulty to administer NIV in sickle cell disease patients, who may be reluctant to accept NIV for treating established ACS, as suggested by the least satisfaction and compliance with NIV, as compared with oxygen (see Online Resource 4 and Fig. E5 in the Electronic Supplementary Material). Finally, our study may have been underpowered to show a difference on the main end-point. In summary, NIV failed to significantly decrease the rate of hypoxemic patients on day 3 in patients with moderately severe early-stage ACS complicating sickle cell disease. Unfortunately, there were baseline differences in pain scores and breathing rates favoring the oxygen group. Moreover, NIV use was only 4 h/day in
the NIV group. Despite these limitations, however, there were some benefits of gas exchanges in the NIV group although these did not translate into reduced narcotic and blood transfusion requirements and lengths of stay. Our results should prompt larger study targeting longer periods of NIV in the more severely hypoxemic patients. Acknowledgments The authors thank Dr Pierre Yves Ancel (De´partement de Sante´ Publique INSERM U 149. Hoˆpital Tenon, Assistance Publique-Hoˆpitaux de Paris and Universite´ Pierre et Marie Curie) for his critical statistical revision of the manuscript. Conflict of interest statement
None.
References 1. Platt OS (2000) The acute chest syndrome of sickle cell disease. N Engl J Med 342:1904–1907 2. Vinchinsky EP, Neumayr LD, Earles AN (2000) Causes and outcomes of the acute chest syndrome in sickle cell disease: national acute chest syndrome study group. N Engl J Med 342:1855–1865 3. Aldrich TK, Dhuper SK, Patwa NS, Makolo E, Suzuka SM, Najeebi SA, Santhanakrishnan S, Nagel RL, Fabry ME (1996) Pulmonary entrapment of sickle cells: the role of regional alveolar hypoxia. J Appl Physiol 80:531–539 4. Maitre B, Habibi A, Roudot-Thoraval F, Bachir D, Desvaux Belghiti D, Galacteros F, Godeau B (2000) Acute chest syndrome in adults with sickle cell disease. Therapeutic approach, outcome, and results of BAL in a monocentric series of 107 episodes. Chest 117:1386–1392 5. Haynes J, Kirkpatrick MB (1993) The acute chest syndrome of sickle cell disease. Am J Med 305:326–330 6. Needleman JP, Benjamin LJ, Sykes JA, Aldrich TK (2002) Breathing patterns during vaso-occlusive crisis of sickle cell disease. Chest 122:43–46 7. Bellet PS, Kalinyak KA, Shukla R, Gelfand MJ, Rucknagel DL (1995) Incentive spirometry to prevent acute pulmonary complications in sickle cell diseases. N Engl J Med 333:699–703
8. Hsu LL, Batts BK, Rau JL (2005) Positive expiratory pressure device acceptance by hospitalized children with sickle cell disease is comparable to incentive spirometry. Respir Care 50:624–627 9. Ortiz F, Karwa M, Najeebi S, Benjamin LJ, Aldrich TK (1998) Non-invasive ventilatory support shortens the duration of vaso-occlusive crisis in sickle cell disease. Am J Respir Crit Care Med 157(3):A225 10. Padman R, Henry M (2004) The use of bilevel positive airway pressure for the treatment of acute chest syndrome of sickle cell disease. Del Med J 76:199–203 11. van Agtmael MA, Cheng JD, Nossent HC (1994) Acute chest syndrome in adult afro-caribbean patients with sickle cell disease. Analysis of 81 episodes among 53 patients. Arch Intern Med 154:557–561 12. Platt OS, Brambilla DJ, Rosse WF (1994) Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med 330:1639–3644 13. Powars DR, Weidman JA, OdomMaryon T, Niland JC, Jonhson C (1988) Sickle cell chronic lung disease: prior morbidity and the risk of pulmonary failure. Medicine (Baltimore) 67:66–76
14. Reynolds J (1965) The roentgenological features of sickle cell disease and related hemoglobinopathies. Charles C Thomas, Springfield 15. Emre U, Miller ST, Rao SP, Rao M (1993) Alveolar-arterial oxygen gradient in acute chest syndrome of sickle cell disease. J Pediatr 123:272–275 16. Haynes J, Allisson RC (1986) Pulmonary edema. Complication in the management of sickle cell pain crisis. Am J Med 80:833–840 17. Kacmarek RM (1988) The role of pressure support ventilation in reducing work of breathing. Respir Care 33:99–120 18. MacIntyre NR (1986) Respiratory function during pressure support ventilation. Chest 89:677–683 19. Kress JP, Pohlman AS, Hall JB (1999) Determination of hemoglobin saturation in patients with acute sickle chest syndrome. A comparison of arterial blood gases and pulse oximetry. Chest 115:1316–1320