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The Physiologic Effects of Inhaled Amphotericin B
The Physiologic Effects of Inhaled Amphotericin B* James Dubois, MHA, RRT; Thaddeus Bartter, MD, FCCP; Jeff Gryn, MD; and Melvin R. Pratter, MD, FCCP Our institution used an experimental protocol for the use of inhaled amphotericin B as a prophylactic measure to prevent fungal disease in severely immunocompromised patients. We did a prospective study of the physiologic effects of amphotericin B administration. We looked specifically at oxygen saturation levels, peak flow values, and symptoms of patients given amphotericin B. We collected data on a series of 18 patients and of 132 amphotericin B administrations. Four (22%) of the patients stopped treatments because of nausea and vomiting which were believed to be due to the inhaled amphotericin B. For the remaining patients, no treatment was stopped because of symptoms or physiologic changes caused by amphotericin B, although there were 9 instances of clinically significant
patients with sustained neutropenia are at increased risk for fungal pneumonia,1 which has a high mortality once established. 2•3 Early empiric amphotericin B treatment for febrile granulocytopenic patients who For editorial comment see page 600 do not respond to broad-spectrum antimicrobial agents has become a standard of care, 4 but prevention is a much more rational approach to the problem of fungal infection in granulocytopenic patients.1·5·8 Environmental control (air filtration ) to avoid exposure and antifungal prophylaxis to prevent infection both have been studied. High efficiency particulate air filtration has been shown to be effective 1•2•9 but is often unavailable and is expensive. 1 Of the fotential routes of delivery of chemoprophylaxis, oral, intravenous,5 •6 and inhaled, 1•8 the inhaled route has shown the most promise. First, the bronchial tree appears to be the route of access entry into the body when Aspergillus infects neutropenic patients. 2·9.I0 Second, there is animal evidence that inhalation of amphotericin B can yield concentrations in the lung similar to those achieved with systemic therapy, while levels in other tissues are undetectable.11 Finally, there have been promising animal8 and human 1 data from the use of inhaled amphotericin B. These reports of the successful use of inhaled amphotericin B for prophylaxis *From the Division of Pulmonary and Critical Care Medicine and the Division of Hematology and Oncology, Cooper HospitaVUnive rsity Medical Center, Camden, NT. Manuscript received October 28, 19g4; revision accepted Januruy 31, 1995. 750
bronchospasm as defined by a drop in peak flow of 20% or more, 9 clinically relevant increases in cough, and 3 clinically relevant increases in dyspnea. Forty-eight percent of the clinically relevant changes occurred in patient 8. Another 16% occurred in asthmatic subjects who were significantly more likely (p=0.03) to experience a 20% or more drop in peak flow than were patients without asthma. The physiologic profile of the response to inhaled amphotericin B is acceptable. (CHEST 1995; 108:750-53)
Key words: amphotericin B; aspergillosis; bone marrow transplantation; fungal infection; granulocytopenia; inhalation therapy
against fungus caused pneumoniaU 2 led us to develop a protocol for inhaled amphotericin B in patients who become neutropenic after bone marrow transplantation or after chemotherapy for leukemia. Because other pharmacologic inhalation therapies have been associated with respiratory side effects,13•14 we sought to delineate the respiratory effects of inhaled amphotericin B. M ETHODS
All patie nts at our institution who were expected to have a period of prolonged granulocytopenia due to bo ne marrow transplantation or to induction for leukemia were conside red for prophylactic amphotericin B inhalation the rapy. The intent was to treat all granulocytopenic patie nts until eithe r granulocytopenia had resolved or side effects of therapy forced discontinuation. The following we re the inclusion crite ria: (1) granulocytopenia, defined as less than 500 granulocytes/m m 3 , which was projected to pe rsistfor more than 2 weeks; (2) expected life span of more than 2 wee ks; (3) ability to give informed consent; (4) more th an 18 years o f age; and (5 ) lack of fever. Patients were excluded if they (1) had a p1ior histmy of fungal infection; (2) had a history of severe asthma; (3) were being treated with amphote ricin B at the time of possible enrollme nt; (4) had a history of an anaphylactic response to amphotericin B; (5)had a c re atinine value of more than 2 mgldL; or (6) refused to sign the informed consent. Patie nts were treated daily with nebulized amphotericin B. Three millilite rs of a solution, lO mglmL, we re delive red vi a a Respirgard II ne bulizer (Marquest Medical; Englewood, Colo) using oxygen at a flow rate of6 Umin, and the nebulizer was run to "dryness," which required 7 to lO min. Extrapolating from prior studies of pentamidine inhalation,15 approximately 5% of this dose, or 1.5 mg, was deposited in the lungs. The dose nebulized per day was lower than that nebulized with a Cirrus ne bulizer in a prior report,1 while the Respirgard II has been shown to deliver more uniform dosing and Clinical Investigations
0
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3
13
10
11
15
8
6
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Patient# FIGUJ\E
more.
l. Treatment-associated drops in peak flow of 20% or
better alveolar deposition than nebulizers with which it has been directly compared. 15•16 All patients were treated in single-patient rooms. The therapist administering the treatment wore a face mask approved by the National Institute of Safety and Health during administration (North 7700 Series respirator with N7500-8 filter; North Safety Products; Cranston, HI). Any other personnel entering the room during treatment or within 15 min after treatment also wore masks. Amphotericin B inhalation treatments were discontinued if the granulocyte count rose to more than 500/mL; the serum creatinine value rose to over 1.0 mglmL; there was evidence of a systemic reaction (such as hypotension, tachycardia, or rigors); or if intravenous administration of amphotericin B was started. Heart rate and oxygen saturation were monitored throughout the administration of amphotericin B. The baseline value and the highest heart rate and the lowest saturation level which occurred during therapy were recorded. Peak flow values were measured immediately before and after therapy using the best of three flow values registered on an Assess peak flowmeter (Healthscan Products; Cedar Grove, NJ ). Using a Borg scale, patients rated both cough and dyspnea immediately prior to and then again at the end of therapy. The amphotericin protocol was approved by the Human Subjects Committee of our institution.
Using paired t tests, there were no significant changes in heart rate or oxygen saturation level during amphotericin B administration. Mean heart rate was 85±16 (range, 57 to 130) at the outset and 88±16 (range, 56 to 140) at the end of administration. Only 5 treatments were associated with a rise in heart rate of greater than 20 beats per minute, with the greatest rise being 33 beats per minute. The maximum fall in heart rate was 42 beats per minute. The nebulizer which contained the amphotericin was driven by an oxygen gas source. Mean arterial oxygen saturation level was 97% (SD, 1.71 %) at outset, with the mean saturation at the end of therapy being 98% (SD, 1.91 %). The largest drop in saturation was a drop of 4%, which occurred with only 1 treatment. The only patient with a saturation level below 90% had a saturation value of 86% before treatment and of 83% at the end of treatment. Mean peak flow prior to amphotericin B treatment was 539 Umin, while the mean peak flow after treatment was 520 Umin. Although the difference was statistically significant (p<0.001 with paired t testing), it was thought to be of little clinical importance. However, using a 20% or more drop in peak flow as clinically significant, there were 9 instances (6.8% of treatments) of a clinically significant drop in peak flow (Fig 1). Two patients (No.8 and 13) experienced a drop of 20% or more twice, and five other patients had one episode each. Patient 13 experienced a 67% drop during one and a 32% drop during another of his ten treatments. The second largest drop, 45%, was the only drop of 20% or more out of the 5 treatments given to patient 3. No treatment was discontinued because of symptoms associated with a drop in peak flow. The amphotericin B treatments were associated with increases in dyspnea and cough. The mean Borg scale rating for cough was 0.4±0.7 before and 0.9±1.5 after amphotericin B treatment (p<0.001). The mean
RESULTS
Between May 1991 and March 1993, 18 patients received a total of 132 treatments with inhaled amphotericin B. Sixteen subjects were bone marrow transplant patients, and the remaining two had undergone leukemic induction therapy. The 18 patients had a mean age of 40.4±11.8 years (range, 21 to 62 years). Patients received a mean of 4.98 treatments (range, 1 to 17). Patients stopped receiving amphotericin B treatments for the following reasons: 10 stopped when their granulocyte counts rose above 500/mL, 4 stopped due to vomiting (thought to be related to amphotericin B) which made inhalation therapy impossible, 3 became comatose and could not continue, and 1 had mucositis which made inhalation therapy painful. Respiratory side effects were not responsible for discontinuation in any patient.
Patient # 6 8 8 8 8 8 8 8
:
17 17
Before
15 0
2
3
4
5
6
7
After I 8
9
10
Borg Rating FJGUHE
2. Increase in cough by more than two Borg descriptors. CHEST I 108 I 3 I SEPTEMBER, 1995
751
Patient# 8 8
8 8 17
After
Before 0
2
3
4
5
6
7
8
9
10
Borg Rating FIG UHE
3. Increase in dyspnea by more than two Borg descriptors.
rating for dyspnea was 0.3±0.7 before and 0.7±1.2 after amphotericin B treatment (p<0.001). Though statistically significant, the changes in mean values were quite small; the descriptor for the Borg rating 0.5 is "very, very slight"; that for 1 is "very slight"; and that for 2 is "slight." We therefore looked at all cases in which the Borg rating for cough or for dyspnea increased by more than two Borg descriptors and in which symptom level was rated as moderate or worse at the end of treatment in an attempt to find individual cases of clinically important increases. Cough increased by more than two Borg descriptors to a level of moderate or worse for nine treatments (Fig 2). This was true for six of seven treatments given to patient 8 and in single instances for three more patients. Dyspnea increased by more than two Borg descriptors to a level of moderate or greater in three cases (Fig 3). The increase occurred with two of seven treatments for patient 8 and once for patient 9. We looked at the patients with a stated history of asthma (patients 3, 11, and 13) to see if they were more likely to experience respiratory side effects from amphotericin B inhalation. Collectively, they were given a total of 19 amphotericin B treatments. When the mean values for the treatments given to asthmatic subjects were contrasted with those for patients without known asthma, there were no significant differences in heart rate and oxygen saturation before and after amphotericin therapy. The asthmatic subjects had significantly higher baseline (pre-amphotericin) Borg ratings for cough (0.7±0.6 vs 0.3±0.7; p<0.001) and dyspnea (0.9±1.0 vs 0.2±0.5; p<0.05), but there were no differences between asthmatic and nonasthmatic subjects in the amount of increase in cough or dyspnea induced by amphotericin. The asthmatic subjects did have significantly lower peak flow values prior to treatment (324±70vs 568±147; p<0.001), and a larger mean drop in peak flow (-34 Umin vs -16 Umin; p=NS, not significant). The difference in drops 752
in peak flow was probably not significant because of the relatively small number of treatments given to asthmatic subjects. More important than the mean drops in peak flow is the fact tl1at four (44%) of the nine drops of 20% or more in peak flow associated with amphotericin B inhalation occurred in asthmatic subjects (Fig 2). Patient 13 experienced marked drops of 67 and 32%, associated with 2 of 11 treatments; patient 3 experienced a 45% drop associated with 1 of 4 treatments; and patient 11 experienced a 25% drop with 1 of 3 treatments. A significant drop in peak flow occurred with 21% of treatments given to asthmatic subjects and with 4.4% of treatments given to patients without known astl1ma. This difference was significant, with a probability of 0.03 by Fisher's exact test. DISCUSS ION
Our study looked at the physiologic response to amphotericin B inhalation to determine whether tllis is a prophylactic treatment which can be given safely. In four cases, nausea and vomiting precluded further inhalation therapy. In most cases, no clinically significant changes occurred. Respiratory side effects did not force discontinuation of treatments in any case, although subsequent analysis did show some changes which were thought to be clinically significant. There were 9 instances of clinically significant bronchospasm as defined by a drop in peak flow of 20% or more, 9 clinically relevant increases in cough, and 3 clinically relevant increases in dyspnea. Only one patient, patient 8, consistently had a clinically relevant response to every treatment; 12 (48%) of the changes defined as clinically relevant occurred in patient 8. Another 16% occurred in identified asthmatic subjects. All of the clinically significant changes in asthmatic subjects were drops in peak flow values. One treatment often was associated with more than one clinically significant response; in all, 25 of 132 treatments (19%) were associated with changes deemed clinically relevant, and treatments were discontinued in 4 of 18 patients (22%). Our conclusions are specific for the nebulizer used, the Respirgard II. The Respirgard II produces very small droplets (mass median diameter of 1.0 pm with a maximal droplet size of6.9 pm), 16 and nebulizers that produce larger droplets may lead to greater deposition in large airways and more respiratory symptoms. 15.16 The results of our study led us to the following conclusions. First, most prophylactic amphotericin B treatments are well-tolerated and do not cause any clinically or physiologically significant changes. Second, inhaled amphotericin might in some cases cause nausea and vomiting which would lead to discontinuation of therapy. Third, asthmatic subjects are more likely to experience significant drops in peak flow values. It may be worth monitoring peak flow and using Clinical Investigations
bronchodilators prior to amphotericin B inhalation for known asthmatic subjects. Fourth, an occasional patient with no known history of asthma will consistently experience adverse symptoms with amphotericin B inhalation. Any patient who appears to have marked symptoms should probably be monitored, although treatments probably can be continued. We have documented the physiologic response to inhaled amphotericin B for a series of patients in our institution. While side effects do occur, neither the frequency nor severity of reactions appear to preclude the use of inhaled amphotericin B in the majority of cases; usage should be determined by clinical efficacy. REFERENCES
1 Conneally E, Cafferkey MT, Daly PA. Nebulized amphotericin B as prophylaxis against invasive aspergillosis in granulocytopenic patients. Bone Marr Trans 1900; 5:403-06 2 Ruutu P, Valtonen V, Tiitanen L, e t al. An outbreak of invasive aspergillosis in a haematologic unit. Scand J Infect Dis 1987; 19:347-52 3 Burch PA, Karp JE, Merz WG, et al. Favorable outcome of invasive aspergillosis in patients with acute leukemia. J Clin Oneal 1987; 5:1985-93 4 Walsh TJ, Lee J, Lecciones J, et al. Empiric therapy with amphotericin B in febrile granulocytopenic patients. Rev Infec Dis 1991; 13:496-503 5 Mora NP, Klintmalm G, Solomon H , et al. Selective amphotericin B prophylaxis in the reduction of fungal infections after liver transplant. Trans Proc 1992; 24:154-55 6 Wimperis JZ, Baglin TP, Marcus RE , e tal. An assessment of the
efficacy of antimicrobial prophylaxis in bone marrow autografts. Bone Marr Trans 1991; 8:363-67 7 Philpott-Howard JN, Wade JJ, Mufti GJ, et al. Randomized comparison of oral fluconazole versus oral polyenes for the prevention of fungal infection in patients at risk of neutropenia. J Antimicrob Chemother 1993; 31:973-84 8 Schmitt HJ, Bernard EM, Hauser BM, et al. Aerosol amphotericin B is effective for prophylaxis and therapy in a rat model of pulmonary aspergillosis. Antimicrob Agents Chemother 1988; 32:1676-79 9 Rhame FS, Streifel AJ, Kersey JH, et al. Extrinsic risk factors for pneumonia in the patient at high risk of infection. Am J Med 1984; 76(5A):42-52 10 Walsh TJ, Pizzo PA. Nosocomial fungal infections: a classification for hospital-acquired fungal infections and myocoses arising from endogenous flora or reactivation. Am Rev Microbial 1988; 42:517-45 11 Niki Y, Bernard EM, Schmitt HJ, et a!. Pharmacokinetics of aerosol amphotericin b in rats. Antimicrob Agents Chemother 1990; 34:29-32 12 Schmitt HJ, Bernard EM , Hauser M, etal. Aerosol amphotericin B is effective for prophylaxis and therapy in a rat model of pulmonary aspergillosis. Anti Agen Chern 1988; 1676:1679 13 Leoung GS, Feigal DW, Montgomery AB, et al. Aerosolized pentamidine for prophylaxis against pneumocystis carini pneumonia. N Eng! J M ed 1990; 323:769-75 14 Toronto Aerosolized Pentamidine Study (TAPS ) Group. Acute pulmonary effects of aerosolized pentamidine: a randomized controlled study. Chest 1990; 98:907-10 15 Ilowite JS, Baskin MI, Sheetz MS, et al. Delivered dose andregional distribution of aerosolized pentamidine using different delivery systems. Chest 1991; 99:1139-44 16 Simonds AK, Newman SP, Johnson MA, e tal. Alevolar targeting of aerosol pentamidine. Am Rev Respir Dis 1990; 141:827-29
CHEST /108/3/ SEPTEMBER, 1995
753
patients with sustained neutropenia are at increased risk for fungal pneumonia,1 which has a high mortality once established. 2•3 Early empiric amphotericin B treatment for febrile granulocytopenic patients who For editorial comment see page 600 do not respond to broad-spectrum antimicrobial agents has become a standard of care, 4 but prevention is a much more rational approach to the problem of fungal infection in granulocytopenic patients.1·5·8 Environmental control (air filtration ) to avoid exposure and antifungal prophylaxis to prevent infection both have been studied. High efficiency particulate air filtration has been shown to be effective 1•2•9 but is often unavailable and is expensive. 1 Of the fotential routes of delivery of chemoprophylaxis, oral, intravenous,5 •6 and inhaled, 1•8 the inhaled route has shown the most promise. First, the bronchial tree appears to be the route of access entry into the body when Aspergillus infects neutropenic patients. 2·9.I0 Second, there is animal evidence that inhalation of amphotericin B can yield concentrations in the lung similar to those achieved with systemic therapy, while levels in other tissues are undetectable.11 Finally, there have been promising animal8 and human 1 data from the use of inhaled amphotericin B. These reports of the successful use of inhaled amphotericin B for prophylaxis *From the Division of Pulmonary and Critical Care Medicine and the Division of Hematology and Oncology, Cooper HospitaVUnive rsity Medical Center, Camden, NT. Manuscript received October 28, 19g4; revision accepted Januruy 31, 1995. 750
bronchospasm as defined by a drop in peak flow of 20% or more, 9 clinically relevant increases in cough, and 3 clinically relevant increases in dyspnea. Forty-eight percent of the clinically relevant changes occurred in patient 8. Another 16% occurred in asthmatic subjects who were significantly more likely (p=0.03) to experience a 20% or more drop in peak flow than were patients without asthma. The physiologic profile of the response to inhaled amphotericin B is acceptable. (CHEST 1995; 108:750-53)
Key words: amphotericin B; aspergillosis; bone marrow transplantation; fungal infection; granulocytopenia; inhalation therapy
against fungus caused pneumoniaU 2 led us to develop a protocol for inhaled amphotericin B in patients who become neutropenic after bone marrow transplantation or after chemotherapy for leukemia. Because other pharmacologic inhalation therapies have been associated with respiratory side effects,13•14 we sought to delineate the respiratory effects of inhaled amphotericin B. M ETHODS
All patie nts at our institution who were expected to have a period of prolonged granulocytopenia due to bo ne marrow transplantation or to induction for leukemia were conside red for prophylactic amphotericin B inhalation the rapy. The intent was to treat all granulocytopenic patie nts until eithe r granulocytopenia had resolved or side effects of therapy forced discontinuation. The following we re the inclusion crite ria: (1) granulocytopenia, defined as less than 500 granulocytes/m m 3 , which was projected to pe rsistfor more than 2 weeks; (2) expected life span of more than 2 wee ks; (3) ability to give informed consent; (4) more th an 18 years o f age; and (5 ) lack of fever. Patients were excluded if they (1) had a p1ior histmy of fungal infection; (2) had a history of severe asthma; (3) were being treated with amphote ricin B at the time of possible enrollme nt; (4) had a history of an anaphylactic response to amphotericin B; (5)had a c re atinine value of more than 2 mgldL; or (6) refused to sign the informed consent. Patie nts were treated daily with nebulized amphotericin B. Three millilite rs of a solution, lO mglmL, we re delive red vi a a Respirgard II ne bulizer (Marquest Medical; Englewood, Colo) using oxygen at a flow rate of6 Umin, and the nebulizer was run to "dryness," which required 7 to lO min. Extrapolating from prior studies of pentamidine inhalation,15 approximately 5% of this dose, or 1.5 mg, was deposited in the lungs. The dose nebulized per day was lower than that nebulized with a Cirrus ne bulizer in a prior report,1 while the Respirgard II has been shown to deliver more uniform dosing and Clinical Investigations
0
?;
0 LL
.::.:.
-20
co Q)
0...
c
0..
0 ......
0
-::!2.
0
-40 -60 -67 -80 13
3
13
10
11
15
8
6
8
Patient# FIGUJ\E
more.
l. Treatment-associated drops in peak flow of 20% or
better alveolar deposition than nebulizers with which it has been directly compared. 15•16 All patients were treated in single-patient rooms. The therapist administering the treatment wore a face mask approved by the National Institute of Safety and Health during administration (North 7700 Series respirator with N7500-8 filter; North Safety Products; Cranston, HI). Any other personnel entering the room during treatment or within 15 min after treatment also wore masks. Amphotericin B inhalation treatments were discontinued if the granulocyte count rose to more than 500/mL; the serum creatinine value rose to over 1.0 mglmL; there was evidence of a systemic reaction (such as hypotension, tachycardia, or rigors); or if intravenous administration of amphotericin B was started. Heart rate and oxygen saturation were monitored throughout the administration of amphotericin B. The baseline value and the highest heart rate and the lowest saturation level which occurred during therapy were recorded. Peak flow values were measured immediately before and after therapy using the best of three flow values registered on an Assess peak flowmeter (Healthscan Products; Cedar Grove, NJ ). Using a Borg scale, patients rated both cough and dyspnea immediately prior to and then again at the end of therapy. The amphotericin protocol was approved by the Human Subjects Committee of our institution.
Using paired t tests, there were no significant changes in heart rate or oxygen saturation level during amphotericin B administration. Mean heart rate was 85±16 (range, 57 to 130) at the outset and 88±16 (range, 56 to 140) at the end of administration. Only 5 treatments were associated with a rise in heart rate of greater than 20 beats per minute, with the greatest rise being 33 beats per minute. The maximum fall in heart rate was 42 beats per minute. The nebulizer which contained the amphotericin was driven by an oxygen gas source. Mean arterial oxygen saturation level was 97% (SD, 1.71 %) at outset, with the mean saturation at the end of therapy being 98% (SD, 1.91 %). The largest drop in saturation was a drop of 4%, which occurred with only 1 treatment. The only patient with a saturation level below 90% had a saturation value of 86% before treatment and of 83% at the end of treatment. Mean peak flow prior to amphotericin B treatment was 539 Umin, while the mean peak flow after treatment was 520 Umin. Although the difference was statistically significant (p<0.001 with paired t testing), it was thought to be of little clinical importance. However, using a 20% or more drop in peak flow as clinically significant, there were 9 instances (6.8% of treatments) of a clinically significant drop in peak flow (Fig 1). Two patients (No.8 and 13) experienced a drop of 20% or more twice, and five other patients had one episode each. Patient 13 experienced a 67% drop during one and a 32% drop during another of his ten treatments. The second largest drop, 45%, was the only drop of 20% or more out of the 5 treatments given to patient 3. No treatment was discontinued because of symptoms associated with a drop in peak flow. The amphotericin B treatments were associated with increases in dyspnea and cough. The mean Borg scale rating for cough was 0.4±0.7 before and 0.9±1.5 after amphotericin B treatment (p<0.001). The mean
RESULTS
Between May 1991 and March 1993, 18 patients received a total of 132 treatments with inhaled amphotericin B. Sixteen subjects were bone marrow transplant patients, and the remaining two had undergone leukemic induction therapy. The 18 patients had a mean age of 40.4±11.8 years (range, 21 to 62 years). Patients received a mean of 4.98 treatments (range, 1 to 17). Patients stopped receiving amphotericin B treatments for the following reasons: 10 stopped when their granulocyte counts rose above 500/mL, 4 stopped due to vomiting (thought to be related to amphotericin B) which made inhalation therapy impossible, 3 became comatose and could not continue, and 1 had mucositis which made inhalation therapy painful. Respiratory side effects were not responsible for discontinuation in any patient.
Patient # 6 8 8 8 8 8 8 8
:
17 17
Before
15 0
2
3
4
5
6
7
After I 8
9
10
Borg Rating FJGUHE
2. Increase in cough by more than two Borg descriptors. CHEST I 108 I 3 I SEPTEMBER, 1995
751
Patient# 8 8
8 8 17
After
Before 0
2
3
4
5
6
7
8
9
10
Borg Rating FIG UHE
3. Increase in dyspnea by more than two Borg descriptors.
rating for dyspnea was 0.3±0.7 before and 0.7±1.2 after amphotericin B treatment (p<0.001). Though statistically significant, the changes in mean values were quite small; the descriptor for the Borg rating 0.5 is "very, very slight"; that for 1 is "very slight"; and that for 2 is "slight." We therefore looked at all cases in which the Borg rating for cough or for dyspnea increased by more than two Borg descriptors and in which symptom level was rated as moderate or worse at the end of treatment in an attempt to find individual cases of clinically important increases. Cough increased by more than two Borg descriptors to a level of moderate or worse for nine treatments (Fig 2). This was true for six of seven treatments given to patient 8 and in single instances for three more patients. Dyspnea increased by more than two Borg descriptors to a level of moderate or greater in three cases (Fig 3). The increase occurred with two of seven treatments for patient 8 and once for patient 9. We looked at the patients with a stated history of asthma (patients 3, 11, and 13) to see if they were more likely to experience respiratory side effects from amphotericin B inhalation. Collectively, they were given a total of 19 amphotericin B treatments. When the mean values for the treatments given to asthmatic subjects were contrasted with those for patients without known asthma, there were no significant differences in heart rate and oxygen saturation before and after amphotericin therapy. The asthmatic subjects had significantly higher baseline (pre-amphotericin) Borg ratings for cough (0.7±0.6 vs 0.3±0.7; p<0.001) and dyspnea (0.9±1.0 vs 0.2±0.5; p<0.05), but there were no differences between asthmatic and nonasthmatic subjects in the amount of increase in cough or dyspnea induced by amphotericin. The asthmatic subjects did have significantly lower peak flow values prior to treatment (324±70vs 568±147; p<0.001), and a larger mean drop in peak flow (-34 Umin vs -16 Umin; p=NS, not significant). The difference in drops 752
in peak flow was probably not significant because of the relatively small number of treatments given to asthmatic subjects. More important than the mean drops in peak flow is the fact tl1at four (44%) of the nine drops of 20% or more in peak flow associated with amphotericin B inhalation occurred in asthmatic subjects (Fig 2). Patient 13 experienced marked drops of 67 and 32%, associated with 2 of 11 treatments; patient 3 experienced a 45% drop associated with 1 of 4 treatments; and patient 11 experienced a 25% drop with 1 of 3 treatments. A significant drop in peak flow occurred with 21% of treatments given to asthmatic subjects and with 4.4% of treatments given to patients without known astl1ma. This difference was significant, with a probability of 0.03 by Fisher's exact test. DISCUSS ION
Our study looked at the physiologic response to amphotericin B inhalation to determine whether tllis is a prophylactic treatment which can be given safely. In four cases, nausea and vomiting precluded further inhalation therapy. In most cases, no clinically significant changes occurred. Respiratory side effects did not force discontinuation of treatments in any case, although subsequent analysis did show some changes which were thought to be clinically significant. There were 9 instances of clinically significant bronchospasm as defined by a drop in peak flow of 20% or more, 9 clinically relevant increases in cough, and 3 clinically relevant increases in dyspnea. Only one patient, patient 8, consistently had a clinically relevant response to every treatment; 12 (48%) of the changes defined as clinically relevant occurred in patient 8. Another 16% occurred in identified asthmatic subjects. All of the clinically significant changes in asthmatic subjects were drops in peak flow values. One treatment often was associated with more than one clinically significant response; in all, 25 of 132 treatments (19%) were associated with changes deemed clinically relevant, and treatments were discontinued in 4 of 18 patients (22%). Our conclusions are specific for the nebulizer used, the Respirgard II. The Respirgard II produces very small droplets (mass median diameter of 1.0 pm with a maximal droplet size of6.9 pm), 16 and nebulizers that produce larger droplets may lead to greater deposition in large airways and more respiratory symptoms. 15.16 The results of our study led us to the following conclusions. First, most prophylactic amphotericin B treatments are well-tolerated and do not cause any clinically or physiologically significant changes. Second, inhaled amphotericin might in some cases cause nausea and vomiting which would lead to discontinuation of therapy. Third, asthmatic subjects are more likely to experience significant drops in peak flow values. It may be worth monitoring peak flow and using Clinical Investigations
bronchodilators prior to amphotericin B inhalation for known asthmatic subjects. Fourth, an occasional patient with no known history of asthma will consistently experience adverse symptoms with amphotericin B inhalation. Any patient who appears to have marked symptoms should probably be monitored, although treatments probably can be continued. We have documented the physiologic response to inhaled amphotericin B for a series of patients in our institution. While side effects do occur, neither the frequency nor severity of reactions appear to preclude the use of inhaled amphotericin B in the majority of cases; usage should be determined by clinical efficacy. REFERENCES
1 Conneally E, Cafferkey MT, Daly PA. Nebulized amphotericin B as prophylaxis against invasive aspergillosis in granulocytopenic patients. Bone Marr Trans 1900; 5:403-06 2 Ruutu P, Valtonen V, Tiitanen L, e t al. An outbreak of invasive aspergillosis in a haematologic unit. Scand J Infect Dis 1987; 19:347-52 3 Burch PA, Karp JE, Merz WG, et al. Favorable outcome of invasive aspergillosis in patients with acute leukemia. J Clin Oneal 1987; 5:1985-93 4 Walsh TJ, Lee J, Lecciones J, et al. Empiric therapy with amphotericin B in febrile granulocytopenic patients. Rev Infec Dis 1991; 13:496-503 5 Mora NP, Klintmalm G, Solomon H , et al. Selective amphotericin B prophylaxis in the reduction of fungal infections after liver transplant. Trans Proc 1992; 24:154-55 6 Wimperis JZ, Baglin TP, Marcus RE , e tal. An assessment of the
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