Cost Ratio of New Therapy

communications to the editor Communications for this section will be published as space and priorities permit. The comments should not exceed 350 words in length, with a maximum of five references; one figure or table can be printed. Exceptions may occur under particular circumstances. Contributions may include comments on articles published in this periodical, or they may be reports of unique educational character. Specific permission to publish should be cited in a covering letter or appended as a postscript.

Carbon Monoxide Poisoning To the Editor: Carbon monoxide poisoning accounts for 3,800 deaths in the United States per year and is the leading cause of death from poisoning. This fact is mirrored in other countries as well. 1 Further, there is a high incidence of late neurologic sequelae in patients who survive the poisoning. One study in Britain found that while 2.2% of survivors had obvious neuropsychiatric deficits at hospital discharge, 43% of these patients had some memory dysfunction at 3-year follow-up. 2 The pathophysiology of the poisoning arises from the avid binding of the carbon monoxide (CO) to hemoglobin, occupying oxygen binding sites. Further, the CO has an allosteric effect on hemoglobin causing oxygen to bind more tightly at lower oxygen concentrations, leading to further decreases in tissue oxygen delivery. Current treatment consists of supplying high concentrations of inspired oxygen or even hyperbaric oxygen to establish favorable concentration gradients for tissue oxygen delivery. These therapies do result in more rapid removal of CO-breathing room air, the half-life of CO in the body is 320 min; 80 min on 100% oxygen by face mask; and 23.3 min in hyperbaric oxygen at three atmospheres. 1 Hyperbaric oxygen, however, has not been shown to be a superior treatment in controlled clinical trials. Its use is advocated when the patient shows persistent neurologic or cardiovascular dysfunction after treatment with 100% oxygen. 1 Unfortunately, hyperbaric oxygen chambers are not widely available. Thus, this treatment involves possibly lengthy transport of unstable patients to facilities with such equipment. An alternative therapy could use exchange transfusions. Just as when exchanges are used in cases where sickle hemoglobin leads to neurologic dysfunction, they could be used to remove carboxyhemoglobin from the body when its presence causes neurologic damage. Interestingly, this therapy seems to have not been investigated in humans. Using Medline searches, we found a single reported case of CO poisoning treated with an exchange transfusion of 2,000 mL of whole blood and subsequent hyperbaric oxygen. This patient recovereda There is a report of total body asanguineous hypothermic perfusion used as treatment for CO poisoning in dogs. This study showed a favorable outcome but was extremely invasive. 4 Also of note, exchange transfusions have been advocated in the past for other poisonings including aniline dyes, chlorates, and nitrates. 5 An exchange transfusion of half the blood volume could be accomplished in 2 to 3 h. Because newly infused blood would

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avidly combine with the CO already present in the body, the discarded blood would be expected to carry carboxyhemoglobin, whether it was originally from the patient or had been newly infused. Approximating the half-life of CO with exchange transfusions-using a rate of half the blood volume (5 U packed red blood cells) exchanged in 2 h- at 120 min, in a patient also on 100% oxygen (CO half-life of 80 min) the resultant combined treatment half-life would be 48 min. This represents a significant improvement in removal of CO compared with treatment with 100% oxygen alone and decreases the time the myocardium and nervous system are subjected to anoxic damage. This form of treatment is more widely available, thus limiting transport of patients who are critically ill and decreasing the total time the body is subjected to anoxic damage. Further study of this treatment option seems warranted.

Mark]. Shumate, MD , Emory University, Decatur, Georgia REFERENCES

1 Dolan MC. Carbon monoxide poisoning. Can Med Assoc J1985; 133:392-99 2 Smith JS, Brandon S. Morbidity from acute carbon monoxide poisoning at three-year follow-up. BMJ 1973; 1:318-21 3 Yee LM, Brandon GK. Successful reversal of presumed carbon monoxide-induced semicoma. Aviat Space Environ Med 1983; 54(7):641-43 4 Agostini JC, Ramirez RG, Albert SN, et al. Successful reversal of lethal carbon monoxide intoxication by total body asanguineous hy{iothermic perfusion. Surgery 1974; 75(2):213-19 5 Arena JM. Poisoning: general treatment and prevention. JAMA 1975; 233(4):358-63

Efficacy/Cost Ratio of New Therapy To the Editor: In her editorial on the "Efficacy /Cost Ratio of New Therapy ," 1 Dr. Susan K. Pingleton characterized inappropriately the new approved cystic fibrosis drug Pulmozyme (dornase alfa, Genentech) as having "limited benefit and huge cost." In so doing, she offered only a partial picture of this drug's research and development. More important, she understated the considerable value of Pulmozyme for patients who respond positively. It should be noted that her editorial was prepared after the FDA Pulmonary and Allergy Drugs Advisory Committee, on which Dr. Pingleton served, unanimously recommended approval of Pulmozyme (August, 1993). Dr. Pingleton observed that the development of Pulmozyme was expedited in accordance with the FDA 's "laudable" new commitment to " more quickly review drugs for life-threatening ailments." As one of the participating investigators, Ican confirm that the quality of the research was not sacrificed for expediency. Pulmozyme is one of the most studied drugs with cystic fibrosis as a primary indication. It is effective and safe. 2-5 This accomCommunications to the Editor

plishment testifies to the commitment of Genentech, the FDA, the Cystic Fibrosis Foundation of the United States and Canada, as well as of their numerous accredited care centers, similar centers in Europe, and thousands of cystic fibrosis patients worldwide. Focusing on the US phase III trial,4 which provided the key data supporting approval of Pulmozyme, Dr. Pingleton lamented that "spirometry improved only 5.8 percent. " Such improvement should be understood in the context of the typical decline in FEV 1 of 2 to 3% per year among cystic fibrosis patients receiving standard care.6 Accordingly, the improvement with Pulmozyme was an incremental benefit, as all patients in the study were continued on standard therapies.2-5 As to Dr. Pingleton's observations that "mortality was unchanged" and "long-term patient benefit could not be ascertained," these are hardly surprising given that cystic fibrosis is a life-long disease and the study lasted only 6 months. Significant alterations in mortality would require many years-perhaps decades-to show. Nevertheless, the benefits seen with Pulmozyme in this study were consistent with a delay in the progression of the disease. In a 6-month, open label extension of the phase III trial,5 the groups initially receiving Pulmozyme continued to show reduction in pulmonary exacerbations and improvement in FEV 1 while placebo-treated patients who were crossed over to the active drug showed comparable benefits to those maintained on Pulmozyme. While Dr. Pingleton stated correctly that antibodies were detected in 3 to 5% of patients receiving Pulmozyme, they appear to have no clinical significance.2· 5 Moreover, no Pulmozyme specific immunoglobulin E antibodies were detected. 2· 5 Regarding age-related differences in response to Pulmozyme, once-daily administration is recommended for most cystic fibrosis patients. 2·5 However, some patients-including those >23 years old-may benefit from twice daily administration, higher doses, or both.z-s Dr. Pingleton's admonition that "physicians should review the available data and prescribe the drug according to FDA guidelines" is as true for Pulmozyme as for any drug. Last, Dr. Pingleton's questioning of " a drug that cost millions to develop but which treats a patient population of only 30,000 in the United States" speaks to many Americans' concern that health-care reform will discriminate against them if they suffer from a relatively uncommon illness like cystic fibrosis. Certainly, physicians have always had a fiduciary responsibility to their patients. However, it is our patients' health and well-being-not just their pocketbook-with which we must continue to be most concerned. Until such time as definitive treatment, eg, gene therapy, for cystic fibrosis becomes a reality, we owe it to our patients with this devastating disease to offer those therapies like Pulmozyme that make a demonstrable difference in their overall well-being.

Stanley B. Fiel, MD, FCCP, Pulmonary / Critical Care Medicine , Medical College of Pennsylvania, Philadelphia, Pennsylvania Reprint requests: Dr. Fiel, Medical College of Pennsylvania, 3300 Henry Ave, Philadelphia, PA 19129 REFERENCES

Pingleton SK. Efficacy / cost ratio of new therapy: what is the physician's fiduciary responsibility? [editorial]. Chest 1994; 105:329-30 2 Pulmozyme® (dornase alfa) recombinant inhalation solution. South San Francisco, Calif: Genentech, December 1993 3 Ramsey BW, Dorkin HL. Consensus conference: practical applications of Pulmozyme. Pediatr Pulmonol 1994; 17:404-08 4 Fuchs HJ, Borowitz DS, Christiansen DH, et al. The effect of

aerosolized recombinant human DNase on respiratory exacerbations and pulmonary function in patients with cystic fibrosis. N Eng! J Med 1994; 331:637-42 5 Ramsey B. A summary of the results of the phase III multicenter clinical trial: aerosol administration of recombinant human DNase reduces the risk of respiratory tract infections and improves pulmonary function in patients with cystic fibrosis [abstract S13.3]. Pediatr Pulmonol 1993; (suppl 9):152-53 6 Corey M, Levison H, Crozer D. Five- to seven-year course of pulmonary function in cystic fibrosis. Am Rev Respir Dis 1976; 11 :1085-92

To the Editor: I very much appreciate the opportunity to respond to Dr. Fiel's letter regarding my editorial called " The Efficacy / Cost Ratio of New Therapy " published in Chest. (Chest 1994; 105:329-30). As Dr. Fie! noted and as I had alluded to in the editorial, my interest in this subject was piqued after reviewing available data and participating on the FDA Pulmonary and Allergy Drugs Advisory Committee. Indeed, review of Pulmozyme (dornase alfa, Genentech) by that committee was difficult involving long and laborious discussion because of the central issue of efficacy / cost ratio. Dr. Fie! raised the issue of the expedited FDA review of Pulmozyme because of its " orphan drug" status. In no way did I wish to infer that the shortened duration of review in any way suggested inadequate quality of research. Indeed, my feeling is that the FDA serves our profession and patients admirably by extensive cooperation with pharmaceutical companies to streamline the entire review process. This streamlining translates into a shorter duration of time required from drug inception to final drug review. It should be noted, however, that Pulmozyme phase III review was almost entirely composed of only one large multicenter 6-month trial to accomplish this purpose. As FDA committee members, we were privy to all available data on Pulmozyme. Unfortunately, to my knowledge, this study is not yet published, and therefore only available in abstract form as cited in my editorial and Dr. Fiel's letter. I think this limits other physicians' evaluation and subsequent decision making about this drug. Data interpretation with Pulmozyme as with any drug is always open to individual evaluation. Clearly, this drug improved spirometry in a 6-month trial. Prolonged improvement, continued improvement, or both remain to be documented. The issue, however, that I wished to comment on is the difficult decisions physicians have in assessing what reasonable benefit should ensue from a certain cost. Pulmozyme is now a recognized FDA approved therapy for cystic fibrosis. I believe our responsibility as physicians is to assess the available data regarding benefits to our patients and make clinical decisions about recommendations. Into this clinical decision making in this day and age, in my opinion, should come some measure of cost-benefit assessment.

Susan K. Pingleton, MD, FCCP, Division of Pulmonary and Critical Care Medicine, The University of Kansas Medical Center, Kansas City, Kansas

Which PEF Value is the Best? To the Editor: At least five consensus articles on management and treatment of asthma were published 1· 5 since the explosion of international concern in asthma morbidity and mortality. The authors exposed CHEST I 107 I 5 I MAY, 1995

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