© 2005 American Thoracic Society
"Low-Level" Carbon Monoxide Administration May Carry RiskFrom the Authors:Drs. Hampson, Weaver, and Piantadosi have accused us of performing a "questionable" study (1) that "did not meet accepted standards for ethical research" and caused "needless harm" to research participants. Although we are convinced that critical assessment by colleagues is invaluable, we feel that this harsh criticism is not warranted. Our study was the first conducted in humans with the goal to reproduce the antiinflammatory effects of carbon monoxide (CO) inhalation observed in a murine endotoxemia model (2). Phase I studies are always troublesome with respect to potential individual benefits, since participants are healthy and do not directly benefit from treatment. Thus, one has to assess whether potential societal benefits in terms of knowledge justify the excess risk to individual subjects. As discussed in our article (1), CO inhalation with similar concentrations has been performed in healthy volunteers previously. Our carboxyhemoglobin (HbCO) cut-off level was determined after extensive review of the literature, which showed that short-term exposure to CO concentrations of 500 ppm had no "appreciable effect" and exposure to concentrations as high as 1,000 to 1,200 ppm were not detrimental (3). Furthermore, we addressed potential adverse effects of low-dose CO inhalation in great detail and strongly focused on safety issues. To demonstrate our awareness, we conducted a placebo-controlled four-way, crossover, dose-escalation pilot trial (without endotoxemia) to evaluate safety and tolerability of CO inhalation in humans with serial HbCO measurements performed every 15 minutes and continuous monitoring of vital parameters (i.e., ECG, heart rate, blood pressure, and pulse oximetry). Although experts in the field (including one reviewer) advised us to prolong CO treatment or increase CO concentrations, we rejected these suggestions because of potential safety concerns and lack of up-to-date published data. We are also aware that clinical severity of CO poisoning often poorly correlates with HbCO values and has to be evaluated in context with duration of exposure, the concentration of CO inhaled, and degree of activity during exposure (4). For example, HbCO levels are higher in volunteers who have an elevated heart rate. Our volunteers had mean heart rates of 67 beats per minute and were confined to bed rest. As we also discussed in our article, impairment of cognitive and psychomotor abilities in acute CO intoxication at HbCO levels as low as 5% is well described. However, there is no evidence that mild CO intoxication leads to permanent neuropsychologic sequelae as assessed by neuropsychologic testing. For example, moderate to severe CO intoxication (median HbCO levels of 23% at admission, i.e., threefold our peak HbCO levels) had no permanent neuropsychologic sequelae in subjects without risk factors for cognitive disturbances (similar to our healthy volunteers) (5). Recommended exposure limits for CO exposure at workplaces are heterogeneous. For example, the National Institute for Occupational Safety and Health recommended exposure limit for CO is 35 ppm for an 8-hour time-weighted average exposure, with a ceiling limit of 200 ppm for short-term exposure, and is designed to protect workers from health effects associated with HbCO concentrations in excess of 5% (6). These recommendations differ from those of the American Conference of Governmental Industrial Hygienists, which again are different from the standards recommended by the Occupational Safety and Health Administration and the National Research Council (7, 8). Although our volunteers reached maximum HbCO values slightly higher than 5% (1), these values dropped below 5% approximately 2 hours after the end of inhalation. All participants were observed until 8 hours after the end of inhalation before being dismissed from our study ward.
Hampson and colleagues also maintain that the antiinflammatory effects of CO should have been tested in vitro before "exposing human volunteers to a recognized toxin." Before exposing our volunteers to CO, we were able to demonstrate that CO had antiinflammatory effects in human peripheral blood monocytes in vitro (M.B., unpublished data). In short, monocytes were cultured and pretreated with 250 ppm CO or air for 3 hours. Thereafter, cells were incubated with 1 µg/ml LPS for 1 hour and tumor necrosis factor (TNF)- In conclusion, we do not think that the harsh criticism of Drs. Hampson, Weaver, and Piantadosi is justified. Data from a rodent model (2) as well as results from human and murine in vitro experiments provided a sound rationale to investigate putative antiinflammatory effects of CO in humans.
Medical University of Vienna, Vienna, Austria FOOTNOTES Conflict of Interest Statement: None of the authors have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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was determined in the supernatant. Consistent with the murine studies, TNF-