cell lung cancer: a review of the current evidence. Chest, 2003;123. (1 Suppl):137Sâ146S. Impaired Arousals and Sudden Infant Death Syndrome. Preexisting ...
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as PET, is required. Clearly these suggestions need prospective validation in a multicenter study. Who should perform this procedure? Gastrointestinal endoscopists will not be eager to surrender a procedure and technology that they have pioneered. Pulmonologists interested in using the technology will need to learn this technically challenging procedure in a cooperative educational setting. This is a perfect opportunity for subspecialty organizations such as the American Thoracic Society and American Gastroenterological Association to jointly set standards as demand for interdisciplinary application of endoscopic ultrasound technology grows. Conflict of Interest Statement : J.A.K. has no declared conflict of interest.
Jeffrey A. Kern, M.D. Case Western Reserve University Cleveland, Ohio References 1. Bulzebruck H, Bopp R, Drings P, Bauer E, Krysa S, Probst G, van Kaick G, Muller KM, Vogt-Moykopf I. New aspects in the staging of lung cancer: prospective validation of the International Union Against Cancer TNM classification. Cancer 1992;70:1102–1110. 2. Watanabe Y, Shimizu J, Oda M, Hayashi Y, Watanabe S, Tatsuzawa Y, Iwa T, Suzuki M, Takashimi T. Aggressive surgical intervention in N2 non-small cell cancer of the lung. Ann Thorac Surg 1991;51:253–261. 3. Toloza EM, Harpole L, McCrory DC. Noninvasive staging of non-small cell lung cancer: a review of the current evidence. Chest, 2003;123 (1 Suppl):137S–146S.
4. Pieterman RM, van Putten JW, Meuzelaar JJ, Mooyaart EL, Vaalburg W, Koeter GH, Fidler V, Pruim J, Groen HJ. Preoperative staging of non-small-cell lung cancer with positron-emission tomography. N Engl J Med 2000;343:254–261. 5. Kernstine KH, Stanford W, Mullan BF, Rossi NP, Thompson BH, Bushness DL, McLaughlin KA, Kern JA. PET, CT, and MRI with Combidex for mediastinal staging in non-small cell lung carcinoma. Ann Thorac Surg 1999;68:1022–1028. 6. Gupta NC, Graeber GM, Bishop HA. Comparative efficacy of positron emission tomography with fluorodeoxyglucose in evaluation of small (⬍ 1 cm), intermediate (1 to 3 cm), and large (⬎ 3 cm) lymph node lesions. Chest 2000;117:773–778. 7. Fritscher-Ravens A, Davidson BL, Hauber H-P, Bohuslavizki KH, Bobrowski C, Lund C, Kno¨fel WT, Soehendra N, Brandt L, Pepe MS, et al. Endoscopic ultrasound, positron emission tomography, and computerized tomography for lung cancer. Am J Respir Crit Care Med 2003;168:1293–1297. 8. Harewood GC, Wiersema MJ, Edell ES, Liebow M. Cost-minimization analysis of alternative diagnostic approaches in a modeled patient with non-small cell lung cancer and subcarinal lymphadenopathy. Mayo Clin Proc 2002;77:155–164. 9. Harrow EM, Wang KP. The staging of lung cancer by bronchoscopic transbronchial needle aspiration. Chest Surg Clin N Am 1996;6:223–235. 10. Keller SM, Adak S, Wagner H, Johnson DH. Mediastinal lymph node dissection improves survival in patients with stages II and IIIa nonsmall cell lung cancer: Eastern Cooperative Oncology Group. Ann Thorac Surg 2000;70:358–365; discussion 365–366. 11. Oda M, Watanabe Y, Shimizu J, Murakami S, Ohta Y, Sekido N, Watanabe S, Ishikawa N, Nonomura A. Extent of mediastinal node metastasis in clinical stage I non-small-cell lung cancer: the role of systematic nodal dissection. Lung Cancer 1998;22:23–30..
DOI: 10.1164/rccm.2309014
Impaired Arousals and Sudden Infant Death Syndrome Preexisting Neural Injury?* In a report on the spontaneous incidence of “full” arousals (those accompanied by electroencephalographic signal changes) and incomplete or “subcortical” arousals (arousals with cardiovascular or momentary muscles signs, but not electroencephalographic desynchronization), Kato and colleagues, in this issue of the Journal (1), raise several important issues in the description of developmental sleep physiology in infants who later succumb to sudden infant death syndrome (SIDS). The dataset examined in this study could only be described as extraordinary; namely, a subset of a very large number of infants who had undergone earlier all-night polysomnographic recording, not just heart rate and respiratory monitoring; this subset later succumbed to SIDS. The recordings were collected from 10 hospitals in Belgium; the database was sufficiently large (more than 20,000 infants) that a large sample of SIDS victims (n ⫽ 16) became available for study; a significant achievement, considering the now relatively low incidence of SIDS in the general population. The large numbers of initial recordings also ensured adequate matching with control subjects. The major findings suggest that homeostatic systems that recruit forebrain participation may exert a protective role in restoring vital functions when SIDS-susceptible infants are physiologically challenged. The data indicate a diminished incidence of spontaneous full arousals, those associated with activation of neocortical electroencephalographic signals, during sleep in
* Supported by a grant (HD-22695) from the National Institute of Child Health and Human Development.
future victims. Assigning the full arousal process a protective role as a means to maintain respiratory integrity during sleep has been proposed earlier for adult breathing patterns (2), and directs attention to potential failing mechanisms in developing infants. The study of Kato and coworkers (1), however, also demonstrates that arousal processes that do not incorporate neocortical signs, “subarousals,” occurred more frequently in later SIDS victims. This finding may be a key to determining pathologic processes in the syndrome. Increased numbers of subarousals suggest processes that are unable to dampen or filter stimuli that normally are suppressed during sleep, and hence trigger muscle or heart rate responses. We could speculate that several mechanisms may underlie the increased incidence of subarousals; however, undampened release of motor, cardiac, and neural signal patterns occur in response to loaded breathing following the cerebellar damage that accompanies disordered breathing in adults (3, 4). Routine stimulation of the body, encountered during sleep, might elicit undampened muscle and cardiovascular responses, a hallmark of cerebellar damage, if similar neural damage occurred in infants. Such damage might emerge after cerebellar maldevelopment, or an earlier undetected hypoxic or ischemic event. Cerebellar structures are especially sensitive to injury from such events (5). In SIDS victims, a principal nucleus which projects to cerebellar structures, the inferior olive, shows prenatal brainstem injury (6); infants who succumb also show delayed cerebellar cortex development (7). The functional deficits shown by Kato and coworkers (1) in future SIDS victims appear to have a basis in structural damage. The cerebellar processes that may mediate the undampened subarousal responses could play a role in diminishing the num-
Editorials
bers of full arousals in future SIDS victims. Deficient influences from cerebellar deep nuclei projections to thalamic sites have the potential to modify thalamocortical interactions, and thus alter cortical synchronization. Several other ascending arousal systems, however, affect cortical activation, and some use ventral pathways, bypassing the thalamus, and incorporate input from limbic structures to elicit activation (8). Multiple neural sites, including neocortical and limbic regions regulating arousalrelated cardiovascular and electroencephalographic responses, are both structurally and functionally compromised in adults with a history of disordered breathing (3, 4). The potential for involvement of these multiple cortical arousal systems in the fatal events of SIDS remains to be clarified. The findings further demonstrate that arousal deficiencies are present at least six weeks before death, reinforcing a suspicion from multiple sources that, although future SIDS victims present an apparently unremarkable physical condition before the fatal event, subtle physiologic deficits are present much earlier. Indeed, other evidence suggests that abnormalities exist from fetal life: prenatal nicotine exposure is a significant risk factor for the syndrome (9), and aberrant respiratory patterns are present shortly after the first month of life (10). The deficient arousal responses should be viewed in the context that the infants are physiologically compromised for some time before death from SIDS occurs. Any indication of physiologic differences that predict which infants are at risk for SIDS should be of immediate clinical interest. It is important to note, however, that despite the importance of these data in determining failing systems in SIDS, the described deficiencies required assessments of all-night sleep patterns, identification and partitioning of sleep state (quiet sleep or rapid eye movement sleep) and measures of transitions from one state to another, in addition to the physiologic signal evaluation. Such an assessment is not achieved in an acute examination, but requires long-term signal acquisition with multiple physiologic measures, and necessitates evaluation of those changes against a substantial database of normative data. The findings direct attention to potential defective mechanisms underlying the syndrome, suggest that reflexive brainstem compensatory mechanisms for arousal are aberrant, and that processes that recruit neocortical regions are lacking. Examination of processes by which critical challenges incorporate these ascending pathways may be of benefit in evaluating vital functions during sleep.
1263 Conflict of Interest Statement : R.M.H. has no declared conflict of interest.
Ronald M. Harper, Ph.D. Department of Neurobiology and the Brain Research Institute David Geffen School of Medicine at UCLA Los Angeles, California
References 1. Kato I, Franco P, Groswasser J, Scaillet S, Kelmanson I, Togari H, Kahn A. Incomplete arousal processes in infants who were victims of sudden death. Am J Respir Crit Care Med 2003;168:1298–1303. 2. Orem J. The nature of the wakefulness stimulus for breathing. Prog Clin Biol Res 1990;345:23–30. 3. Macey PM, Henderson LA, Macey KE, Alger JR, Frysinger RC, Woo MA, Harper RK, Yan-Go FL, Harper RM. Brain morphology associated with obstructive sleep apnea. Am J Respir Crit Care Med 2002; 166:1382–1387. 4. Macey PM, Macey KM, Henderson LA, Alger JR, Frysinger RC, Woo MA, Yan-Go F, Harper RM. Functional magnetic resonance imaging responses to expiratory loading in obstructive sleep apnea. Respir Physiol Neurobiol 2003;138/2–3:275–290. 5. Welsh JP, Yuen G, Placantonakis DG, Vu TQ, Haiss F, O’Hearn E, Molliver ME, Aicher SA. Why do Purkinje cells die so easily after global brain ischemia? Aldolase C, EAAT4, and the cerebellar contribution to posthypoxic myoclonus. Adv Neurol 2002;89:331–359. 6. Kinney HC, McHugh T, Miller K, Belliveau RA, Assmann SF. Subtle developmental abnormalities in the inferior olive: an indicator of prenatal brainstem injury in the sudden infant death syndrome. J Neuropathol Exp Neurol 2002;61:427–441. 7. Cruz-Sa´nchez FF, Lucena J, Ascaso C, Tolosa E. Quinto`, L, Rossi M. Cerebellar cortex delayed maturation in sudden infant death syndrome. J Neuropathol Exp Neurol 1997;56:340–346. 8. Dringenberg HC, Vanderwolf CH. Involvement of direct and indirect pathways in electrocorticographic activation. Neurosci Biobehav Rev 1998;22:243–257. 9. Blair PS, Fleming PJ, Bensley D, Smith I, Bacon C, Taylor E, Berry J, Golding J, Tripp J. Smoking and the sudden infant death syndrome: results from 1993–5 case-control study for confidential inquiry into stillbirths and deaths in infancy: confidential Enquiry into Stillbirths and Deaths Regional Coordinators and Researchers. BMJ 1996;313: 195–198. 10. Schechtman VL, Harper RM, Wilson AJ, Southall DP. Sleep apnea in infants who succumb to the sudden infant death syndrome. Pediatrics 1991;87:841–846.
DOI: 10.1164/rccm.2309010
Bronchoscopic Sampling of Drug Concentrations Penetration to Tissue Is the Issue When selecting antibiotics for treatment of severe infections, the traditional approach has been to eradicate pathogens by achieving high serum drug concentrations relative to the minimum inhibitory concentration for infecting organisms. Reliance on serum pharmacokinetics for establishing susceptibility breakpoints and appropriate drug dosing regimens has largely ignored the fact that most infections do not occur in the serum and that penetration of antibiotics to the actual site of infection is not always accurately reflected by serum concentrations (1). The study of antimicrobial pharmacodynamics attempts to integrate in vitro activity of antibiotics with pharmacokinetic characteristics of the drugs to predict and optimize clinical and bacteriological responses to therapy. Antibiotic penetration to tissues and fluids at the specific site of infection, rather than concentrations in serum, has been increasingly recognized as being much more
valuable in predicting response to drugs. Epithelial lining fluid (ELF) has become a well-accepted medium in which to study intrapulmonary penetration of drugs because it provides a good model for the ability of drugs to cross from blood through various tissue barriers and is representative of the extracellular environment in which pulmonary pathogens are often located (2). In this issue of the Journal (pp. 1304–1307), Yamazaki and colleagues (3) describe a novel method of sampling intrapulmonary drug concentrations using bronchoscopy with a bronchoscopic microsampling probe. This microsampling method uses a polyethylene sheath containing an inner polyester fiber probe that immediately adsorbs fluid. The probe is advanced into a distal airway and ELF is directly sampled through adsorption of fluid onto the probe; the volume of epithelial lining fluid and corresponding drug concentrations are easily determined through
