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Vol. 333 No. 11 INCENTIVE SPIROMETRY FOR PULMONARY COMPLICATIONS IN SICKLE CELL DISEASES 699

INCENTIVE SPIROMETRY TO PREVENT ACUTE PULMONARY COMPLICATIONS IN SICKLE CELL DISEASES

AUL

S. B

ELLET

, M.D., K

AREN

A. K

ALINYAK

, M.D., R

AKESH

HUKLA

, P

.D., M

ICHAEL

J. G

ELFAND

, M.D.,

AND

ONALD

L. R

UCKNAGEL

, M.D., P

.D.

Abstract

Background.

This study was designed to de- termine the incidence of thoracic bone infarction in pa- tients with sickle cell diseases who were hospitalized with acute chest or back pain above the diaphragm and to test the hypothesis that incentive spirometry can decrease the incidence of atelectasis and pulmonary infiltrates.

Methods.

We conducted a prospective, randomized trial in 29 patients between 8 and 21 years of age with sickle cell diseases who had 38 episodes of acute chest or back pain above the diaphragm and were hospitalized. Each episode of pain was considered to be an independ- ent event. At each hospitalization, patients with normal or unchanged chest radiographs on admission were ran- domly assigned to treatment with spirometry or to a con- trol nonspirometry group. Each patient in the spirometry group took 10 maximal inspirations using an incentive spi- rometer every two hours between 8 a.m. and 10 p.m. and while awake during the night until the chest pain subsid- ed. A second radiograph was obtained three or more days after admission, or sooner if clinically necessary, to de- termine the incidence of pulmonary complications. Bone

scanning was performed no sooner than two days after hospital admission to determine the incidence of thoracic bone infarction.

Results.

The incidence of thoracic bone infarction was 39.5 percent (15 of 38 hospitalizations). Pulmonary complications (atelectasis or infiltrates) developed during only 1 of 19 hospitalizations of patients assigned to the spirometry group, as compared with 8 of 19 hospitaliza- tions of patients in the nonspirometry group (P

�

0.019). Among patients with thoracic bone infarction, no pulmo- nary complications developed in those assigned to the spirometry group during a total of seven hospitalizations, whereas they developed during five of eight hospitaliza- tions in the nonspirometry group (P

�

0.025).

Conclusions.

Thoracic bone infarction is common in patients with sickle cell diseases who are hospitalized with acute chest pain. Incentive spirometry can prevent the pul- monary complications (atelectasis and infiltrates) associat- ed with the acute chest syndrome in patients with sickle cell diseases who are hospitalized with chest or back pain above the diaphragm. (N Engl J Med 1995;333:699-703.)

From the Division of General Pediatrics (P.S.B.), the Division of Hematology– Oncology and the Cincinnati Comprehensive Sickle Cell Center (K.A.K., D.L.R.), and the Department of Radiology (M.J.G.), Children’s Hospital Medical Center; and the Department of Environmental Health, Division of Biostatistics and Epidemiology, University of Cincinnati College of Medicine (R.S.) — all in Cincinnati. Address reprint requests to Dr. Bellet at the Department of Pedi- atrics, Children’s Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229-3039.

Supported in part by a grant (5 P60 HL 15996) from the National Heart, Lung, and Blood Institute.

ATIENTS with sickle cell diseases are prone to an acute chest syndrome of chest pain and the pres-

ence of pulmonary infiltrates on chest radiography.

The cause of most cases of the acute chest syndrome is uncertain.

Pneumonia is often among the causes con- sidered, but bacterial, viral, or mycoplasma infection is infrequently documented.

3-8

Vaso-occlusion due to in- travascular sickling of red cells in the lung and embo- lism of thrombus or bone marrow

have never been shown conclusively to be present in the majority of cas- es. Although the illness is frequently self-limited when the infiltrate is confined to a small area, it can progress rapidly and may be fatal.

In some patients with the acute chest syndrome, ra-

dionuclide imaging showed focal changes in the bony thorax (ribs, sternum, and thoracic vertebrae) indica- tive of bone infarction.

In a retrospective analysis of bone scans, we found a high degree of correlation be- tween thoracic bone infarction and the presence of a pulmonary infiltrate.

We propose that in many cases the primary event leading to the acute chest syndrome is thoracic bone infarction, which predisposes patients to the development of the acute pulmonary complica-

tions of atelectasis or infiltrates. Analgesia to relieve the pain of splinting and the use of the incentive spi- rometer to ensure lung aeration may prevent these complications. The incentive spirometer measures the inspiratory capacity of the lungs and is designed to en- courage deeper inspiratory effort. To test our hypothe- sis, we conducted a prospective, randomized trial of in- centive spirometry in patients with sickle cell diseases who were hospitalized with acute chest or back pain above the diaphragm. The incidence of thoracic bone infarction was also determined.

ETHODS

Patients and Study Design

All patients received health care at the Comprehensive Sickle Cell Center at Children’s Hospital Medical Center, Cincinnati. Twenty-nine patients (14 female and 15 male) between 8 and 21 years of age with sickle cell diseases who had acute chest or back pain above the diaphragm and who were admitted to the hospital were enrolled in the study between October 1, 1990, and August 1, 1994. Twenty-three patients had homozygous sickle cell anemia, three had sickle cell–hemoglobin C disease, two had sickle cell–

�

- thalassemia, and one had sickle cell–hemoglobin D disease (Los An- geles). Reasons for hospital admission included acute chest or back pain, usually unrelieved by two doses of intravenous morphine; fe- ver; respiratory distress; a sharp decrease in the hemoglobin concen- tration; and a need for oxygen. These 29 patients were hospitalized a total of 38 times — 21 had 1 hospitalization, 7 had 2 , and 1 had 3. Patients less than 7 years old were not enrolled because of their difficulty in learning how to use the incentive spirometer effectively. Patients were admitted to the Hematology– Oncology Service of the Children’s Hospital Medical Center, and the attending hematologist was responsible for their treatment. The investigators supervised the use of the incentive spirometer and the collection of data. The study protocol was approved by the institutional review board, and

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700 THE NEW ENGL AND JOURNAL OF MEDICINE Sept. 14, 1995

informed consent was obtained from all study patients or their par- ents or legal guardians.

A complete history was taken and a physical examination per- formed when the patients presented to the Comprehensive Sickle Cell Center or the emergency department. Some had pain elsewhere than in the chest or back, and others did not. The following tests were per- formed: complete blood and differential counts, reticulocyte count, measurement of hemoglobin F and S concentrations, blood culture if the patient was febrile, measurement of oxygen saturation with a pulse oximeter while the patient breathed room air, and chest radi- ography. At each hospitalization, patients with normal chest radio- graphs or radiographs that were unchanged since the previous exam- ination were randomly assigned to one of two groups — a spirometry group that received standard care as well as the use of the incentive spirometer, and a nonspirometry group that received standard care only. Bone scanning was performed during each hospitalization to de- termine the incidence of thoracic bone infarction.

Incentive spirometry was used by patients in the spirometry group every two hours between 8 a.m. and 10 p.m. and while they were awake at night until the chest pain had subsided. The stand- ard Volurex volumetric incentive spirometer (Diemolding Health- care Division, Canastota, N.Y.) was used to measure inspiratory ca- pacity. The patients were asked to take 10 maximal inspirations, and the inspiratory capacities on the 4th, 5th, and 6th inspirations were measured and recorded. A second chest radiograph was ob- tained at least three days after admission to the hospital, or sooner if clinically necessary, to determine whether pulmonary complica- tions (atelectasis or infiltrates) had developed. We grouped atelec- tasis and infiltrates together because it is often difficult to distin- guish between them radiographically. The chest radiographs were interpreted in a blinded manner; that is, the radiologists did not know whether a patient was assigned to the spirometry group or the nonspirometry group during a given hospitalization. Bone scanning was performed two hours after the intravenous administration of technetium Tc 99m medronate (0.185 mCi per kilogram of body weight; maximum, 12 mCi) no sooner than two days after admis- sion to the hospital to determine the incidence of thoracic bone in- farction. General-purpose or high-resolution parallel-hole collima- tion was used. Intravenous fluid — 5 percent dextrose in 0.45 percent sodium chloride — was routinely given at 1 to 1.5 times the maintenance rate for at least the initial 24 hours of hospitalization. Antibiotics were given for oral temperatures greater than 38

C and for suspected or known bacterial infection. Blood transfusions were given when the hemoglobin concentration fell below 6 g per deci- liter.

Different analgesic agents were used to treat pain. The narcotics included morphine, hydromorphone, meperidine, methadone, fenta- nyl, oxycodone, and codeine (with acetaminophen). The dosage was adjusted according to the patient’s comfort or tolerance. Non-narcot- ic analgesic agents included ketorolac, naproxen, ibuprofen, and acetaminophen. The amount of narcotics given during each hospital- ization was recorded in milligrams of morphine equivalents per kilo- gram of body weight

and for ketorolac in milligrams of morphine equivalents per kilogram, assuming that 30 mg of intravenous keto- rolac equals 12 mg of intravenous morphine.

The total narcotic dos- age was compared in the spirometry and nonspirometry groups (Ta- ble 1) as a measure of the amount of pain that was experienced.

Statistical Analysis

The data were entered in our computer data base and analyzed with SAS software. Patients were randomly assigned to the spirome- try or nonspirometry group at each hospitalization, according to the forced-randomization procedure of Taves.

All dichotomized data were analyzed with Fisher’s exact test for two-by-two tables, and all continuous data were analyzed with Student’s t-test. All the tests were two-tailed. Logistic-regression analysis was used to assess the effect of incentive spirometry on decreasing the incidence of pulmo- nary complications (atelectasis or infiltrates), independent of other confounding variables.

Since 8 of 29 patients had more than one hospitalization, we in-

vestigated whether each hospitalization could be treated as an inde- pendent event. To do this, we used the method described by Liang and Zeger.

Two sets of analyses were compared to assess the effec- tiveness of incentive spirometry in preventing pulmonary complica- tions. In one analysis, the existence of within-patient correlation was assumed, whereas in the other, a within-patient correlation of zero was assumed. The P values for the regression coefficients for treat- ment effect were almost identical (0.0252 and 0.0261 for the inde- pendence model and the exchangeable-correlation model, respec- tively). These two Liang–Zeger analyses gave P values close to that obtained with Fisher’s exact test (P

�

0.019). Therefore, Fisher’s ex- act test, which assumes the independence of events, could be used in the analysis to determine whether incentive spirometry prevents pulmonary complications.

As a measure of the effectiveness of the patient’s performance in

*Plus –minus values are means

�

SD.

†N denotes number of hospitalizations. Patients were assigned to one of the two groups at each admission.

‡N

�

14. §N

�

16. ¶N

�

17.

Table 1. Selected Clinical Features of Patients Assigned to Spi- rometry or Standard Care without Spirometry during

Hospitalization.

LINICAL

EATURE

PIROMETRY

�

19)† N

ONSPIROMETRY

�

19)†

Sex — F/M 8/11 11/8 Age — yr 15.0

�

4.2 16.8

�

3.0 Genotype — no.

Homozygous sickle cell anemia 14 16 Sickle cell–hemoglobin C disease 3 1 Sickle cell–hemoglobin D disease

(Los Angeles) 0 2

Sickle cell–

�

-thalassemia 2 0 Temperature (oral) on admission —

C 37.6

�

1.2 37.3

�

0.8 Respiratory rate — per min 24.2

�

6.5 22.1

�

4.3 Pleuritic pain — no. (%) 10 (53) 9 (47) Nonpleuritic pain — no. (%) 9 (47) 10 (53) Abdominal pain — no. (%) 6 (32) 9 (47) Back pain — no. (%) 10 (53) 14 (74) Long-bone pain — no. (%) 13 (68) 10 (53) Sternal pain — no. (%) 15 (79) 12 (63) Cough — no. (%) 5 (26) 2 (11) Rales — no. (%) 1 (5) 1 (5) Rib tenderness — no. (%) 13 (68) 8 (42) Chest-wall tenderness — no. (%) 11 (58) 9 (47) Sternum tenderness — no. (%) 13 (68) 8 (42) Thoracic-spine tenderness — no. (%) 3 (16) 2 (11) Oxygen saturation by pulse oximetry while

breathing room air — % 92.6

�

6.2‡ 93.5

�

4.0 §

White-cell count —

�

/mm

14.2

�

4.8 17.7

�

6.5 Segmented neutrophils — % 63

�

11.4 66

�

13.0 Hemoglobin — g/dl 8.8

�

2.1 8.9

�

1.4 Reticulocyte count — % 9.6

�

8.1 10.3

�

7.1 Hemoglobin S

— % 71.2

�

21.0 ¶ 74.0

�

21.8§ Hemoglobin F — % 4.5

�

3.1§ 5.1

�

4.4§ Infarction of bones other than thoracic —

no. (%) 6 (32) 5 (26)

Intravenous fluids — no. (%) 18 (95) 18 (95) Oxygen — no. (%) 11 (58) 10 (53) Antibiotics — no. (%) 12 (63) 11 (58) Blood transfusion — no. (%) 6 (32) 6 (32) Exchange transfusion — no. (%) 0 (0) 1 (5) Narcotics — mg of morphine equivalents/kg 2.9

�

4.5 3.3

�

3.9 Narcotics plus ketorolac — mg of morphine

equivalents/kg 4.2

�

5.1 4.8

�

5.4

Days between first and second chest radiographs

2.6

�

1.7 2.6

�

1.6

Bone scanning — days after admission 5.0

�

2.1 4.9

�

3.6 Duration of chest pain before hospitaliza-

tion — days 2.4

�

3.1 1.1

�

1.6

Total duration of chest pain — days 6.2

�

4.6 5.5

�

2.9 Hospital stay — days 3.8

�

2.0 4.7

�

2.7

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Vol. 333 No. 11 INCENTIVE SPIROMETRY FOR PULMONARY COMPLICATIONS IN SICKLE CELL DISEASES 701

using the incentive spirometer, the mean ra- tio of observed inspiratory capacity to ex- pected inspiratory capacity was calculated at each hospitalization. The mean observed in- spiratory capacity was determined on hospi- tal days 1, 2, and 3 and for the entire hospi- tal course. We calculated the expected vital capacity using the method of Hsu et al.

The expected inspiratory capacity was assumed to be 75 percent of the vital capacity.

ESULTS

Table 1 lists selected clinical fea- tures of the spirometry and non- spirometry groups. The groups were well balanced. In eight patients in the spirometry group and eight in the nonspirometry group, the oxy- gen saturation measured by pulse oximetry was less than 90 percent or arterial-blood gas analysis was per- formed because of suspected hypox- emia. Of 25 bacterial blood cultures, none were posi- tive. One viral blood culture was positive for cytomeg- alovirus. No sputum or pleural-fluid cultures were obtained. There were no deaths.

During 15 of the 38 hospitalizations, thoracic bone infarction was demonstrated by bone scanning (39.5 percent; 95 percent confidence interval, 24 to 55 per- cent). Segmental rib infarction was observed during 14 hospitalizations (one rib was involved in 5 cases, two to five ribs in 5, and six or more ribs in 4), and isolated thoracic vertebral infarction was observed dur- ing 1 hospitalization. Infarction of one or more thorac- ic vertebral bodies was found during seven of these hospitalizations, and infarction of the sternum was found once.

Pulmonary complications developed during only 1 of 19 hospitalizations of patients assigned to receive spi- rometry, as compared with 8 of 19 hospitalizations in the nonspirometry group (P

�

0.019). Of seven hospi- talizations in which a patient in the spirometry group had thoracic bone infarction, none involved pulmonary complications, as compared with five of eight hospital- izations in the nonspirometry group (P

�

0.025). Logis- tic-regression analysis confirmed that the risk of pul- monary complications was lower during spirometry hospitalizations than during nonspirometry hospital- izations, even when adjusted for the amount of narcot- ics used during each hospitalization (P

�

0.02). Table 2 describes the abnormalities on the second

chest radiograph in eight patients assigned to the non- spirometry group and one in the spirometry group. The left lower lobe was involved in all nine cases. Four of five patients with thoracic bone infarction also had involvement of the right lower lobe. The paren- chymal lesions consisted of patches and densities, which ranged from 1 cm in greatest dimension to in- volvement of the entire lobe. Five patients had small pleural effusions; in three they were bilateral. Two pa-

tients with demonstrable thoracic bone infarction had pleural effusions. In the 9 hospitalizations during which pulmonary complications occurred, the mean hospital stay was 6.4

�

1.9 days, as compared with 3.6

�

2.1 days in the 29 hospitalizations during which no pulmonary complications occurred (P

�

0.001). The mean number of days between the first and second chest radiographs in these 9 hospitalizations was 2.4

�

1.0 days, as com- pared with 2.8

�

1.8 days for the 29 hospitalizations during which no pulmonary complications occurred (P

�

0.58). The spirometric data were analyzed for 17 of the 19

hospitalizations in which the spirometer was used; the data for 2 hospitalizations were lost. The mean ratio of observed inspiratory capacity to expected inspiratory capacity during these hospitalizations was 75 percent on day 1, 75 percent on day 2, 70 percent on day 3, and 74 percent for the entire hospital course. This ratio was similar during hospitalizations of patients who did and patients who did not have thoracic bone infarction on day 1 (67 percent vs. 80 percent, P

�

0.39), day 2 (67 percent vs. 79 percent, P

�

0.36), or day 3 (69 percent vs. 70 percent, P

�

0.94).

ISCUSSION

The results of this prospective, randomized trial demonstrate that use of the incentive spirometer with 10 maximal inspirations every two hours from 8 a.m. to 10 p.m. and when the patients were awake at night significantly decreased the incidence of pulmonary complications (atelectasis or infiltrates) in patients with sickle cell diseases who were hospitalized with acute chest or back pain above the diaphragm. When pa- tients with thoracic bone infarction were analyzed sep- arately, the effect of incentive spirometry was also sta- tistically significant.

The incentive spirometer has been used successfully for many years to prevent pulmonary atelectasis and its

*Plus signs denote positive results, minus signs negative results, N nonspirometry, S spirometry, RLL right lower lobe, and LLL left lower lobe.

†Values are greatest dimensions.

Table 2. Abnormalities on Chest Radiography That Developed in Patients Assigned to Spirometry or Standard Care without Spirometry during Hospitalization.

ATIENT

. A

SSIGNMENT

DURING

OSPITALIZATION

IZE

(cm)† A

PPEARANCE

NATOMICAL

OCATION

LEURAL

FFUSION

HORACIC

ONE

NFARCTION

1 N 4 5

Patch Patch

RLL LLL

None

�

2 N 1 4

Patch Linear density

RLL LLL

None

�

3 N Lobar 5

Density Density

RLL LLL

None

�

4 N 4.5 5.5

Linear density Density

RLL LLL

Small, right side

�

5 N 2.5 Patch LLL Small, bilateral

�

6 N 3.5 Linear density LLL Small, bilateral

�

7 N 5 Density LLL Small, left side

�

8 N 7 Density LLL None

�

9 S 5 Density LLL Small, bilateral

�

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702 THE NEW ENGL AND JOURNAL OF MEDICINE Sept. 14, 1995

complications in postoperative patients.

19-21

Bendixen et al. have shown that healthy people usually take deep breaths or sigh 9 to 10 times per hour to prevent alve- olar collapse.

The absence of these periodic deep breaths during spontaneous ventilation in anesthetized patients, even when breathing is adequate to eliminate carbon dioxide, contributes to atelectasis and hypox- emia.

Incentive spirometry presumably counteracts the effect of splinting in patients with sickle cell diseas- es who are unable to take deep breaths because of chest pain and helps prevent the development of atelectasis or infiltrates.

The characteristic recurrent pain and organ damage of sickle cell diseases are thought to be due to vaso- occlusion resulting from decreased deformability of sick- le cells and their adherence to vascular endothelium

24,25

and to each other.

Much of the pain is due to vaso- occlusion in bone, which may progress to frank infarc- tion.

In our study no clinical, hematologic, or plain ra- diographic measure could reliably diagnose thoracic bone infarction, which can be suspected when rib or vertebral tenderness is present. The diagnosis of tho- racic bone infarction can be confirmed only by radionu- clide scintigraphy. Thoracic bone infarction in patients with sickle cell disease has been demonstrated previ- ously by bone scanning,

11,12,28-30

but the present study estimates the frequency of the problem. The incidence of 39 percent for thoracic bone infarction in our group of patients is likely to be an underestimate, since scan- ning may not detect small areas of infarction because of limited spatial resolution. Moreover, some of the scans may have been obtained too early in the clinical course of the episode to demonstrate bone infarction. In some patients, not enough time may have elapsed for the bone scan to reveal increased uptake of the radio- pharmaceutical agent by osteoblasts, which are mobi- lized to repair the damaged bone. It is not known how long the findings of bone infarction persist on bone scans, but in this study, three patients with evidence of thoracic bone infarction on the first scan did not have any evidence of infarction on subsequent scans ob- tained 24, 133, and 483 days later, respectively.

Some investigators have proposed that narcotics may predispose patients with sickle cell diseases to hypoven- tilation and atelectasis or infiltrates.

6,31

In our study, it is unlikely that the higher complication rate in the non- spirometry group was due to greater use of narcotics, because the amount of narcotics used in the spirometry and nonspirometry groups did not differ significantly. Moreover, logistic-regression analysis showed that in- centive spirometry was effective even when we adjusted for the amount of narcotics used.

Prevention of the radiographically evident abnormal- ities of atelectasis and infiltrates is important in the short-term prognosis of the acute chest syndrome. Al- though the acute chest syndrome is usually self-limited, single episodes may progress and cause substantial morbidity and even death. We do not know whether the association of the acute chest syndrome with a poor

long-term outcome in patients with sickle cell diseases is related to presentation with symptoms localized to the thorax or to the presence of abnormalities on the chest radiograph. Powars et al.

reported that the most important risk factor associated with chronic lung dis- ease in patients with sickle cell diseases was the total number of episodes of the acute chest syndrome. Platt et al.

determined that the acute chest syndrome was a significant risk factor for early death in patients with sickle cell anemia who were 20 years of age or older. Whether these acute episodes alone lead to terminal pulmonary dysfunction, or whether they punctuate an ongoing occlusion of the pulmonary vascular bed by sickling, is unknown.

Our findings suggest that in many cases thoracic bone infarction with subsequent atelectasis or develop- ment of an infiltrate due to chest splinting is the pri- mary pathogenesis of the acute chest syndrome. We found that incentive spirometry can prevent the pulmo- nary complications (atelectasis or infiltrates) associated with the acute chest syndrome in patients with sickle cell diseases who are hospitalized with chest or back pain above the diaphragm. This inexpensive interven- tion might prevent chronic lung disease and early death in patients with sickle cell diseases.

We are indebted to Ms. Annette Saylor for assistance in the prep- aration of the manuscript.

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Images in Clinical Medicine, a weekly

Journal

feature, presents clinically important visual images, emphasizing those a doctor might encounter in an average day at the office, the emergency department, or the hospital. If you have an original unpublished, high-quality color or black-and-white photograph representing such a typical image that you would like considered for publication, send it with a descriptive legend to Kim Eagle, M.D., University of Michigan Medical Center, Division of Cardiology, 3910 Taubman Center, Box 0366, 1500 East Medical Center Drive, Ann Arbor, MI 48109. For details about the size and labeling of the photographs, the requirements for the legend, and authorship, please contact Dr. Eagle at 313-936-5275 (phone) or 313-936-5256 (fax), or the

New England Journal of Medicine at [email protected] (e-mail).

The New England Journal of Medicine Downloaded from nejm.org at SLIPPERY ROCK UNIV on May 3, 2020. For personal use only. No other uses without permission.