Hydrogen peroxide (Hp ), 2. Urine Hydrogen Peroxide During Adult Respiratory Distress Syndrome in Patients With and Without Sepsis*

Transcription

1 Urne Hydrogen Peroxde Durng Adult Respratory Dstress Syndrome n Wth and Wthout Sepss* Mal Mathru, M.D., F.C.C.P.; Mchael W. Rooney, Ph.D.; Davd]. Dres, M.D.; F.C.C.P.; Leroy]. Hrsch, Ph.D.; Lonel Barnes, B.S.; and Martn]. Tobn, M.D., F.C.C.P. BackgrountL The lung njury n adult respratory dstress syndrome (ARDS) has been usocated wth ncreased expratory hydrogen peroxde ("s0 ) 1 ooncentratons. F'lll' thermore, patents wth sepss and ARDS are reported to have greater serum scavengng of "s than patents wth ARDS only. We hypotheszed that the systemc presence of "s would he deteclable n the urne of these two groups of patents and that, n the case of ARDS sepss, the relatve contrbuton of each dsease to the producton ths analyte would he dscernble. Accordngly, we used an n vtro radosotope assay to follow the weekly course of urne "s levels n ARDS patents wth and wthout sepss, and n samples from control non-ards patents wth sepss wth ndwellng urnary catheters and n samples provded by healthy volunteers. Methods: Thrty patents wth ARDS were ncluded n the study: 23 had sepss and 7 were sepss free. An ndwellng catheter was used to collect urne from each patent over a 24-h perod, 6rst wthn 48 h of CU admsson and then every seventh day over the course of ther llness. Urne "s was measured by compettve decarboxylaton of 1-14Calpha-ketoglutarc add by "' Urne samples were provded by 20 heallhy volumeers wble, n 10 ooo-ards patents wth sepss, urne was codected over one 24-h perod followng a 5-<lay mnmum wth an ndwellng urnary catheter. Haulta: Urne "s concentraton n healthy control subjects (88 ± 4 ~ and ) non-ards patents wth urnary catheters (96 ± 5 ~ ) wnot sgn6cantly a s dfferent. Durng the 6rst 48 h n the CU, urne "s n patents wth ARDS < 0.05)than dfferentate the severty of oxdant processes n patents only(295 ± 29 ~ ) w a s s g n f c a n t l y l wth o w ARDS e r ( and p sepss alhet the prognoss appears to he patents wth ARDS and sepss (380 ± 13 ~ ) ; h o w e survval v e r or, llolsu'vval (Chest 1994; 105:232-36) Hydrogen peroxde (Hp ), 2 under normal condtons, s derved from phagocytc cells to act as an antmcrobal toxn and s produced as a by-product from oxdant enzymes that can be used, for example, as a cofactor for mono-oxygenase dehydrogenaton and decarboxylaton. 1 2 n the case of adult respratory dstress syndrome (ARDS), an excessve producton of has been detected n expred breath from these *From the Departments of Anesthesology (Drs. Mathru, Rooney, and Hrsch, and Mr. Barnes), Surgery (Dr. Dres), and Medcne (Dr. Tobn), Loyola Unversty Medcal Center, Maywood ll, and Dvson of Pulmonary and Crtcal Care Medcne (Dr. Tobn), Edward Hnes VA Hosptal, Hnes, ll. and Loyola Unversty Chcago Strtch School of Medcne, Maywood, ll. Supported by the Department of Anesthesology Research and Educaton Fund. Manuscrpt receved October 27, 1992; revson accepted May 27. Reprnt requests: Dr. Rooney, Department of Anesthesology, Loyola Unversty Medcal Center, Maywood, the lung njury scores of these two groups dd not dffer. Furthermore, wthn the frst 48 h, the urne "s of the patentswthardsandsepsnvboddnotsunve(427 ± 19 JUDOW..; n = 7) was sgnflmntly hgher than that n patents who survved sepss (352 ± 14 ~ n = 15). Thereafter, the lung njury scores and urne H 1 levels of the nonsurvvor ARDS-sepss group remaned sgnfcantly hgher compared wth the other two groups. At lung njury scores of 3 and 2, regardless of days n CU, the patents wth ARDS only had sgnfcantly lower urne H 1 (266 ± 30 ~ and 167 ± 24 J.l.lllO)L, respectvely) compared wth the survvor ARDS-sepss group (376 ± 19 J.LDC)lL and 250 ± J.UDOl'L). When the patents wth ARDS (both ARDS only and wth sepss) recovered, ther urne H 1 concentraton dd not dffer from the control groups (healthy donors and patents wthout ARDS). Conclua8on: Lung njury scores dd not dfferentate patents wth ARDS and sepss from patents wth ARDS only durng the 6rst 10 days n the CU; however, urne "s levels were sgn6cantly greater n the patents wth ARDS and sepss. Moreover, despte no ntal dfference n lung njury, patents who dd not sunve ARDS and sepss had ~ teotly greater urne "s coocentratoo than patents who survved sepss. The urne "s level n the ARDS-only group was about 70 percent of the level n the survvor ARDS and sepss group, suggestng that ARDS alone s the major contrbutor to the "s oxdant processes durng combned ARDS and sepss. Furthermore, these studes demonstrate that urne 0, may he a useful analyte to patents whch s attrbuted to the abundance of actvated phagocytes that have n6ltrated ther lungs.3-5 However, the specfc role of excessve producton n ARDS lung abnormalty s unknown. n the case of sepss wth ARDS, n vtro studes of patents blood have determned that scavengng of s greater n ARDS patents wth sepss compared wth sepss alone. 6 Furthermore, Nahum et al 7 have demonstrated, n vtro, that patents wth sepss only have greater producton n mxed venous actvated neutrophls compared wth arteral neutrophls whle the opposte s true for patents wth ARDS only. Measurement of n the expred breath of patents wth ARDS s made usng a peroxdase-based system that s subject to nterference by ascorbc acd and thol compounds. 8 n addton, obtanng a sample of expred gas n mechancally ventlated patents s 232 Urne Hydrogen Peroxde Durng ARDS (Mathru at a/)

2 subject to dluton problems. Furthermore, ths technque s unrelable n nonntubated patents, because oropharyngeal bactera are known to generate when exposed to oxygen. 9 These problems may be avoded by measurng drectly n body fluds. Although measurng n blood s cumbersome, a hghly senstve and less dffcult method has been developed to drectly measure n urne. 10 However, as of yet, t has not been appled to the clncal settng. We hypotheszed that wll be found n the urne of patents wth ARDS wth and wthout sepss. Accordngly, the present study examnes levels n the urne of patents wth ARDS and sepss and patents wth ARDS only over the course of ther llness. These two dseases have ARDS as a common etology, and we postulated that the relatve contrbuton of from ARDS alone would be dfferentated. Furthermore, urne level as a functon of lung njury score n these two dseases may have a prognostc value. METHODS The study was approved by the nsttutonal Revew Board of the Hosptal and nformed consent was obtaned from each patent and each subject n the study. Twenty-three patents from the surgcal CUs of Loyola Unversty Medcal Center wth the dagnoss of both septc shock and ARDS were studed. These conssted of 16 men and 7 women, wth an (mean :!: standard error) age of 51 :!: 3 years. Ths group of patents s referred to as havng ARDS and sepss. A second group of seven patents wth ARDS were dentfed who dd not have sepss but who had a focal or dffuse nfltrate on ther chest radographs. Ths group conssted of sx men and one woman aged 57 :!: 7 years. Ths group of patents s referred to as havng ARDS only. Both groups of patents were ntubated and mechancally ventlated. Control measurements were obtaned n 20 healthy, nonsmokng men (n = 12) and women (n = 8), age 34 :!: 2 years, and n 10 patents age 62 :!: 2 years, who had an ndwellng urnary catheter for at least 5 days wthout respratory falure. All patents had ndwellng pulmonary artery catheters for montorng purposes. The patents receved conventonal therapy. ncludng antbotcs, flud resusctaton, notropc drugs, parenteral nutrton, and mechancal ventlaton. Septc shock was defned accordng to the crtera of Bone et al: 11 (1) temperature > 38.3 c or < 35.6.C; (2) tachypnea (rate > 20) or ventlator rate> 10; (3) alveolar partal pressure of oxygen (Pa )/ fracton of nspred oxygen (Fo 2 ) < 280 (wthout other pulmonary or cardovascular dsease as the cause); (4) elevated lactate level (> 1.5 mmovl); (5) olgura,< 0.5 ml of urne per klogram of body weght for at least 1 h; (6) blood cultures revealng Gram-postve or Gram-negatve organsms; and (7) epsode of hypotenson (systolc pressure of < 90 mm Hg or a decrease from baselne of > 40 mm Hg) that was responsve to ntravenous fluds or pharmacologc nterventon. who met fve or more of the above crtera were ncluded n the study. The defnton of ARDS was based on the followng crtera: presence of dffuse nfltrates nvolvng all four lung quadrants of the anteroposteror chest radograph, severe hypoxema (arteral partal pressure of oxygen [Pa ]/)Fo 2 < 200 wth postve endexpratory pressure (PEEP), and a pulmonary arteral wedge pressure of :Sl8 mm Hg. Severty of parenchymal lung njury was quantfed each day by the use of the lung njury score descrbed by Murray et al_ll The score s based on a chest radograph score, a Pa0/Fo 2 score, a PEEP score (when ventlated), and evaluaton of respratory complance. who had a lung njury score greater than 2.5, whch has been shown to represent severe ARDS, were ncluded n the study. Urnary Measurement Protocol: n all patents, 24-h urne samples were collected and refrgerated at - 4oc for further analyss wthn 48 h of the dagnoss of septc shock. Urne was collected on a weekly bass startng wthn 48 h of the tme of admsson nto the CU, hereafter referred to as day 2. Measurements were repeated every seventh day durng the course of ther llness at day 9, 16, 23, 30, etc. wth postve urne cultures, urne volume < 1 mvkglh, and abnormal renal functon (creatnne > 1.5 mg!dl) were excluded from the study. A fnal urne sample was obtaned when the patents had completely recovered from septc shock and respratory falure, as defned by hemodynamc stablty wthout the need for flud resusctaton, notropc support, or mechancal ventlaton. Measurement: Urnary was determned by the method of Varma and Devamanoharan. 10 Brefly, ths s a radoactve method based on the decarboxylaton of l- 14 C-alpha-ketoglutarc acd by The lberated 14 C was counted n a lqud scntllaton counter. n our study, the reacton was carred out n a customdesgned test tube (8.5 em x 1.5 em) wth a sde arm (2.0 em x 0.5 em) stuated 2.5 em from the bottom (Supelco Separaton Technologes, Belleconte, Pa). A mxture of rado labeled and non labeled a-ketoglutarate was placed n the test tube that was then covered wth a C trap. A urne sample, dluted 1:20 wth Tyrode buffer, was njected through a rubber stopper n the sde arm. After an ncubaton perod, the sample was acdfed wth trchloroacetc acd and then further ncubated. The C trap was then transferred to a scntllaton val and counted. The content n the urne sample was calculated as follows: H. ( JLmolL) DPM...,,.. -DPMbackgroundxDluton Factor D P M.. r. ~ " " ' where DPM...,pk s the number of dsntegratons per mnute n the urne sample contanng the radolabeled analogue of a-ketoglutarate, DPMbackgn>und s the number of dsntegratons per mnute n the sample wthout the radolabeled analogue, and D P M ~ r s ~ " " ' the number of dsntegratons per mnute n a quantty (JLmoVL) of the pure radolabeled analogue. n our study, the techncan performng the assay was blnded to the dentty of the patent and healthy control donor. Statstcal Analyss Statstcal comparsons were made wth the help of a computerdrven software program (Systat 5.0, Systat nc, Evanston, ll). Sgnfcant dfferences between the group means were determned wth a completely parametrc randomzed block analyss of varance n conjuncton wth Student-Newman-Keuls test. To determne temporal correlaton of lung njury score and urne, a Pearson correlaton matrx was generated usng all values from all patents. The same correlaton matrx was mplemented for wthn-group comparsons. Dfferences n correlaton coeffcents were tested wth multvarate analyss of covarance. All values were expressed as mean :!: standard error of the mean. A p < 0.05 was consdered sgnfcant. RESULTS The 23 patents wth ARDS and sepss were dvded nto two groups: 15 survvors and 8 nonsurvvors. Tables 1 through 3 gve the clncal descrptons of the survvor ARDS-sepss, nonsurvvor ARDS-sepss, and CHEST JANUARY,

3 Table!-Clncal Ducrpton oflbtenta Watla ABDS and Sepftl Who Sumved Patent NoJ C ntra-abdomnal abscess 9/ Endocardts Perforated bowel Gram-negatve pneumona Penetratng trauma, abdomnal abscess Cerebral abscess Ascendng cholangts Necrotzng pancreatts Empyema thoracs 1ot Sgmod resecton, abdomnal abscess Rght upper lobectomy 12/ Penetratng trauma, abdomnal abscess Pancreatc abscess W ,000 Esophagastrectomy, abdomnal abscess Perforated bowel Table!-Clncal Ducrpton oflbtenta Wth ABDS and SepN Who Dd Not Survve Patent NoJ C Sgmod perfusant Necrotzng pancreats Abdomnal abscess.u6q Perforated bowel Left pneumonectomy pneumona Abdomnal abscess 1no 2.8 1,060 Fecal perforaton Acute mesenterc arteral occluson Patent NoJ C Table 3-CUncal Ducrpton oflbtenta Wth ABDS Alone ,100 Abdomnal aneurysm ,300 Acute lac occluson Aspraton pneumona.ws Multple trauma, ()Ontuson lung and heart ,100 Head njury, noncardogenc edema Multple trauma, head njury ,000 Lymphoma ARDS-only groups, respectvely. Lung njury scores and urne concentratons as a functon of tme n the CU are shown n Fgures 1 and 2, respectvely, for the three groups of patents. Durng the frst 48 h n the CU, urne n ARDSonly patents (295 ± 29 J.LmoVL) was sgnfcantly lower (p < 0.05) than that n all patents wth ARDS and sepss (380 ± 13 J.Lmol!L; n = 23), however, the lung njury scores of these two groups dd not dffer (data not reproduced n fgures). n Fgures 1 and 2, wthn the frst 48 h (day 2), the urne of the patents wth ARDS and sepss who dd not survve (427 ± 19 J.LmoVL; n = 7) was sgnfcantly hgher than n patents who survved sepss (352 ± 14 J.LmoL; n = 15), agan wth no sgnfcant dfference n lung njury score. At r. 3 2 T 2 ~ 1 ~ DAYS.. LC.U. FGURE 1. Lung njury scpres durng days n the ntensve care unt (CU) of patents wth ARDS and sepss who dd not survve (open crcles), patents wth ARDS and sepss (trangles who survved), and patents wth ARDS alone (squares). Astersk ndcates p < 0.05vs survvor ARDS-sepss or ARDS-only groups. day 9, the lung njury scores of the survvor ARDSsepss and ARDS-only groups were not sgnfcantly dfferent; however, the urne concentraton of the survvor patents wth ARDS and sepss was sgnfcantly greater. n the nonsurvvor group wth ARDS and sepss, the lung njury scores and concentratons at days 9 to 30 had not changed sgnfcantly from day 2 of ths group and these data remaned sgnfcantly hgher compared wth the other two groups. The lung scores and urne data at days 16 to 37 of the survvor and ARDS-only groups decreased n parallel; however, these data are not as meanngful snce by day 23 most of the patents wth ARDS only no longer had ARDS. Fgure 3 compares the urne concentraton wth lung njury score for the three groups. The nonsurvvor patents had lung njury scores of 5 to 3. The correlaton of all lung scores to all urne concentratons from the three groups was 0: , y Q ~ ~ _ DAYS.. Lc.u. FGURE 2. Urne hydrogen peroxde ( ) concentratons durng days n the ntensve care unt (CU) of patents wth ARDS and sepss who dd not survve (open crcles), patents wth ARDS and sepss who survved (trangles), and patents wth ARDS alone (squares). Astersk ndcates p < 0.05 vs survvor ARDS-sepss or ARDS-only groups; plus sgn, p < 0.05 vs ARDS-only group. Urne Hydrogen Peroxde Durng ARDS (Mathru st al)

4 E ~. t ~ ~ ~ FGUR E 3. Urne hydrogen peroxde ( ) concentratons vs lung njury scores of patents wth ARDS and sepss who dd not survve (open crcles), patents wth ARDS and sepss who survved (trangles), and patents wth ARDS alone (squares). Astersk ndcates p < 0.05 vs survvor ARDS-only group. However, wthn-group correlatons were as follows: for patents wth ARDS only; for survvors wth ARDS and sepss; and for nonsurvvors wth ARDS and sepss. n general, there were not enough urne data at every lung njury score n each group to make meanngful statstcal comparsons at each score. However, at a lung njury score of 3, the data showed sgnfcantly hgher urne concentratons n both ARDS-sepss groups compared wth the ARDS-only group. At lung score of 2, the urne concentraton of the survvor patents wth ARDS and sepss remaned sgnfcantly ncreased compared wth the patents wth ARDS only. The dfference, between the groups, n urne level at these lung njury scores (3 and 2) are reflected n the sgnfcantly (p<0.05) poorer correlaton (0.754) when correlatng all data from the three groups. The urne concentratons n the healthy subjects and non-ards patent groups were not sgnfcantly dfferent from each other or from the ARDS-sepss and ARDS-only groups at the tme when ther lung njury scores were zero (Table 4). DSCUSSON Consstent wth studes that detected abnormal levels of n expred breath of patents wth ARDS, 3.s we observed excessve n the urne of Table 4-Urne H,O, UroelB n Healthy Donora, ltjtenta Wthout ABDS, and ltjtenta Wth ABDS Who Had 'hro Lung njury Scoret Urne H.o., J.Lmo/L Healthy Subjects (n=20) 88±4 *Values are mean± SE. Non-ARDS (n= 10) 96±5 ARDS-Only (n=7) 91±3 ARDS-Sepss (n= 15) 97±3 patents wth ARDS and n patents wth combned ARDS and sepss. Hydrogen peroxde s an actve oxygen metabolte that has been mplcated as a possble medator of the lung abnormalty n ARDS For example, applcaton of -generatng systems, such as glucose oxdase and xanthne oxdase, to anmal lung tssue preparatons results n lung njury that s very smlar to human ARDS Furthermore, n other anmal models of ARDS, catalase, an scavenger, has been shown to attenuate the lung njury n addton, studes of patents wth ARDS have revealed that blood glutathone, a potent nactvator of 0, 2 s defcent. 22 n the present study, we demonstrated that lung njury scores dd not dfferentate between patents wth ARDS only from patents wth ARDS and sepss; however, urne levels not only dfferentated ARDS-only from ARDSsepss but also dstngushed patents who survved sepss from those who dd not survve ARDS plus sepss. n addton, our data suggested that the majorty of producton n patents wth ARDS and sepss s due prmarly to ARDS rather than sepss abnormalty. The major source of the abnormal levels of n the urne of patents wth ARDS are phagocytes and endothelal cells that generate from NADPH oxdase and xanthne oxdase, respectvely. 23 Other mnor sources of nclude cyclo-oxygenase, mxed functon oxdases, and mtochondral enzymes. 23 The patents wth sepss wth ARDS had hgher levels of n ther urne compared wth patents wth ARDS only. The addtonal source of n patents wth sepss s undoubtedly related to the extra noxous stmul provded by endotoxn whch s known to further prme leukocytes and actvate cyclo-oxygenase systems. 24 Yet another possblty for the observed hgher levels of may be a reflecton of ncreased producton of by dfferent bacteral strans. n any case, snce urne levels n the ARDS-only group were about 70 percent of those n the ARDSsepss group, these fndngs suggest that the ARDS abnormalty alone s the major producer of ths oxygen metabolte n patents wth both ARDS and sepss. An mportant fndng n these studes was that at the tme of admsson nto the CU, the lung njury scores dd not dfferentate the nonsurvvor ARDSsepss group from the survvor ARDS-sepss group; however, the nonsurvvor group had sgnfcantly hgher urne concentratons compared wth the latter group. t s possble that n the nonsurvvor patents wth ARDS and sepss, the oxygen delvered by ventlaton resulted n a greater producton of toxc oxygen metaboltes. Although studes have ndcated that hgh concentratons of nhaled oxygen can generate 0, other nvestgatons suggest that the amount of nspred oxygen may not be physologcally sgnfcant. 15 Knnula et al 25 observed that ntracellular CHEST JANUARY,

5 producton n rat type 2 pneumocytes, macrophages, and cultured endothelal cells was not affected by exposure to a hgh concentraton of oxygen (95 percent). On the other hand, maybe the degree of septcema n the nonsurvvor ARDS-sepss group had an effect on the urnary tract, such that a urethra or bladder nfecton caused producton of epthelal cell We controlled for ths possblty by excludng patents wth postve urne cultures, and furthermore, normal levels of urne were observed n patents wth an ndwellng urnary catheter, suggestng that local nflammaton was not a contrbutng factor. Thus, the greater urne level n the nonsurvvor patents wth ARDS and sepss s probably due to a greater effect of septcema on oxdant processes. Moreover, the urne data appear to have a more obvous prognostc value than lung njury score n patents wth sepss wth ARDS wthn the frst 48 h n the CU. n concluson, we have demonstrated a postve correlaton between the severty of lung njury (lung njury score) and urne levels. However, the correlaton was best when the patents were separated nto ther respectve groups because of the relatvely hgher urne concentraton, at varous lung njury scores, of the ARDS-sepss group vs the ARDS-only group. Although the ARDS-sepss group had greater amounts of n ther urne compared wth ARDSonly group, thereby reflectng more uncontrolled oxdant processes, our data suggest that the ARDS component approxmates about 70 percent of the total generated n the patents wth both ARDS and sepss. Thus, t may be possble to use urne to montor the effectveness of treatment, partcularly antoxdant regmens, on the respectve components (ARDS vs sepss) of producton n the patent wth combned ARDS and sepss. n keepng wth ths, these studes have already demonstrated that urne can dfferentate the severty of oxdant processes n patents wth ARDS and sepss albet the prognoss appears to be survval or nonsurvval. ACKNOWLEDGMENTS: The authors wsh to thank Annette Zecca and Elane Fluder for ther techncal assstance. REFERENCES Babor BM. Oxdants from phagocytes: agents of defense and destructon. Blood 1984; 64: Metzler DE. Bochemstry: the chemcal reactons of lvng cells. Orlando, Fla: Academc Press, 1977; Baldwn SR, Smon RH, Grum CM, Keta LH, Boxer LA, Devall LJ. Oxdant actvty n expred breath of patents wth adult respratory dstress syndrome. Lancet 1986; 1: Sznajder J, Framan A, Hall JB, Sanders W, Schmdt G, Crawford G, et al. ncreased hydrogen peroxde n the expred breath of patents wth acute hypoxemc respratory falure. Chest 1989; 96: Ketzmann D, Kahl R, Muller M, Burchard H, Kettler D. Hydrogen peroxde n expred breath condensate of patents wth acute respratory falure and wth ARDS. ntensve Care 236 Med 1993; 19: Leff JA, Parsons PE, Day CE, Moore EE, Moore FA, Oppegard MA, et al. ncreased serum catalase actvty n septc patents wth the adult respratory dstress syndrome. 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Hydrogen peroxde producton by alveolar type cells, alveolar macrophages and endothelal cells. Am J Physol 1991; 261:L86-L91 Urne Hydrogen Peroxde Durng AROS (Mathru 81 al)