Issues in Ventilator Weaning

It is true that the application of the anti-iNOS antibody was associated with an increase in staining in the ARDS group as compared to the control group. This result could be true of any antibody. The investigators should demonstrate that the increase holds when comparing the specific anti-iNOS antibody to a nonspecific antibody within the ARDS group. We respectfully suggest that further experiments be performed with a nonspecific antibody of the same subclass as the anti-iNOS antibody included. With these control experiments, a conclusion could be made that references the nature of the specific anti-iNOS antibody’s pattern of staining in ARDS alveolar macrophages as compared to the pattern of the nonspecific-isotype antibody with a similar fluorochrome. Peter E. Morris, MD, FCCP Assistant Professor Division of Pulmonary/Critical Care Medicine Elizabeth A. Fitzpatrick, PhD Department of Microbiology and Immunology University of Kentucky Lexington, KY Correspondence to: Peter E. Morris, MD, FCCP, Division of Pulmonary/Critical Care Medicine, 800 Rose Street, MN 614, Lexington, KY 40536 – 0084

Reference

dinucleotide phosphate are excitation 5 350 nm and emission 5 460 nm, we could not understand what they meant. In our experience, the static cytometer is not sensitive enough to measure autofluorescence of neutrophils and macrophages even when using an appropriate selection of filter unit. For such an experiment, we have another set of fluorescent microscopy equipped with cooled charge coupled device camera and light pass for UV light. In addition, the shapes of the cells are quite different in flow cytometric sample and in static cytofluorometric sample, ie, round in flow cytometry and very flat in static cytofluorometry. The difference in the cellular thickness may cause the difference of observed fluorescence pattern. So, cytoplasmic diffuse fluorescence in cytocentrifuged cells will be very weak compared with flow cytometric specimen. These may be the reasons why we could not observe any autofluorescence brighter than the background one. If we use a flow cytometer in the future, we will remember their kind advice and will use longer wave-length dye instead of FITC. We also have unpublished data (1998) that these activated alveolar macrophages in ARDS patients with sepsis show significant expression of inducible nitric oxide synthase messenger RNA. This finding also supports the result of this article. Unfortunately, our clinical findings did not show any significant role of inducible nitric oxide synthase in the pathogenesis of ARDS. We hope further investigation by earnest researchers like Morris and Fitzpatrick will elucidate the significance of this finding.

1 Kobayashi A, Hashimoto S, Kooguchi, K, et al. Expression of inducible nitric oxide synthase and inflammatory cytokines in alveolar macrophages of ARDS following sepsis. Chest 1998; 113:1632–1639

Atsuko Kobayashi, MD, PhD Satoru Hashimoto, MD, PhD Department of Intensive Care Yoji Urata, MD, PhD Department of Pathology Kyoto Prefectural University of Medicine Kyoto, Japan

To the Editor: We thank Drs. Morris and Fitzpatrick for their comments about our manuscript, “Expression of Inducible Nitric Oxide Synthase and Inflammatory Cytokines in Alveolar Macrophages of ARDS Following Sepsis” (June 1998).1 They pointed out the importance of control experiments, especially focusing on the nonspecific fluorescence of activated macrophages. We, of course, did control experiments routinely using both nonimmunized sera and Tris-buffered saline solution. Unfortunately, we have no data from experiments using absorbed antibodies. As a result, we did not observe significant nonspecific fluorescence within macrophages, except for coarse granular fluorescence within “dust cells” showing very wide fluorescent spectrum. This kind of fluorescence was easily distinguished from fluorescein isothiocyanate (FITC) fluorescence. The procedure was always conducted under supervision of an experienced pathologist (Y.U.). In our Table 2, macrophages of ARDS patients with sepsis did not always show positive staining. This finding meant another kind of control experiment that supports the fact that our immunofluorescent staining was not nonspecific. Of course, we do not know whether or not commercially available primary antibodies used were really specific. To avoid the contamination of nonspecific fluorescence in the measured value, we did not display fluorometric values in this article, but we showed percentages of positive-staining cells under fluorescent microscopy. So, our data are not quantitative, but qualitative. Drs. Morris and Fitzpatrick also pointed out that the activated alveolar cells in the FITC wavelength probably fluoresce in greater intensity than control cells. We have no experience in measuring autofluorescence of neutrophils and macrophages by flow cytometry using FITC filter set. As the fluorescent spectra of autofluorescence mainly derived from nicotinamide adenine

Correspondence to: Atsuko Kobayashi, MD, PhD, Kyoto Prefectural University of Medicine, Kyoto, 602-0841, Japan; e-mail: [email protected]

Reference 1 Kobayashi A, Hashimoto S, Kooguchi, K, et al. Expression of inducible nitric oxide synthase and inflammatory cytokines in alveolar macrophages of ARDS following sepsis. Chest 1998; 113:1632–1639

Issues in Ventilator Weaning To the Editor: I read with great interest the recent review on ventilator liberation/weaning by Manthous and colleagues (September 1998).1 Their comments on ventilator dependency factors, liberation criteria, and the need to do daily assessments for liberation potential in patients recovering from respiratory failure are most appropriate, and I certainly agree with them. There are three issues that they raise, however, upon which I would like to comment. First, the authors make the statement that since the ventilator cannot “be used to expedite recovery from respiratory failure,” clinician attention should be turned elsewhere.1 I certainly agree that the ventilator is not a therapeutic device and cannot be expected to reverse underlying lung pathologic condition. Having said that, however, I think it is critical to point out that the ventilator can do considerable harm to the cardiorespiratory CHEST / 115 / 4 / APRIL, 1999

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system. Examples include volutrauma, cardiac compromise, muscle overload, patient discomfort (and thus continued sedation need), and infection risk. I think it is clear that while good management may not reverse lung disease, bad management can surely worsen it. The focus of clinical attention must include ventilator management during this recovery phase of illness. Second, the authors suggest that in patients failing a liberation trial, subsequent ventilator management could involve any mode or setting “as long as the patient gets adequate rest.”1 Clearly, excessive muscle loading from inadequate ventilatory support can delay recovery and prolong the need for mechanical ventilation. Total muscle rest, however, may not be optimal either. Unlike skeletal muscles, ventilatory muscles (much like cardiac muscles) were never designed to rest. Indeed, there is evidence that only a few days of controlled ventilation can produce muscle dysfunction2 and that near total muscle unloading (as compared to normal loading) may delay fatigue recovery.3 This suggests that perhaps the clinical goal should be focused on near normal muscle loading rather than complete rest. In this regard, partial support modes that can normalize muscle loading by providing variable flows and a continuous pressure bias (eg, pressure support, pressure assist, proportional assist) would seem preferable to fixed flow volume assist-control breaths. Third, as the authors point out, intrinsic positive end-expiratory pressure (PEEP) from airflow limitation can clearly function as a significant inspiratory threshold load and thereby has the potential to delay muscle recovery. Applied circuit PEEP can be helpful in reducing this load, but determining the appropriate amount can be difficult. Manthous and colleagues1 suggest analysis of the flow graphic and use of the expiratory hold maneuver. Unfortunately, in flow-limited patients, expiratory flow may be so slow that incomplete emptying may not be detectable. In addition, the expiratory hold maneuver is often impossible to perform in patients attempting to trigger ventilator breaths. I would therefore suggest that clinicians instead learn to recognize the intrinsic PEEP phenomenon by observing a time delay between ventilatory muscle activity (chest motion or accessory muscle contraction) and either the drop in airway pressure detected by the ventilator or the change in ventilator circuit flow. If clinically indicated, an esophageal pressure tracing can be used to specifically measure this imposed load and guide application of circuit PEEP. It is clear, as Manthous and colleagues point out, that daily assessment for liberation potential is important to do. In the patients who fail to meet liberation criteria, however, it is equally important to manage them properly for the next 24 h until the next liberation assessment can be done. Neil R. MacIntyre, MD, FCCP Duke University Hospital Durham, NC Correspondence to: Neil R. MacIntyre, MD, FCCP, Duke University Medical Center, Respiratory Care Services, Box 3911, Durham, NC, 27710; e-mail: [email protected]

References 1 Manthous CA, Schmidt GA, Hall JB. Liberation from mechanical ventilation: a decade of progress. Chest 1998; 114: 886 –901 2 Anzueto A, Peters JI, Tobin MJ, et al. Effects of prolonged controlled mechanical ventilation on diaphragmatic function in healthy adult baboons. Crit Care Med 1997; 25:1187–1190 3 Uchiyama A, Imanaka H, Nishimura M, et al. Effects of pressure-support ventilation on recovery from acute diaphragmatic fatigue in rabbits. Crit Care Med 1998; 26:1225– 1230 1216

To the Editor: The authors of “Liberation From Mechanical Ventilation: A Decade of Progress”1 would like to thank Dr. MacIntyre for his comments. Regarding his first point, we agree that clinical attention should focus on ventilator management throughout the ventilated course, and we recognize that poor ventilator management can do great harm. Our aim was to emphasize that the solutions to most of the clinician’s questions, (ie, Why is the patient still on a ventilator?) and most of the patient’s problems, ie, shortness of breath, lie within the patient, not the ventilator. We are struck by how frequently doctors think they can free patients from their ventilators by adjusting the machine, while the pathophysiologic processes which cause ventilator dependence remain undefined and untreated. It is our approach to restore the normally compensated balance between respiratory load and neuromuscular competence in the patient, since it is then that the ventilator becomes unnecessary. The role of rest and exercise of the respiratory muscles in mechanically ventilated patients is complex and controversial. We, too, believe that complete rest may lead to dysfunction, although the baboon study cited2 involved continuous muscle relaxation with pancuronium, a drug commonly associated with weakness. The delayed recovery from fatigue in rabbits who were ventilated is interesting and may point to the value of some level of exercise,3 but even the concept of diaphragm fatigue may not pertain to human ventilatory failure. We await additional studies before we can recommend specific strategies for muscle conditioning. Finally, there is no question that intrinsic positive end-expiratory pressure (PEEP) can be very difficult to detect unless flow waveforms are continuously displayed. In a study recently completed by one of us, we were able to quantify the amount of intrinsic PEEP using the end-expiratory occlusion technique in only 30% of all ventilated patients in whom it was present.4 Further, as suggested by Dr. MacIntyre, we confirmed that the clinical examination is very useful in detecting the presence of intrinsic PEEP. In our practice of patients ventilated for exacerbations of COPD, we generally apply 7 to 10 cm H2O extrinsic PEEP when our goal is to reduce the work of triggering, adjusting this value based on shortening of the time delay between obvious patient effort and onset of the ventilator breath, but have not sought to validate this approach. Constantine A. Manthous, MD, FCCP Yale University School of Medicine Bridgeport, CT Gregory A. Schmidt, MD, FCCP Jesse B. Hall, MD, FCCP University of Chicago Chicago, IL Correspondence to: Constantine A. Manthous, MD, FCCP, Bridgeport Hospital, West Tower 6, 267 Grant Street, Bridgeport, CT 06610-2870; e-mail: [email protected]

References 1 Manthous CA, Schmidt GA, Hall JB. Liberation from mechanical ventilation: a decade of progress. Chest 1998; 114: 886 –901 2 Anzueto A, Peters JI, Tobin MJ, et al. Effects of prolonged controlled mechanical ventilation on diaphragmatic function in healthy adult baboons. Crit Care Med 1997; 25:1187–1190 3 Uchiyama A, Imanaka H, Nishimura M, et al. Effects of pressure-support ventilation on recovery from acute diaphragmatic fatigue in rabbits. Crit Care Med 1998; 26:1225– 1230 4 Kress JP, O’connor MF, Schmidt GA. Clinical examination reliably detects intrinsic positive end-expiratory pressure in critically ill, mechanically ventilated patients. Am J Respir Crit Care Med 1999; 159:290 –294 Communications to the Editor