CC (in oitro)=computation constant for in oitro 8uid Row;

Detection of Renal Blood Flo Abnormalities in Septic and Critically Ill Patients Using a Nely Designed Indelling Thermodiltion Renal Vein Catheter* Matthe Brenner; M.D.; Gary L. Schaer; M.D.; Doglas L. Mallory, M.D.; Anthony F. Sffredini, M.D.; and joseph E. lbrrillo, M.D. To evalate alterations in renal blood fto in sepsis-indced renal failre, e developed and stdied a perctaneosly placed thermodiltion renal blood Oo catheter in eight critically ill patients. Para-aminohipprate extraction coefficients ere decreased, spporting the need for renal vein sampling to determine C..AH in sepsis. Thermodiltion and CrAH methods correlated strongly, coo6rming the reliability of this thermodiltion method. Renal vasclar resistance, an indicator of renal vasclar fnction, remained nchanged throghot the bots of sepsis. The fraction of total body arterial blood 8o going to the kidneys rose signi6cantly dring recovery from sepsis. Glomerlar filtration rate, hich as redced in for of seven septic patients, correlated ith the fraction of total blood fto going to the kidneys. These reslts sggest that renal vasclar abnormalities may be occrring dring septic shock. Or stdy demonstrates that sepsis-indced renal dysfnction may occr despite normal ranges of total renal blood Oo dring sboclc. (Chat 199; 98:17-79) CC (in oitro)=comptation constant for in oitro 8id Ro; C.AH =clearance of j N U " ate; I lcf= - correction factor for in oitro 8id Ros (CC/{6 VI); ERPF=effec:tive renal plasma Ro; GFR=glomerlar atioo rate; PAH=paraamioobipprate; RBF= renal blooclllo; RVR =renal vasclar resistance; TB =temperatre of blood; TI =temperatre of injectate; VI= volme of injectate; U...,. =rinary PAH concentration; V PAH =rine volme; Artr.t =arterial PAH concentration; VeOrAH=veoos PAH coooentratioo;.. =rinary inlin coocentratioo; v.. =rine volme; Art,.=arterial inlin concentration eptic shock complicating severe bacterial infections S is the leading case of mltiple organ failre and death in intensive care nit patients. 1 2 Renal dysfnction develops freqently in septic patients and is associated ith a sbstantially increased mortality. 3 4 The severity of the nderlying infection ith the resltant hemodynamic abnormalities and the se of potentially nephrotoxic vasoactive agents may contribte to the development of renal failre. The high mortality of sepsis-indced renal failre nderscores the need to nderstand the mechanisms leading to renal failre and to develop methods for the preservation of renal fnction in critically ill patients. Alterations in renal blood Bo are a major mechanism of acte renal failre in animal models of renal injry and may play a central role in the pathophysiology of renal failre in septic patients. Brief alterations *From the Critical Care Medicine Department, Clinical Center, National Instittes of Health, Bethesda, MD. Presented in part at the annal meeting, American Federation for Clinical Research, San Diego, CA, May 1987, and the 16th Annal Edcational and Scientific Symposim, Society of Critical Care Medicine, Anaheim, CA, May 1987. Pblished in abstract fonn in Clin Res 1987;34:884a, and Crit Care Med 1987;15:435. Manscript received October 26; revision accepted Janary 31, 199. Reprint reqests: Dr. Brenner; Bldg 53, Rm 199, Plmonary and Critical Care, UCIMC, 11 City Drive Soth, Orange, CA 92714 17 in renal blood Bo may be sfficient to initiate the events hich lead to renal failre. 7 The role of altered blood Bo in the pathogenesis of renal dysfnction in hmans remains difficlt to characterie becase of limitations associated ith the measrement of renal blood Bo dring sepsis. Althogh rine otpt is sed clinically to evalate shock, rine Bo does not closely correlate ith renal blood Bo. A standard method of estimating total renal blood Bo in healthy persons is the CPAn 8 Greater than 9 percent of PAH is removed from the circlation dring a single passage throgh the kidneys in normal hmans. This almost complete removal of PAH reslts in clearances that accrately estimate overall renal blood Bo. Hoever, sepsis redces PAH extraction throgh a variety of mechanisms.s- 18 This decrease in PAH extraction dring sepsis ths introdces serios errors in the renal blood Bo determination. Additionally, the time reqired for eqilibration of indicator levels for the clearance method measrements limits the se ofcpah in the intensive care nit here freqent physiologic changes reqire rapid, reprodcible methods of measrement.11 12 19-22 We have developed a specially shaped catheter hich is placed perctaneosly nder floroscopic Renal Blood Flo AbnonnaNIIes in Septic and Critically Ill (Brenner et al}

lnjectate Port Opening (Opening on Convex Portion of Catheter Crve! FIGURE I. Design of RBF catheter sed in present stdy. Tht catheter has a 18 bend in the catheter 2 em from the distal end designed to crl the tip into the renal vein orifice, and a 45 he nd 6 em from the distal tip to allo access to the renal vein. gidance into the renal vein. The placement of the catheter in the renal vein allos direct sampling of renal venos blood, and determinations of the arteriovenos PAH extraction can be performed, alloing accrate calclations of CPAII We report herein the reslts of or experience ith this renal vein catheter. Frther development of sch techniqes shold provide a means for measring serial thermodiltion and CPAH renal blood flo measrements in critically ill patients. Catheter Design MATERIALS AND METHODS The catheter as designed ith the folloing specifications (Critikon Corporation, Tampa, FL): 5-F, doble lmen, radiopaqe polyvinylchloride catheters, ith 1cm of sable length, containing a rapid response thermistor ith standard Edards connectors. The catheter is fashioned ith a 18 bend 2 em from the distal end, alloing the catheter tip to crl ithin the renal vein. A 45 bend 6 em from the distal tip allos access to the renal vein (Fig 1). Catheter Calibration In vitro Bo experiments ere sed to verify the accracy and reprodcibility of the thermodiltion measrements. The accracy of the catheter as validated and comptation constants ere determined by comparing catheter-determined thermodiltion Ro rates against a range of standard Bo rates of Rid pmped throgh a plastic tbing system (Appendix 1). Thermodiltion comptation constants ere determined for the catheter. lbtient Poplation From November 1985 to April 1987, eight critically ill patients (seven ith septic shock) nderent serial renal fnction stdies and concrrent systemic hemodynamic fnction stdies in the medical intensive care nit at the National Instittes of Health. The stdy protocol as approved by the Instittional Hman Research Revie Board at the National Instittes of Health and all patients gave informed ritten consent. Septic shock entry criteria ere defined as either: (a) temperatre >38 C, hypotension (mean arterial pressre <6 mm Hg, or FtclliiE 2. Upper: Diagram represt'lllillg the i vit>o position of the renal vein eatllt'lt r hen plaet d pt rt larlt'osly from the femoral n in into tl n nal n i11. Cold injedalt t xits tl renal \"l'in eatllt r at the silt- lal>< lt d "" injedate port." ami passt s tilt' tlrmistor as hlch><i flos into the inlt rior n na eil\ a (IV(.'). Catllt'tt-r ports at the injedalt and tllt'rmislor silt s allo renal n in sampling li>r aceratt determination of PAll t xtradion eoellidc nts. Lmcc r : Alxlominal radiograph shoi11g tilt' n nal ve i11 eatlodt r in tilt' t orred position fi>r RBF dt'lermination in tl left n nal in of a critically ill patil nl. CHEST I 98 I 1 I JULY. 199 171

greater than 5 mm decrease in systolic pressre from baseline), and positive blood cltres, or (b) fever, hypotension (mean arterial pressre <6 mm Hg, or greater than 5 mm decrease in systolic pressre from baseline), netropenia (netrophils <5 cells/cb mm) and negative blood cltres that ere ascribed to concomitant treatment ith broad-spectrm antibiotics. Systemic Hendynamk Evalations Arterial pressre as monitored via an indelling arterial catheter in the radial or femoral artery in all patients. A plmonary artery balloon Rotation catheter as placed in the plmonary artery of each patient and its position as confirmed radiographically. Serial measrements (every 6 to 8 h) of central venos pressre, plmonary capillary edge pressre and cardiac otpt by the thermodiltion techniqe ere obtained. Measrements of the plmonary capillary edge pressre ere made from tracings on graph paper at end-expiration. Cardiac index and systemic vasclar resistance ere calclated according to standard formlas: Cl (U minim ) = COIBSA (m ), and SVR (dynesos-cm - ) = ( M [mm A Hg]) X BC.'(CO). Renal vasclar resistance as calclated as =(MAP. renal vein pressre) X 8/RBF (Umin) 1..., PAH _...,, lreatment Protorol All the patients ere treated by the same grop of critical care physicians employing the folloing seqential treatment protocol to maintain a MAP>6 mm Hg. Initially, patients received 8ids intravenosly to maintain a plmonary capillary edge pressre of 15 mm Hg. Dopamine as added if the patient remained hypotensive. If the patient reqired >2 p.g/kg min of dopamine, levarterenol as added, and the dopamine as tapered to 2 to 3 jl.g/kg min. All patients received broad-spectrm antibiotic coverage, sally inclding an aminoglycoside, a cephalosporin, and a semisynthetic penicillin active Bgllinst P8etldmnonas aergir&a. When blood cltre reslts ere obtained, the antibiotic agents ere adjsted accordingly. Respiratory spport as given as needed to maintain a normal ph and an Sa 1 >9 pereent. Metabolic parameters, inclding serm electrolytes, blood rea nitrogen, creatinine, phosphate, calcim, magnesim and glcose, ere determined every 4 to 8 h and any treatable abnormalities promptly corrected. Catheter Plocement Using sterile procedres, the femoral area as locally infiltrated ith 1 percent lidocaine and a 6-French introdcer (Cordis Co, Miami, FL) as introdced into the femoral vein peretaneosly sing the Seldinger techniqe. The renal vein catheter as passed throgh the introdcer and into the renal vein nder ftoroscopic gidance. The left renal vein as the preferred site for renal blood Bo measrements becase of its greater length. Correct positioning of the catheter in the renal vein as confirmed by (a) abdominal radiograph, (b) characteristic thermodiltion crve, and (c) high venos oxygen satration in samples dran from the renal catheter ports in comparison to concrrently obtained vena caval samples (Fig 2). When cold saline soltion as injected into the femoral introdcer port, the absence of a detectable temperatre change in the renal vein catheter thermistor as sed to con61;111 that the catheter position as not in the inferior vena cava. The se of ftoroscopic dye to confirm the placement of the renal vein catheter as not necessary. No other vessels in the area of the renal vein are large enogh to accommodate the renal vein catheter. PAH and Inlin Clearanc Para-aminohipprate and inlin clearance determinations ere made sing standard methods (Appendix 2). The folloing derived measrements ere made: PAH extraction coefficient percentage= 1 X ( a r t e renal P A Hv Je -i P A H a Effective r t e P A H J renal plasma Bos ere corrected for the decreased extraction of PAH sing the formla: ERPF = CPA,.IPAH extraction coefficient. Renal blood flo as calclated as: R B F " ", " ' PAHJ " " = ERPF/ (1-hematocrit). '111ennodiltion Renal Blood Flo Determinations Thermodiltion RBF determinations ere obtained at the midpoint of each 3-min collection period for PAH and inlin. For each determination, seven maximal hand-force injections of room temperatre DSW ere obtained. The high and lo vales ere discarded and the remaining five otpts ere averaged. Thermodiltion crves ere obtained for each injection. Concrrent complete hemodynamic evalations ere obtained ith each set of thermodiltion RBFs. Hendynamk and Renal Measrements Concrrent RBFs, inlin clearances, and complete systemic hemodynamic evalations ere obtained ithin 18 h of admission to the intensive care nit for shock and repeated over the next 24 to 72 h hen feasible (Fig 3). Statistical Analysis Descriptive statistics are reported as means± standard errors and ranges. Initial and follo-p vales ere compared among patients sing to-tailed paired t tests. Correlations beteen continos variables ere assessed sing linear regression analysis. REsLTS In Vitro Catheter Calibration and Comptation Determination Thermodiltion catheter measrements correlated strongly (r=.997, p<.1)hencompared ith the amonts collected volmetrically in the in vitro system (Appendix 1, Fig 2). The catheter measrements ere shon to be accrate over the range of flos from 15 to 2,5 mvmin. Time lminsl PAH Bols and Infsion Inlin Bols and Infsion t 1st Collection 2nd Collection Eqilibration Period Period Period 6 9 12 t Systemic Hemodynamic t t Determinations t Thermodiltion Renal Blood t Flo Determinations PAH and Inlin Levels t obtained (rine, arterial, renal vein I FIGURE 3. Protocol for concrrent measrement of RBF and GFR determination by CPAH inlin clearance and thermodiltion methods. lime in mintes is depicted on the horiontal line; PAH and inlin bolses ere administered at time, folloed immediately by continos infsions ofboth. After a 6-min eqilibration period, to 3-min collection periods ere begn; PAH and inlin level ere obtained from rine, arterial, and renal vein blood samples at 6, 9 and 12 min. Systemic hemodynamic and thermodiltion RBF measrements ere obtained miday throgh each collection period at 75 and llo min. t t 172 Renal Blood Flo AbnonnaJities in Septic and Critically Ill (Btenner et al)

Catheter Insertion Clinicallbtient Data Eight critically ill (seven septic) patients ere stdied ith RBF and renal fnction determinations ithin 18 h of admission to the intensive care nit. All patients had hypotension. Five of the seven septic patients had positive blood cltres ith the folloing organisms: Staphylococcs ares (to patients), betahemolytic streptococci (one patient), Escherichia coli (one patient), and mixed Enterococcs and Klebsiella pnemonia (one patient). Both septic patients ith negative blood cltres had been treated ith broadspectrm antibiotics prior to admission to the intensive care nit. Six of the seven septic patients srvived. One patient died of progressive sepsis ith mltiorgan system failre. Six of the septic patients had serial RBF and systemic hemodynamic data obtained. One septic patient recovered rapidly ( <24 h) and repeat RBF and fnction stdies ere not obtained. One patient reqired volme spport ithot pressors to maintain blood pressre. Six patients reqired pressor spport ith intravenosly administered catecholamines dring the stdy: levarterenol and lodose dopamine (one patient), moderate-dose dopamine (to patients) and lo-dose dopamine (2J.Lg/kg/ min, three patients). Dopamine doses ranged from to 8 J.Lg/kg/min at the onset of the stdy (mean, 2.57 X A 1 8 pns 1- (/) B Correct positioning of the renal vein catheter as confirmed by both floroscopic imaging and simltaneos renal vein, arterial and vena caval blood oxygen levels. Renal vein Po 2 levels averaged 9.2 mm Hg higher than vena caval Po 2 (p<o.ol) and 52.3 mm Hg loer than systemic Pa 2 (p<.5) vales. Characteristic thermodiltion crves frther verified correct placement by rling ot all contact and recirclation artifact. 9 No complications de to the catheter se developed in any of the patients. In one patient the renal vein diameter appeared to be too small to accommodate the fll renal vein catheter loop, ith only the proximal portion able to be inserted into the renal vein. In this patient, PAH clearances ith extraction coefficients alone ere obtained, since thermodiltion RBFs cold not be accrately determined. iii,.- 12 1... a:: 8 -.. 6 a:: E - E C: ::>G> -' " 6 - - E "' o- 4 ( / ) a:-' Q) - > 4 S:?9 2 E 1- (/) 2 ---- > (/) INITIAL FINAL INITIAL FINAL F a; 2 5 " \"' c p<.5.. ;;; 3:.!! 1-4 (/)_ " _, _.:t (/),... E Oo.. " 3 O'tl a: o:! 1 il...ju...j"' m!? ::> 2...Jo "' (/)., Z>.o >e a: c...j 1! ::::::::::: ::s ::::: :g a: INITIAL FINAL INITIAL FINAL " ---- c D 18 '#. 12 a:: ::> a:: (/) 16 ::> 11 (/) (/) (/) a:: Q, a:: 1 Q, oc. 14..JO> o:t : I : OE 9 -' E a; E m_ 12 e 1-- a:: :::; 8 1- (/) 1 7 > (/) G p<.5 8 6 I N I T IFINAL A INITIAL FINAL 15 1 p<.5 c a:! 8 :g <2-3:# 1 o- 6..JI- U.::> ca.. a: ot- 4 o=>...j...jo 5 m...j :::; 2 :::> / a: INITIAL FINAL INITIAL FINAL F1<:URE 4. l n d i ds s a l hmei m c y n arenal r n ihemodynamics c s, and renal fnction tests in septic patients.t?e t time of mhal evalation and at the time of follo-p evalation 24 to 72 h later. A, Cl vales at mthal and follo-p evalation. B, SVR. C, Systolic blood pressre. D, MAP. E, RBF as measred by corrected CPAH vales. F, RVR. G, Change in the RBF/C ratio. H, GFR. H CHEST I 98 I 1 I JULY. 199 173

16 c: e -14 E o- i = 12 o.. ::JQ...J...J oo a:o...j :::a:l 1-...J <{ a: 1 8 Y=553+.53X 6 R=.79 o P=.36 4 1 PARA-AMINOHIPPURATE 2 RENAL BLOOD FLOW (ml/min) FIGURE 5. Correlation of initial RBFs measred by thermodiltion ith CrAH methods in milliliters per minte. A correlation coefficient of.94 as obtained ith a slope of.47 (p<o.ol). Althogh thermodiltion RBFs overestimated PAR-determined blood flos at lo rates and nderestimated blood Bo at high rates, this cold be corrected for by the regression eqation. J.Lg/kg/min; SEM, 1.4) according to the standard patient therapetic protocol. At the conclsion of the stdy, dopamine dosages ranged from to 2 J.Lg/kg/ min (mean,.57 J.Lg/kg/min, SEM,.36). Initial RBF did not correlate ith the initial dopamine dose (p=.129; r=.63). Additionally, the change in RBF from onset of sepsis to follo-p also did not correlate ith dopamine dose (p=.66; r=.25) or the change in dopamine dosage ith recovery (p=.226; r=.58). Dopamine concentrations also did not correlate ith the GFR (p=.2; r=.6). Only to patients ere on levophed at any time dring the stdy, making it difficlt to evalate statistically. Hoever, the patient on the highest dose of levophed dring the initial measrement (9 J.Lg/min) had the smallest change in RBF (of all patients in the stdy) at the time of recovery hen all pressors had been discontined. Baseline Renal Fnction All patients had baseline serm creatinine measrements obtained ithin 36 h prior to the onset of sepsis. All bt one patient had a serm creatinine level less than 1.5 mgldl (range,.7 to 3.4; mean, 1.45; SEM,.89). Systemic Hemodynamic Reslts The systemic hemodynamics in the six septic patients ith serial measrements revealed a hyperdynamic state at the time of the initial measrements. The initial CI as elevated (mean, 5.5 ±.43 Uminl 174 m 2 ). Systolic blood pressre (16.5 ± 6.4 mm Hg), MAP (71.9±3.6 mm Hg) and SVR (565± 199 dynes-s-cm - 5 ) ere significantly redced dring the initial evalation hen compared ith levels obtained folloing recovery (Fig 4). All bt one patient had improved clinically hen evalated at follo-p after an average of 44 h (range, 24 to 72 h). Systemic vasclar resistance increased significantly toard normal to 79± 13 dynes-s-cm- 5 (p<o.ol). Systolic blood pressre (mean increase from 16.5±6.4 to 127.3± 12.5 mm Hg, p<.5) and MAP also increased significantly (from 71.9±3.6 to 86.±6.5 mm Hg) (p<o.os). Cardiac index (mean, 5. Umin/m 2 at follo-p) had decreased toard normal, thogh not significantly (p= NS) (Fig 4,A). No significant change occrred in plmonary artery pressres, or plmonary capillary edge pressre throghot the stdy period. Renal Hemodynamics and Renal Fnction: COf"f'8lation beteen Renal Blood Flo by thermodiltion and c,.ah Methods Renal blood Bo determined by the thermodiltion method correlated strongly ith the corrected C,."" clearance (r=.79, p<o.os [Fig 5]). The PAH extraction coefficient percentages ere redced to variable degrees at the time of initial evalation in the patients stdied (mean, 56.3 percent; range, 28 to 9 percent; "# WI- 1- <t a:- : : : : > Q..U.. Q..U.. - ::r:o O 4... <{- <{U a:<{ <{a: o..l-- X 1-8 6 & _g_ 2 1 - - - - - - - - - - - - - - - - - PAH EXTRACTION COEFFICIENT FIGURE 6. Renal PAH extraction coefficients for ten measrements in five septic patients. Mean extraction coefficient as 55.7 percent; normal coefficients are >9 percent. Renal Blood Flo Abnormallles In Septic and Critically IN (Brenner et a/)

12 determinations in six patients; normal, >9 percent [Fig 6]). Renal blood 6.o varied considerably among septic patients at the time of initial evalation ith a range of 112 to 1,767 mvmin (mean, 69± 179 mv min) by corrected CPAH Renal blood 6.o on follop evalation, after 24 to 72 h, increased in septic patients to a mean of 737 ± 168 mvmin (p<.5 [Fig 4,E]). Renal vasclar resistance averaged 15,6±5,822 d y n e s eon s initial o c m evalation and did not change significantly at the time of follo-p evalation (11,5±3,365 d y n e s e p>.2). s o c m, Renal blood 6.o did not correlate directly ith any systemic hemodynamic parameter (CI, SVR or arterial pressre) at the time of initial evalation. The change in the fraction ofblood 6.o going to the kidneys (RBF/ CO) rose at the time of follo-p (Fig 4,H [p<.5]). Renal blood 6.o also did not correlate ith pressor dosage. There as no correlation beteen dopamine dosage or levophed dosage and initial RBF, follo-p RBF vale, percentage of blood 6.o going to the kidneys or changes in any of these parameters dring recovery. Glomerlar filtration rate determined by inlin clearance as redced (initial GFR, <6 mvmin) in for of seven septic patients. Initial GFR varied idely (range, 18 to 126 mvmin). Serm creatinine levels rose significantly (.36 mgldl increase, p =.12) ithin the first 24 h of shock in these patients. Glomerlar filtration rate did not correlate directly ith RBF (r=.55; p=.14). Hoever, GFR correlated closely ith the fraction of total blood 6.o going to the kidneys (RBF/CO; r=.92, p=.3 [Fig 7]). Glomerlar filtration rate did not change significantly on follo-p determinations. <( a: <( :::> 14r------------------------ Y=12+6X R=.92 P=.3 1 6 RBF/CO (%) FIGURE 7. Correlation of the initial fraction of total blood Ho going to the kidneys ith GFR (by inlin clearance) in septic patients. A correlation coefficient of.92 as obtained (p =.3). DISCUSSION We have developed a renal vein catheter that measres RBF in septic and critically ill patients. The catheter can determine RBF by to techniqes: CPAH levels (ith extraction coefficient determination) and thermodiltion-derived RBF. This stdy docments the feasibility of sing indelling renal vein catheters in critically ill patients in the intensive care nit. Previos investigators have fond variable redctions in renal PAH extraction in septic patients de to a variety of cases inclding interference ith renal PAH secretion secondary to tblar dysfnction, competition for anionic secretory sites by drgs, interference of assay measrements by varios medications, and possibly shnting of blood flo.s- 17 Or reslts are in agreement ith observations of altered PAH kinetics and confirm the need for renal vein catheteriation for accrate determination of RBF; PAH extractions ranged from 28 to 9 percent in or patients (mean, 55.7 ± 5.6 percent; normal vales exceed 9 percent). Failre to accont for these decreases in PAH extraction old reslt in significant errors in the estimation ofrbf. A strong correlation as fond beteen thermodiltion-determined RBF and CPAH methods (r =. 79, p<o.os) across the ide range of blood flos in these patients (112 to 1,767 mvmin blood 6.o; [Fig 5]). Renal hemodynamics demonstrated large variability in RBF among patients ith sepsis, similar to reslts fond by previos investigators. 12 23 No direct correlation as fond beteen RBF and CI among patients at the time of initial presentation. All patients shoed an increase in RBF hen comparing initial to follop evalations (p<o.os). Ths, the total RBF and the fraction of blood flo going to the kidneys increased significantly beteen initial and final measrements, as systemic vasclar index increased (p<.5). Renal vasclar resistance did not change significantly throghot the stdy and did not correlate ith SVR. These findings sggest that the profond systemic vasodilation occrring in septic patients is not occrring to a corresponding degree in the renal vasclatre. It is nknon hether these findings represent appropriate renal vasclar reglatory fnctions. The overall adeqacy of RBF is difficlt to assess 4 2 for the patients in or stdy. The rise in the fraction of total blood flo going to the kidneys dring recovery from sepsis sggests that the vasodilation in the systemic circlation dring the initial phase of the a - - - - - - - - - - -septic - episode - - -as- not -matched - - in - the renal circlation. 1 2 As a reslt, these patients had a loer fraction of their total blood 6.o going to the kidneys dring the acte phase of sepsis. Dring recovery, less systemic vasodilation occrred reslting in a higher fraction of renal blood flo. CHEST I 98 I 1 I JULY, 199 175

This stdy as not designed to assess the effects of interventions on RBF or renal fnction. Additionally, ith the limited nmber of patients involved in this stdy, it is not possible to dra conclsions regarding the role of pressors in RBF dring sepsis. All pressor agent adjstments sed in this stdy ere made according to systemic blood pressre parameters. While no correlation beteen pressor doses and RBF as seen, this cannot be taken as evidence against pressor-related effects. Instantaneos thermodiltion RBF techniqes may represent an excellent means by hich sch effects cold be investigated. The correlation as strong beteen instantaneos thermodiltion RBF measrements and continos CPAH clearance methods. This correlation (and slope) is similar to regression eqations reported previosly ith bols injectate RBF catheter models. Thermodiltion RBF determination by this method assmes a single renal vein is present on the side of measrement, that eqal blood flo is occrring to both kidneys, and that there is minimal shnt flo from vessels draining into the renal vein (eg, spermatic, ovarian, adrenal, renal capslar veins). These assmptions have been shon to be valid in most patients. 1 24 25 These data sggest that the se of thermodiltion RBF methods can provide information on rapid, serial changes in RBF that may be valable in critically ill patients ith rapidly changing physiology. A disadvantage of the bols thermodiltion method is that the thermistor mst be completely inslated from the cold injectate before it exits the catheter. This is accomplished by sing the pigtail shape hich as designed to assre that injectate leaves the catheter at a point most proximal in the renal vein, then passes the thermistor on the distal tip of the catheter on the ay to the inferior vena cava (Fig 3). 211 21 The pigtail catheter can generally be inserted only 2 to 3 em into the renal vein. Since both the injectate port and the detector thermistor mst lay completely ithin the renal vein, a maximm distance of only 2 to 3 em can separate them. Complete mixing of the injectate soltion ith blood floing in the renal vein mst take place ithin this distance. Althogh the average rates of RBF approach the theoretic loer limits for the accracy of bols injectate thermodiltion methods, there as a strong correlation ith PAH RBF in these patients. The se of standard bols CO eqipment in this stdy is not optimal for RBF ranges. The close correlation beteen thermodiltion RBF and CPAH shos promise for instantaneos serial thermodiltion measrements in the critically ill. Ftre modifications of these techniqes (inclding continos injection methods, and softare optimied in RBF ranges) may frther improve the accracy. Inlin clearance as sed to determine GFR. 176 Previos investigations have shon that standard creatinine clearance measrements are insensitive measres of the GFR in mild renal dysfnction and become progressively less accrate ith decreasing GFR.l1JS. 28 In this stdy, GFR determined by inlin clearance correlated closely ith the fraction of total blood flo going to the kidneys (RBF/CO), bt not total RBF. The close relationship beteen G FR and the fraction of blood flo going to the kidneys sggests that "relative shnting" aay from the renal circlation may be occrring dring sepsis, ith inadeqate blood spply for increased renal demands. Alternatively, the loer fraction of blood flo to the renal circlation may be a marker of more profond non-renal vasodilation. The correlation beteen decreased GFR and fractional RBF might then be a reflection of the severity of the nderlying sepsis rather than a direct reslt of renal ischemia. One septic patient developed progressive renal failre despite repeated RBFs of greater than 9 mil min. Ths, renal dysfnction in septic patients may occr in the absence of detectable absolte decreases in RBF. Pathophysiologically, this may represent: (l) alteration in the relationship beteen afferent and efferent arteriolar constriction, (2) relative inadeqacy of blood flo de to increased renal tisse metabolic demands de to sepsis, or (3) indction of renal dysfnction by transient blood flo abnormalities that occrred prior to the insertion of the catheter. Alternatively, the renal dysfnction in these patients may be cased by mechanisms that are nrelated to total RBF. Previos reports of renal vein catheteriation and blood Ro determination reveal a lo incidence of complications from procedres involving renal vein cannlation. 9 1 211 29-32 We have not fond any previos reports of renal vein catheters remaining in sit for p to three days as in this stdy. Or patients experienced no complications, althogh complications may become more apparent hen a larger series of patients is stdied. Excrsion of the renal veins dring respiration and body motion cased the catheter to migrate into the inferior vena cava in some patients. The catheter had to be replaced over a gideire for some of the follo-p RBF determinations in five patients. This emphasies the need to serially evalate the catheter position sing abdominal radiographs and characteristic renal vein thermodiltion crves. In conclsion, e have fond that renal vein catheteriation can be performed safely in the intensive care nit environment on critically ill patients. There ere no complications in or patients. Renal vein catheteriation and direct renal blood sampling are reqired for accrate determination of RBF by CPAH de to variable and significantly decreased renal extraction of PAH in septic patients. In or septic and Renal Blood Flo Abnormalities in Septic and Critically Ill (Brenner eta/)

critically ill patients, the perctaneosly placed thermodiltion RBF catheter proved to be accrate and can remain intravasclarly to allo serial instantaneos measrements dring a period of several days. This stdy demonstrates the potential tility of RBF catheters in defining the pathophysiology of renal dysfnction in septic patients. Renal vein catheters also may be sefl in evalating the effects of varios interventions on RBF and renal fnction in critically ill patients. ACKNOWLEDGMENTS: We old like to thank Ms. Debbie Tribett and the 1D-ICU nrsing staff for their help and spport ith this project. We old also like to thank Mrs. Jlie Jordan, Mr. Cary Morrison and the technical staff of 1D for their technical assistance and advice. APPENDIX 1 The comptation constant is the conversion factor for the relationship beteen the integrated area nder the thermodiltion temperatre crve and the actal Ho rate of the flid (Helett-Packard Reference Manal: A Gide to Hemodynamic Monitoring Using the San-Gan Catheter, Helett-Packard Co). Warmed flid as pmped throgh the tbing shon in Figre 1 and collected volmetrically. The CC (in vitro) ere determined as follos: the thermodiltion catheter as introdced 3 em pstream in the tbing against a flo of ater prodced by a variable rotary pmp (Varistaltic Pmp, A series model 72-325-, Monostat Corp, Ne York). Forteen-millimeter internal diameter thermally inslated Silicon rbber tbing as sed in all calibration measrements. Thermodiltion otpts ere measred on a Helett Packard CO compter (HP-78231 C, Helett-Packard Co). Using a modification of the Steart-Hamilton indicator diltion techniqe, 3 otpt (in liters per minte) as determined as: - Thermodiltion Renal Vein Catheter Volmetric Flid Collecting Device Thermodiltion Compter ith Recorder Appendix FIGURE l. This figre depicts the system sed for in vitro standardiation of the RBF catheter. Comptation constants relating the area nder the thermodiltion Ro crve to the Rid Ro rate ere determined and the accracy of the catheter as validated by comparing knon Ro rates measred volmetrically to rates obtained by the thermodiltion catheter. _ CC (in vitro) (TB-TI) tpt- 1.22fo4TB(T)dt Thermal CCs ere determined for each injectate volme sed in or stdies (1, 1.5 and 3 ml) by presetting the rotameter volmetrically to a knon rate and adjsting the in vitro thermodiltion CC to obtain the correct flo rate. The CT for each injectate volme as then calclated as: 24 CT = CC/(6)VI. Rotameter flo rate as then varied from 13 to 2, 7 mvmin. Thermodiltion flo measrements ere obtained and compared ith concrrent volmetric measrements at intervals ithin this range. Temperatre of the perfsate ater bath as maintained beteen 36.1 and 39.7 C sing a heated ater bath (model 25, Precision Scientific Grop, Chicago, IL). All injectates ere performed ith 5 percent dextrose in ater at room temperatre (21.6 to 24.2 C). The VI sed as dependent on the flo rate range sing the Helett-Packard compter system. A VI of 1 ml as sed for lo flo rate range measrements from 13 to 35 mvmin. A VI of 1.5 ml as sed for flos from 35 to 1,5 mvmin, and VI of 3 ml as sed for flo rates of 1,5 to 2,7 mvmin. The bols injection techniqe sing maximal hand force as employed for all measrements. Five thermodiltion flo measrements ere obtained at each flo rate. Thermodiltion crves ere generated for each thermodiltion otpt sing a to-channel recorder to ensre proper positioning and injection techniqe (model R-32P: Lexington Instrments, Waltham, MA). :Ill Taking into accont the difference in specific heat and specific gravity beteen blood, ater, and D5W, the CC sed in vitro ere calclated as: 3 31 CC (in vivo)=(l.8)ct(6)vi density (D5W or ater) X l.8 =specific heat (D5W or ater). density (blood) X specific heat (blood) In this case the comptation constant has been adjsted to sbtract the component of flo added by the VI. Conseqently, the relation beteen thermodiltion RBF and volmetric measrements is nonlinear. Ths, CCs and the VIs have been adjsted accordingly at high and lo flo rate ranges. The comptation constants and their corresponding VIs over the applicable flo ranges for this catheter on the Helett-Packard CO compter monitoring system ere determined to be.37 for flo VI of 1. ml,.63 for VI 1.5 ml, and.122 for VI of 3. mi. Folloing insertion of the catheter into the renal vein, a standard 1.5-ml bols VI as injected. If thermodiltion RBF rate as fond to be above 1,5 CHEST I 98 I 1 I JULY. 199 1n

mvmin, the VI as increased to 3 ml and the appropriate CC selected. Similarly, for 8o rates belo 35 mvmin ith the initial sample, injectates ere decreased to 1. ml ith selection of the corresponding cc. Average variance in 19 separate measrements (95 total injections) in the eight patients as.14. PAH Clearance Method APPENDIX 2 An 8 mglkg bols of PAH as folloed by a continos infsion calclated to obtain a serm level of l to 2 mgldl. After a 1-h eqilibration period, to 3-min collections ere obtained. Bladders ere careflly drained by an indelling Foley catheter and saline soltion and air irrigations of the bladder ere performed if rine otpt as less than 6 mvh dring the collection period. Retial vein, arterial and rine samples ere obtained at the beginning and end of each collection period. PAH levels ere measred in each sample (Fig 2). PAH clearance (ncorrected)= U PAH X V ra/(artra) PAH clearance corrected= U PAH XV rai(artra-venra) All vales ere measred in milligrams per milliliter except V PAH, hich is measred in milliliters per minte. Inlin Clearance Standard inlin clearances ere obtained as a measre of GFR. Bols injection of 5 mglkg as folloed by constant inlin infsion calclated to attain serm levels of 1 to 2 mgldl. Inlin Clearance= ln X VljArtln The U In and Art 1 n ere measred in milligrams per milliliter, and V 1 n is measred in milliliters per minte. Para-aminohipprate and inlin assays ere performed by the Smith-Kline French Laboratories (Van Nys, CA) and by the Georgeton University Labo- 3 2 1 r.tt7 Slope 1.2 p<.1 1 2 Volmelrlc Flo (Limln) Appendix FIGURE 2. In vitro comparison of thennodiltion catheter-detennined flos ag;unst volmetric flo rates. A correlation coefficient of.997 ith a slope of 1.2, p<o.ool. 178 3 ratories Pathology Department (H.G. Press, M.D.). The inlin assay tilied acidification hydrolysis folloed by indoleacetic acid reaction for colorimetric assay qantification. The PAH assay tilied the Bratton-Marshal reaction involving diaonim salt formation folloed by copling to form the ao dye that is assayed colorimetrically (Smith Kline Special Chemistry Procedre Manal: Para-aminohipprate and Inlin, Smith Kline Laboratories, Van Nys, CA). Becase slfamethoxaole interferes ith the standard PAH assay method, a method as developed for assaying PAH levels in patients receiving slfamethoxaoleltrimethoprim. Para-aminohipprate levels ere determined in to patients on trimethoprimslfamethoxaole folloing iso-amyl acetate precipitation of the slfamethoxaole sing recently developed methods. 32 This assay involved removal of slfamethoxaole from the serm and rine samples by precipitation ith iso-amylacetate. The difference in absorbance of the samples before and after isoamylacetate extraction is proportional to the slfamethoxaole concentration, and the residal absorbance folloing extraction is proportional to the PAH concentration. REFERENCES 1 Gardner P. Arno PM. Hospital-acqired infections. In: Harrison T, et al, eds. Harrison's principles of internal medicine. Ne York: McGra-Hill Book Co Inc, 1987:47 2 Schster DP, Lefrak SS. Septic shock. In: Rippe JM, Irin RS, Alpert JS, Dalen JE. Intensive care medicine. Boston MA: Little Bron and Co, 1985:481-97 3 Sladen FN. Acte renal failre in critically ill patients: reslts of management in an intensive care environment. In: Parrillo JE, Ayres SM. Major isses in critical care medicine. Baltimore, MD: Williams and Wilkins, 1984:215-19 4 Werb R, Linton AL. Aetiology, diagnosis, treatment and prognosis of acte renal failre in an intensive care nit. Resscitation 1979; 7:95-1 5 Wardle N. Acte renal failre in the 198's: the importance of septic shock and of endotoxaemia. Nephron 1982; 3:193-2 6 Conger JD, Schrier R. Renal hemodynamics in acte renal failre. Ann Rev Physioll98; 42:63-14 7 Margolis BL, Stein JH. The renal circlation. In: Priebe HJ. International anesthesiology clinics-the kidney in anesthesiology. Boston: Little Bron and Co, 1984; 22:35-63 8 Smith HW. The kidney: strctre and fnction in health and disease. Ne York: Oxford University Press, 1951 9 Hornych A, Brod J, Slechta V. The measrement of the renal venos otflo in man by the local thennodiltion method. Nephron 1971; 8:17-32 1 Abrams HL. Renal venography. In: Abrams HL. Angiography. Boston: Little, Bron and Co, 1983; 1327-63 11 Brenner B, Rector FC. The kidney. Philadelphia: WB Sanders, 1981; 621-33, 38-9 12 Lcas CE, Rector FE, Werner M, Rosenberg IK. Altered renal homeostasis ith acte sepsis. Arch Srg 1973; 16:444-49 13 Donath A. The simltaneos detennination in children of glomerlar filtration rate and eft'ective renal plasma flo by the single injection clearance techniqe. Acta Paediat Scand 1971; 6:512-2 Renal Blood Flo Abnolmdlles in Septic and CrtllcaJiy II (Brenner et al)

14 Aldand K. Methods for measring renal blood Bo: total Ho and regional distribtion. Ann Rev Physiol198; 42:543-55 15 Cole BR, Giangiacomo J, lngelfinger JR, Robson AM. Measrement of renal fnction ithot rine collection: a critical evalation of the constant-infsion technic for determination of inlin and para-aminohipprate. N Eng! J Med 1972; 287:119-14 16 Gagnon JA, Ramell PW, Flamenbam W Pyrogenic renal hyperemia: the role of prostaglandins. Nephron 1978; 22:29-4 17 Sykes BJ, Hoie J, Schenk WG. An experimental stdy into the validity of clearance methods of measring renal blood Ho. Srg Gynec Obstet 135:877-82 18 Rosenberg IK, Gpta SL, Lcas CE, Khan AA. Renal insfficiency after trama and sepsis. Arch Srg 1971; 13:175:83 19 Darte CG, Liedtke RR. Laboratory protocols and methods ror the measrement of glomerlar filtration rate and renal plasma Ho. In: Darte CG. Renal fnction tests. Boston: Little Bron and Co, 198:49-65 l?d Magrini F, Go-Qing L. A critical improvement of the local thermodiltion method ror measring renal blood Bo in man. Cardiovasc Res 1982; 16:35-54 21 Magrini F, Tarai RC. Ne approach to local thermodiltion: se of pigtail catheters to avoid basic difficlties. Cardiovasc Res 1977; 11:576-8 22 Pitts FF. Physiology of the kidney and body 8ids. Chicago: Year Book Medical Pblishers Inc, 1974:14-57 23 Corte A, Zito J, Lcas EE, Gerrick SJ. Mechanism of inappropriate polyria in septic patients. Arch Srg 1977; 112:471-76 24 Leivestad T, Brodall EK, Simonson S. Determination of renal blood Bo by thermodiltion method. Scand J Clin Lab Invest 1978; 38:495-99 25 Hlet WH, Baldin DS, Biggs AW, et al. Renal fnction in the separate kidneys of man: I. hemodynamics and excretion of solte and ater in normal sbjects. J Clin Invest 1959; 389-94 26 Mcintyre KM. Leis JA. Textbook of advanced cardiac life spport. American Heart Association, 1987:XIII-5 27 Kim EK, Onesti G, Ramire, Breast AN. Sart C. Creatinine clearance in renal disease: a reappraisal. Br Med J 1969; 4:11-14 28 BerlyneGM, NilaranglcrS, Varley H. Hoerni M. Endogenos creatinine clearance and glomerlar-filtration rate. Lancet 1964; 11:874-79 29 Sato Y, Matsaa H, Egchi S. Comparative stdy of effects of adrenaline, dobtamine and dopamine on systemic hemodynamics and renal blood Bo in patients folloing open heart srgery. Japan Circ J 1982; 46:159-72 3 Fronek A, Gan V. Measrement of Ho in single blood vessels inclding cardiac otpt by local thermodiltion. Circ Res 196; 8:175-182 31 Gan W, San JH. Measrement of blood Ho by thermodiltion. Am J Cardiol1972; 29:241-46 32 Press HG, Raavi MH, Slemmer D, Zein M. Colorimetry of p-aminohipprate in the presence of slfamethoxaole. Clin Chern 1988; 34:422-23 CHEST I 98 I 1 I JULY, 199 179