Ventilatory Effects of Aerosolized Kanamycin and Polymyxin

Ventilatory Effects of Aerosolized Kanamycin and Polymyxin* Kenneth J. Dickie, M.D., and William J. de Groot, M.D.

Inhalation of nebuHzed antibiotics is associated with respiratory distress in some patients but tbe effect on the airways bas not been studied. Ventilatory function was studied immediately before and 20 minutes after inbalation in patients baving chronic lung disease, wbo were being treated witb inbaled antibiotics. Kanamycin was associated with minor cbanges in ventilatory function but polymyxin (5 to 10 mg) was associated witb significant deterioration in function. Tbe possible barmful effect on the airways sbould be considered wben medication is given by aerosol.

I nhalation of aerosolized antibiotics is reported to

be a safe and effective means for the treatment of respiratory infections.v" In addition, inhalation therapy may have specific advantages over other methods of administration of the antibiotic particularly if therapeutic levels of the antibiotic may be achieved within the airways and lung tissue without causing deterioration in lung function. Furthermore, if this can be achieved without significant blood levels of the antibiotic the toxic effects of these agents on other organs might be avoided." We had observed that some patients had considerable increase in dyspnea during inhalation of antibiotics. In order to determine if this symptomatic change was associated with a deterioration in airway mechanics detectable by simple ventilatory studies, several patients were studied before and after inhalation. MATERIALS AND METHODS

Ventilation was studied in 14 consecutive patients with chronic lung disease who were receiving intermittent inhalation therapy with nebulized solution of either polymyxin or kanamycin as part of their treatment while in the hospital. Informed consent was obtained from the patient's physician who had initiated the therapy (not us) and the patient. Each patient had received at least one treatment prior to being seen by us. The indication for therapy was determined independently by the attending physician. In all instances the indications for the use of polymyxin or karamycin included chronic lung disease, purulent sputum and a bacteriologically °From the Department of Internal Medicine, University of Texas Medica Branch at Galveston.

694

positive culture of sputum. Seven of these patients received a ten-minute nebulization of kanamycin (250 rng dissolved in 3 ml saline solution). Seven other patients received polymyxin in saline solution for ten minutes (5 to 10 mg per 3 ml). This is considerably less than the dose recommended (2.5 mg per kilogram of body weight in divided doses) in the literature accompanying the antibiotic although it is stated that an initial test dose of 5 mg per milliliter or less be given and that inhalation of 1 to 2 ml of solution of 1 to 10 mg per milliliter, four to six times daily has given good results. We found that doses larger than this given without a bronchodilating drug resulted in fatigue, dyspnea and wheezing which precluded completion of the study in some patients. To determine that our technique was repeatable, four normal subjects were studied before and after a 30 minute interval without nebulization and nine normal subjects were studied before and after inhalation of 0.15M NaCl solution ( saline). In addition, four patients were studied before and after nebulized saline. The aerosol was delivered under pressure from a Bird Mark VII ventilator. Prior to the study all patients had been instructed in the use of intermittent positive pressure breathing (IPPB). Each patient was instructed and observed during the treatment period by a therapist to determine that passive inspirations were used. Ventilatory studies were then completed on each patient and the results calculated without knowledge of which medication was being given. Lung volumes and dynamic lung volumes were measured using a Godart Pulmonet. Functional residual capacity was measured by helium dilution technique. A Wright peak How meter was used for peak expiratory How rate. Studies were done immediately before and 20 minutes after inhalation. This period was chosen empirically because it was found that some patients were unable to start the second function tests prior to this time due to dyspnea. The acute effects of shorter duration may have been missed by this expediency.

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VENTILATORY EFFECTS OF AEROSOLIZED KANAMYCIN AND POLYMYXIN Table I-J'entilatory Fune.tion alter Inhalation 01 Nebulised Antibiotic

Vital Capacity Patient

Before

Maximum Functional Residual Forced Expiratory Mid-Expiratory Flow Maximum Voluntary Ventilation Capacity Volume at One Second 25%-75%

After

Before

After

2.00 2.86 3.27 2.90 2.00 1.89 5.44 2.91 1.24

2.39 4.19 2.74 3.40 2.52 3.09 3.56 3.13 0.64

2.51 6.37 2.71 3.20 2.36 3.77 4.55 3.64 1.43

Before

Mter

Before

Mter

1.32 1.63 2.07 1.38 0.96 0.74 3.80 1.70 1.02 <0.05

1.18 0.41 1.40 1.13 0.90 0.33 3.50 1.26 1.06

1.1 0.59 3.93 1.03 0.90 0.50 3.40 1.65 1.41

1.1 0.48 2.27 0.49 0.80 0.20 2.60 1.13 0.94

0.80 1.96 0.40

0.70 1.94 0.40 1.30 0.50 3.80 0.65 1.33 1.33

Before

After

Polymyxin 1 2 3 4 5 6 7 Mean SD P 1 2 3 4 5 6 7

2.27 4.08 4.70 3.28 3.12 2.97 5.19 3.66 1.04 <0.02

Kanamycin 1.03 4.14 1.53 1.50 1.33 5.36 2.17 Mean 2.44 SD 1.65 *NS P

NS* 0.90 3.83 1.67 1.53 1.12 5.40 2.25 2.39 1.65

1.70 2.96 4.57 2.21 2.74 5.11 5.21 3.32 1.49

2.29 3.99 1.86 2.07 5.94 3.11 3.21 1.55 *NS

0.50 3.90 0.75 1.39 1.35 <0.05

NS* 1.70 1.18 0.50 2.90 0.30 2.90 0.40 1.41 1.13

1.20 1.58 0.30 3.90 0.30 3.10 0.29 1.52 1.46

45 24 82

60 43 90 58 28

54

28

133 62.9 37.7 <0.01

43

43 62 21 62 24 127

55

18 75 17 146 24 59 48

56.5 38.8

*NS

30 14 118 52.4 36.6

*NS

*NS = Nof significant. RESULTS AND DISCUSSION

Inhalation of polymyxin was associated with a reduction in vital capacity and air How in the patient studies (Table 1). The change in vital capacity, forced expiratory volumes and maximum voluntary ventilation was sufficient to show statistical significance at the 5 percent level with the use of paired analysis. The maximum mid-expiratory How was decreased in all seven patients (P
show that variation in technique or measurements would not account for the changes seen after inhalation of antibiotics. Ventilatory measurements on normal controls after receiving nebulized saline closely correspond to the measurements prior to treatment. Patient controls show more variation than normals but neither group showed statistically significant changes. The question then is whether the changes seen after polymyxin are due to polymyxin or to the effect of the procedure on this group of patients. The ventilatory studies in the group of patients receiving kanamycin showed little change following therapy. Although the FEV! decrease appeared physiologically insignificant in each patient, the group change was statistically significant by paired analysis. Otherwise kanamycin was not associated with altered ventilatory function.

Table 2-J'entilatory Function with Inhalation 01 Nebuliaed SaUne Solution

Vital Capacity Before

After

Maximum Functional Residual Forced Expiratory Mid-Expiratory Flow Maximum Voluntary Ventilation Capacity Volume at One Second 25%-75% Before

After

Before

After

Before

After

Before

After

Mean SD

Normal Controls (10) 4.99 5.03 0.40 0.47

3.18 0.75

3.18 0.66

3.98 0.40

3.97 0.42

4.69 1.03

4.50 1.15

145 28

159 21

Mean SD

Patient Controls (4) 2.72 0.96

2.78 1.44

2.65 1.12

1.44 0.37

1.31 0.28

1.02 0.10

1.18 0.26

51 17

48 16

2.34 0.89

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696

DICKIE, DEGROOT

This result in combination with the patient control group suggests that the altered ventilation associated with polymyxin inhalation might be related to the polymyxin rather than the procedure itself. Comparisons of the mean percentage changes are seen in Figure 1. The figure emphasizes the changes which occurred. It can be seen that polymyxin is associated with a change of approximately 20 percent in the measurements of ventilation whereas kanamycin is associated with changes similar to those seen in normal controls inhaling saline solution. The volume change in the vital capacity, forced expiratory volume, and the maximum voluntary ventilation associated with polymyxin inhalation was significantly different from the change with kanamycin inhalation. This remains significant for vital capacity and forced expiratory volume when expressed as percentage change from the value prior to inhalation (Fig 1). We conclude from this that both kanamycin and polymyxin may be associated with considerable effect on ventilation in individual patients. Polymyxin is associated with a deterioration of ventilatory function in all patients studied at a dosage considerably reduced from the maximum amount

recommended. The changes suggest airway obstruction to flow which is consistent with the clinical observation that the symptoms may be avoided by adding a bronchodilator to the aerosol. In earlier studies larger amounts of polymyxin resulted in acute dyspnea for which the study was terminated. The dyspnea appeared to respond to isoproterenol inhalation. This suggests that the change in airway mechanics associated ~ith polymyxin results from a local effect but other explanations such as a neural effect have not been excluded. Indeed dyspnea and wheezing occurred in one patient (not included above) with intramuscular injection of polymyxin. Pre-injection and post-injection ventilatory studies showed changes similar to those described above but since this patient was not challenged with placebo, no conclusion can be reached. Apparently polymyxin inhalation aggravates the uneven flow patterns of diseased lungs. If we postulate that the effect would be most noted in diseased areas of the lung this would result in preferential distribution of polymyxin to the more normal areas of the lung. Such an effect would be expected to diminish the therapeutic value to the patient unless other presently unknown characteristics were present to offset this difficulty. Inhaled

FUNCTIONAL RESIDUAL CAPACITY

"

""

RESIDUAL VOLUME I TOTAL LUNG VOLUME

,P

" ..,,········s -,.

K

MAXIMUM VOLUNTARY VENTILATION

MAXIMUM MID EXPIRATORY

FLOW RATE

~S

" ----.K ~----"

"

"

"

"

" '.p

FIGURE 1. Effect of aerosolized antibiotic on several variables of ventilatory function. Data are expressed as percent change from control values. The change following polymyxin is significantly different from that of kanamycin for the vital capacity (P=O.O 18) and forced expiratory volume (P=O.024).

CHEST, VOL. 63, NO.5, MAY, 1973

VENTILATORY EFFECTS OF AEROSOLIZED KANAMYCIN AND POLYMYXIN polymyxin is well absorbed into the systemic circulatiorr':" but the concentration in lung tissue following inhalation apparently has not been studied. It is known to be effective in preventing the implantation of Pseudomonas into the trachea following tracheostomy but this function is not dependent on nebulization of the antibiotic," On the other hand kanamycin has specific advantages by aerosol. It is poorly absorbed into the systemic circulation which results in a decreased possibility of auditory and renal toxicityP With repeated nebulization, a high and accumulative antibiotic level occurs in lung tissue." This study suggests that although kanamycin is associated with a variable airway response, it generally has little effect on ventilatory function as measured in this study and the effect appears to be indistinguishable from that of saline aerosol given to normal patients. Insofar as its effect on the airway is concerned it would be an excellent therapeutic agent by aerosol. The results of this and previous studies suggests that considerable specific investigation is necessary prior to introducing a therapeutic agent for inhalation. The effect on ventilation, the distribution of aerosol in the lung, the concentration in lung tissue and absorption into the blood in normal and

697

diseased patients would assist in determining if any therapeutic advantage might be derived from this type of therapy compared to other methods of administration of an antibiotic. This study suggests that inhalation of polymyxin may have definite deleterious effects on ventilation, which would be of considerable importance in most patients for whom the therapy would be prescribed. REFERENCES

1 Bilodeau M, Roy JC: Aerosoltherapie a la kanamycine dans 200 cas de suppurations broncho-pulmonaires. Canad Med Assoc J 89:537-541,1963 2 Lepper MH, Kofman S, Blatt N, et al: Effect of eight antibiotics used singly and in combination on the tracheal flora following tracheostomy in poliomyelitis. Antibiot Chemother 4:829-843,1954 3 Prisgal SJ: Aerosol therapy in the practice of allergy. New YorkJ Med 56:910-914, 1956 4 Kaplan RS, Fisher AE, Kahn JL: Treatment of pertussis with polymyxin B (aerosporin). J Pediat 35:49-57,1949 5 Kagan BM, Krevsky D, MiIzer A, et aI: Polymyxin Band polymyxin E: clinical and laboratory studies. J Lab Clin Med 37:402-414, 1951 6 Bilodeau M, Roy JC, Giroux M: Studies of absorption of kanamycin by aerosolization. Ann NY Acad Sci 132:870878, 1966 7 Prokhorova II: Absorbability of kanamycin upon inhalation of the aerosol. Antibiotiki 13:351-355, 1968

Plume Hunters and the Snowy Egret In less enlightened days, the snowy egret was slaughtered by the tens of thousands to provide plumes or aigrettes of the millinery trade. The common egret is the symbol of the National Audubon Society which secured the passage of the bill that outlawed the trade in plumes. In 1903 hunters were offered thirty-two dollars an ounce of plumes of these handsome birds. One source alone, the London Commercial Sales Rooms, sold 1608 packages of egret plumes in 1902. It was estimated

CHEST, VOL. 63, NO.5, MAY, 1973

that the average weight of a "package" was thirty ounces, which makes a total of 48,240 ounces. Since the plumes of four birds were required to make an ounce, on the average, this means that 192,960 egrets were killed to provide one year's supply of plumes for a single auction house. Allen RP: Birds of the Caribbean. New York, Viking Press, 1961