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Effects of body weight and composition on gentamicin volume of distribution Boyce, Marilynn Audrey 1988

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EFFECTS OF BODY WEIGHT AND COMPOSITION ON GENTAMICIN VOLUME OF DISTRIBUTION By MARILYNN AUDREY BOYCE B.Sc.(Pharm), The University of Alberta, 1981 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE STUDIES (Faculty of Pharmaceutical Sciences) Division of Cl inical Pharmacy We accept this thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA August 1988 (c)Marilynn Audrey Boyce, 1988 In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. Department of PH-AgMft6B^T\C&i_ SliavlOES The University of British Columbia 1956 Main Mall Vancouver, Canada V6T 1Y3 D a t e Qrjtotxji /a /9fcfr ABSTRACT Gentamicin is an aminoglycoside antibiotic that possesses bactericidal act iv ity against many gram-positive and gram-negative organisms. C l in ica l l y , i t is used most often to treat l ife-threatening infections due to Pseudomonas, Proteus, and the Klebsiella-Enterobacter group. A relationship between gentamicin serum concentrations and c l in ica l response has been demonstrated. Toxicit ies, notably ototoxicity and nephrotoxicity, are also associated with serum concentrations. Gentamicin is given intermittently either intramuscularly or intravenously resulting in peak and trough concentrations. The therapeutic range is defined as peak concentrations between 4-15mg/L (depending in part on the site of infection and the susceptibi l ity of the infecting organism), and trough concentrations less than 2mg/L (to minimize tox ic i ty ) . Gentamicin distributes into a space similar to the extracellular f lu id volume (ECFV). Pathophysiologic changes which alter the extracellular f lu id compartment also alter gentamicin volume of distribution (Vd). One intr ins ic factor known to alter gentamicin Vd is obesity. Leanness is also thought to alter gentamicin Vd but its effect has not been quantitated. The objectives of this study were to: 1) accurately describe a Vd in "normal" patients, that is, those with no factors known to alter gentamicin volume of distr ibution; 2) determine i f there is a continuous i i l inear relationship between gentamicin volume of distribution (L/kg) and percent body fat; 3) determine i f that relationship is associated with changes in ECFV; and 4) develop a formula for predicting Vd in a similar patient population. Twenty patients with no extrinsic factors known to alter gentamicin Vd participated in the study. Five blood samples were drawn around one steady state dose of gentamicin. A one-compartment model was used to calculate Vd. Trit iated water and anthropometric measurements were conducted simultaneously to provide estimates of body composition. Together these values were used to examine the relationship between gentamicin Vd and body composition. We have described a Vd for gentamicin that is larger but no less variable than is currently used to determine in i t i a l dosage regimens. This volume may be larger either due to the selection of patients or method of serum gentamicin analysis. This larger volume should be used to calculate empiric dosage regimens for similarly selected patients to decrease the r isk of treatment fa i lure. We were not able to describe a linear relationship between percent body fat and gentamicin volume of distr ibution. We have postulated several reasons as to why this relationship could not be detected; 1) the sample size may not have been large enough, 2) the relationship is not important in patients who are not at extremes of weight, or 3) the variations caused by changes in body composition were not as significant as other factors that may cause f lu id alterations in hospitalized patients. i i i There was a strong correlation between gentamicin Vd and total body water noted. Having eliminated al l patients in whom the relationship between total body water and ECFV could not be assumed to be normal and constant, we have indirectly demonstrated a strong relationship between ECFV and gentamicin Vd. This relationship s t i l l leaves var iab i l i ty in gentamicin's distribution characteristics to be explained. The predictive formula is based on measurements of height, weight, and a larger Vd [L/kg(ideal body weight)] than has previously been used. The predictive formula recommended for c l in ica l use in adults is Vd=0.30L/kg (Dosing Weight). Dosing weight equals ideal body weight (IBW) when actual body weight (ABW) is < IBW, or 0.4(ABW-IBW)+IBW, when ABW is > IBW. The consequences of estimating a larger Vd are that patients empirically would receive larger doses than are currently being administered, thus more patients should obtain therapeutic serum concentrations within the f i r s t 24 hours of therapy. This information will be useful in our attempts to optimize gentamicin therapy. i v TABLE OF CONTENTS CHAPTER PAGE ABSTRACT i i LIST OF TABLES v i i i LIST OF FIGURES ix SYMBOLS AND ABBREVIATIONS x ACKNOWLEDGEMENTS x i i 1.0 INTRODUCTION 1.1 Cl inical application 1 1.2 Concentration versus response 1 1.3 Concentration versus toxic i t ies 3 1.3.1 Nephrotoxicity 4 1.3.2 Ototoxicity 5 1.4 Pharmacokinetics 7 1.4.1 Absorption 7 1.4.2 Elimination 7 1.4.3 Pharmacokinetic model 1ing 8 1.4.4 Distribution 8 1.4.5 Factors affecting distribution 9 1.4.6 Dosing methods 9 1.5 Objectives 11 1.5.1 Volume of distribution in normal patients 11 1.5.2 Relationship between gentamicin volume of distribution and percent body fat 12 v 1.5.3 Correlation between gentamicin volume of distribution and extracellular f lu id volume 16 1.5.4 Formulas for estimating gentamicin volume of distribution 16 2.0 METHODS 2.1 Site 19 2.2 Selection c r i te r i a 19 2.3 Gentamicin dosage and administration 20 2.4 Blood sampling 21 2.5 Gentamicin serum level determinations 22 2.6 Gentamicin pharmacokinetic parameter calculations 23 2.7 Actual body weight measurements 24 2.8 Ideal body weight calculations 24 2.9 Body composition - Anthropometric measurements 25 2.10 Body composition - Tr it iated water measurements 25 2.11 Data collection 27 2.12 Stat ist ical analysis 27 3.0 RESULTS 3.1 Description of screened/excluded patients 29 3.2 Gentamicin pharmacokinetic parameters 31 3.3 Body composition estimates 31 3.4 Volume of distribution in normal patients 35 3.5 Relationship between gentamicin volume of distribution and percent body fat 35 3.6 Correlation between gentamicin volume of distribution and extracellular f lu id volume 42 vi 3.7 A predictive equation for gentamicin volume of distribution 43 4. ,0 DISCUSSION 4.1 Methods 46 4.2 Gentamicin volume of distribution in normal patients 46 4.3 Relationship between gentamicin volume of distribution and percent body fat 50 4.4 Correlation between gentamicin volume of distribution and extracellular f lu id volume 55 4.5 Developing a c l i n i ca l l y applicable predictive equation 58 5 .0 CONCLUSIONS 5.1 Volume of distribution in normal patients 61 5.2 Relationship between gentamicin Vd and percent body fat 61 5.3 Correlation between ECFV and gentamicin Vd 61 5.4 Development of a c l i n i ca l l y applicable predictive formula 62 6. .0 REFERENCES 64 7 .0 APPENDICES 7.1 Appendix 1 - Data Collection forms 72 7.2 Appendix 2 - Standardizations 75 7.3 Appendix 3 - Consent Form 78 7.4 Appendix 4 - Ethics Approval 80 vi i LIST OF TABLES TABLE PAGE 1 Patients c lass i f ied according to body composition 29 2 Patients excluded 30 3 Patients e l ig ib le for data analysis 31 4 Gentamicin pharmacokinetic parameters 32 5 Body composition - Anthropometric measurements 34 6 Body composition - Tr it iated water measurements 36 7 Volume of distribution described as a function of weight 37 8 Gentamicin volume of distribution versus percent body fat 41 vi i i LIST OF FIGURES FIGURE PAGE 1 Mean serum concentration versus time curve 33 2 Volume of distribution versus actual body weight 37 3 Volume of distribution versus ideal body weight 38 4 Volume of distribution versus lean body mass 39 5 Volume of distribution versus percent body fat (Tritiated Water Measurements) 43 6 Volume of distribution versus percent body fat (Skinfold Caliper Measurements) 44 7 Volume of distribution versus total body water 45 ix SYMBOLS AND ABBREVIATIONS ABW Actual body weight AUC Area under the plasma concentration versus time curve BUN Blood urea nitrogen C Centigrade CCR Cr i t ica l care recovery ecu Coronary care unit cm Centimetres cpm Counts per minute CrCl Creatinine clearance dl Deci l i tre dpm Disintegrations per minute ECFV Extracellular f lu id volume EMERG Emergency EMIT Enzyme immunoassay h Hours IBW Ideal body weight ICU Intensive care unit IM Intramuscular in. Inches IV Intravenous kg Kilograms L Litres LBM Lean body mass LFT Liver Function Tests Max Maximum X MBC Minimum bactericidal concentration MD Medical doctor mg Milligrams Min Minimum MIC Minimum inhibitory concentration ml M i l l i l i t r e s r Pearson correlation coefficient RIA Radioimmunoassay rpm Revolutions per minute SCr Serum creatinine SD Standard deviation SEM Standard error of measurement T Student's T test TBW Total body water uCi Microcuries X Mean Vd Volume of distribution xi This thesis is dedicated to my parents, for giving me the courage to believe in my capabi l i t ies, and to my husband Mark, whose unfailing support and encouragement have carried me through to the completion of this thesis. xi i ACKNOWLEDGEMENTS The author would l ike to thank Dr. Robin Ensom for suggesting the problem and for the time he has devoted to this program. Sincere thanks is also extended to Dr. Francis Rosenberg and Dr. Allan Belzberg for their enthusiasm, assistance, and for the time their very wi l l ing and capable staff donated to this project. The author is grateful for the guidance and constructive cr i t ic ism provided by Dr. Robert Rangno, Dr. Peter Jewesson and Dr. John Sinclair The author is deeply indepted to Dr. James Axel son for the advice, encouragement and friendship provided throughout the course of this study. The support and direction received from Dr. Gail Bellward has been greatly appreciated. The author would also l ike to thank fellow graduate students for their inspiration and humour. The author is grateful for the fellowship received from Merck Frosst Canada and to the Vancouver Foundation for their financial support. xi i i 1. INTRODUCTION 1.1 CLINICAL APPLICATION Gentamicin is a basic, water-soluble, aminoglycoside antibiotic complex. It was isolated from Micromonospora species in 1963 by Weinstein and co-workers (1), and is bactericidal for many gram-positive and gram-negative bacteria (1-5). Gentamicin is most often used to treat l ife-threatening infections due to gram-negative organisms, such as Pseudomonas, Proteus, and the Klebsiella-Enterobacter group (6,7). Toxic it ies, notably ototoxicity and nephrotoxicity have been associated with its use since the f i r s t c l in ica l t r i a l s (8,9). Since that time several studies have examined the relationship between serum concentrations, efficacy, and toxicity in an effort to maximize efficacy and minimize toxic ity. 1.2 CONCENTRATION VERSUS RESPONSE In determining the optimal dosing regimen for any drug, i ts efficacy must be balanced against its tox ic i t ies . Traditionally antibiotic doses have been determined based on ab i l i ty to obtain peak concentrations that are above the minimum inhibitory concentration (MIC) of the infective organism. The dosing interval is determined by the ha l f - l i f e of the drug, or the length of time that the serum concentration is below the MIC of the causative organism. In i t ia l ly gentamicin was given intermittently, either at six (8), eight (5,9), or twelve (5) hour intervals. 1 Bodey et al. (10) proposed using continuous infusions for dosing aminoglycosides in neutropenic patients. In animals intermittent dosing was demonstrated to be as effective and less toxic than continuous infusions (11-13). Studies in humans are not comparable and have provided confl ict ing results (10,13). Intermittent dosing is the regimen most often recommended in humans. In vitro, Gerber et al. (14) demonstrated by comparing continuous infusions to intermittent dosing, that survival of Pseudomonas aeruginosa was related to area under the concentration versus time curve (AUC). MacArthur et a l . (15) and Jackson and Riff (16) have demonstrated that k i l l of Ps. aeruginosa, in vitro, occurred in at least two phases; an i n i t i a l concentration dependant phase and a concentration independent phase. Specif ical ly MacArthur and co-workers (15) found that a 1/10 log increase in serum concentration resulted in a 1 log increase in bacterial k i l l rate. This appears to indicate, in vitro, there is a relationship between concentration and survival of bacteria. It has not been determined whether total AUC or peak concentration is most important. In vivo, several authors have related peak concentrations to efficacy (16-19). From these experiments therapeutic peak serum concentrations have been established as being between 4-15mg/L, depending on the site of infection and the infecting organism (16,17,19). It is also essential that therapeutic concentrations be obtained early in therapy (16-19). Jackson and Riff in 1971 (16) demonstrated that an increasing proportion of their patients survived 2 as progressively higher concentrations of gentamicin were obtained. In 1974, Noone and Pattison (17) reported that in patients who had gram-negative septicemia, 10/15 survived, and a l l obtained peak serum concentrations of 5mg/L within the f i r s t 3 days of therapy. Of the 5/15 patients who died, only one reached a peak serum concentration of 5mg/L. Zaske and co-workers (18) found that i f conventional dosage regimens were used for gentamicin the survival rate was 33%. Whereas, i f individualized dosage regimens were established within 24 hours, patient survival increased to 64%. Moore et al. in 1984 (19), analyzed case reports from 4 prospective t r i a l s of gentamicin, tobramycin, and netilmicin. Eighty-nine patients had proven gram-negative bacteremia. They found a s ignif icantly larger proportion of patients (9/43) with subtherapeutic peak plasma levels drawn within 24-48 hours of starting antibiotic therapy died, compared to those who obtained therapeutic peak concentrations (1/41) within that same time period. It has been established, in vivo, that peak concentrations are related to efficacy and that they should be obtained early in therapy. Whether there is an optimal peak concentration, or value for AUC, relative to the MIC, the minimum bactericidal concentration (MBC), or site of infection, that can be related to efficacy has not been established. 1.3 CONCENTRATION VERSUS TOXICITIES Many authors have investigated the toxic i t ies associated with gentamicin in an attempt to identify the cause(s). To date, a predictive relationship between serum concentrations and toxic i t ies 3 has not been identif ied. However, several investigators have been able to demonstrate an association between serum concentrations and tox ic i t ies . 1.3.1 NEPHROTOXICITY Gentamicin induced nephrotoxicity predominantly occurs within the proximal tubular cel l s (20,21), and most often manifests as a gradual r ise in serum creatinine (SCr), or blood urea nitrogen (BUN), which is usually reversible upon discontinuation of therapy (9,22,23). The incidence and risk factors for the development of nephrotoxicity in humans have been studied by several authors (24-28). The incidence reported varies depending on the population studied, and the definit ion of nephrotoxicity used. It is most often reported as occurring in approximately 10-20% of patients receiving gentamicin (24-26). Risk factors have been assessed by several authors (23-26,29). Dahlgren et a7., 1975 (24) were one of the f i r s t investigators to prospectively monitor nephrotoxicity associated with gentamicin therapy. They found nephrotoxicity was associated with trough serum concentrations >2mg/L. Schentag and co-workers in 1982 (25), also examined gentamicin nephrotoxicity prospectively. In i t ia l ly , patients were dosed based on nomograms, but subsequently they individualized dosage regimens to maintain peak concentrations between 4-10mg/L and troughs between 0.5-2.0mg/L. Nephrotoxicity was defined as an increase in SCr by 4 0.5mg/dl before or within 5 days of discontinuing therapy. They found no predictive relationship between total dosage, sex, i n i t i a l blood levels, i n i t i a l renal function, or duration of treatment and nephrotoxicity. There was a s ta t i s t i ca l l y significant difference between i n i t i a l trough concentrations of patients who became nephrotoxic and those who were nontoxic. Final trough concentrations averaged 4.9+3.0mg/L in nephrotoxic patients compared to 2.1±1.7mg/L in nontoxic patients. Moore et al. (26) also established risk factors for the development of nephrotoxicity. In their studies they maintained peak concentrations between 5-10mg/L but did not control trough concentrations. The factors found to be associated with nephrotoxicity were: high i n i t i a l CrCl, peak aminoglycoside levels, age, sex, l i ver disease, and shock. In these studies al l patients received the same dosage regimen and duration of therapy was short (6.3±3.1 days). In later studies i t became apparent that duration of therapy was also important (23,29). 1.3.2 OTOTOXICITY The ototoxicity noted as a result of aminoglycoside administration encompasses both cochlear and vestibular damage. Most authors report loss of function is due to a degeneration of the sensory hair ce l l s (30,31). Hinojosa and Lerner, 1987 (32) recently demonstrated a decrease in the number of ganglion cel l s in two patients with gentamicin induced ototoxicity, but no alteration of the number of sensory hair ce l l s . 5 Cl in ica l l y significant vestibulotoxicity is reported more frequently than auditory impairment. In most instances vestibulotoxicity is reversible. In other cases balance can be maintained through reliance on visual and proprioceptive inputs. There are few reports of vestibulotoxicity that is permanent and incapacitating (33). Conversely, auditory impairment associated with gentamicin toxicity is usually permanent. It is most often associated high frequency hearing impairment (23), thus, is not often c l i n i c a l l y apparent (9,23). As with studies of nephrotoxicity, comparability of studies of gentamicin ototoxicity is complicated by the heterogeneity of patient populations, dosing methods, and assessment indices. Data from c l in ica l reports to the Food and Drug Administration between 1962 and 1969 indicated the incidence of ototoxicity was approximately 2% (34). Two-thirds of those patients experienced vestibular toxic i ty, whereas, only one-third noted auditory impairment. In approximately half of the patients with auditory impairment vestibular toxicity was also noted (34). More recent studies of select populations have found the incidence of ototoxicity to be higher (20-50%) (23,35,36). In 1971, Jackson and Arcieri (34) in their review of c l in ica l t r i a l s reported that risk factors associated with the development of ototoxicity included: impaired renal function, daily dose mg/kg, and previous use of ototoxic drugs. Moore et al. in 1984 (35) prospectively examined 135 patients receiving one of the following aminoglycosides; tobramycin, gentamicin, or amikacin. Patients receiving gentamicin were individually dosed to maintain peak concentrations between 5-10mg/L. This t r i a l revealed that duration 6 of therapy, total aminoglycoside dose, peak temperature, and bacteremia were associated with aminoglycoside ototoxicity. In summary, although the incidence and factors which best predict toxic i ty depend on the population studied, as well as the definit ion of toxic i ty, i t appears that either minimizing the dose (decreasing the AUC) or maintaining low trough concentrations wil l assist in preventing gentamicin associated nephrotoxicity and ototoxicity. Therefore, in order to maintain efficacy but decrease toxic ity we must not only use substantial doses to achieve therapeutic values for peak or AUC, but also suff icient intervals to minimize toxic i ty. 1.4 PHARMACOKINETICS 1.4.1 ABSORPTION Gentamicin is not well absorbed after oral administration (8). Similar serum levels are achieved by either intramuscular or intravenous injection (37,38). Intramuscular absorption is known to be altered by blood flow (39). Therefore, diseases which alter blood flow to the muscle may delay the absorption of an intramuscularly administered drug. For this reason gentamicin is most often given by the intravenous route. 1.4.2 EXCRETION Gentamicin is not metabolized. Elimination occurs predominantly through glomerular f i l t r a t i on (6,40), thus, renal fa i lure decreases the elimination of gentamicin. A negative, l inear 7 relationship between creatinine clearance and gentamicin serum half-l i f e has been demonstrated (41-43). 1.4.3 PHARMACOKINETIC MODELLING Gentamicin elimination, after an IV bolus injection, is best described by a three compartment model (44-46). After an IV bolus, a distribution phase (7r), with a ha l f - l i f e equal to 0.556h (45), is seen. In the second phase (a) gentamicin is removed from the serum via glomerular f i l t r a t i on and through distribution to the tissues. The ha l f - l i f e of elimination from this compartment is approximately two hours in patients with normal renal function. The third phase (/}) depicts redistribution of the drug from tissue binding sites and subsequent elimination (46,47). Elimination from this compartment has a h a l f - l i f e of 80-110h in patients with normal renal function (46,47). 1.4.4 DISTRIBUTION Gentamicin is a polar compound that has been reported to be 0 to 30 percent bound to plasma proteins (48-50). Because gentamicin is a polar compound and therefore wil l not penetrate cel l s easi ly, and because i t is relat ively unbound in blood, one would expect i t to preferential ly distribute into the extracellular f lu id compartment. The association between gentamicin volume of distribution (Vd) and extracellular f lu id volume (ECFV) has been made by several investigators (6,38,42,47). The apparent Vd used to base empiric dosage regimens on for normal healthy adults is 0.25-0.26L/kg (51,52). 8 1.4.5 FACTORS AFFECTING DISTRIBUTION If gentamicin Vd is similar to the extracellular f lu id compartment, one would expect the Vd to vary as the volume of the extracellular f lu id compartment changes. Pathophysiological changes such as congestive heart fai lure (53), peritonit is (53-56), ascites (55,57), edema (58), and dehydration (53,59) alter the volume of the extracellular f lu id compartment as well as the Vd of gentamicin. Several other groups of patients including: c r i t i c a l l y i l l patients with sepsis (60), surgical intensive care patients (61), patients post-operative (62), cancer patients (63), and patients with renal fa i lure (6,64), a l l have been found to have an increased apparent Vd of gentamicin. Most of the investigators attribute the larger apparent Vd to expansion of the extracellular f lu id volume, although none speci f ica l ly measured the extracellular compartment. 1.4.6 DOSING METHODS There has been a relationship established between serum concentrations and both response (16-19), and toxic i t ies (24-26,34-36) of gentamicin. An optimal dosage regimen has not yet been established. Currently, gentamicin is given intermittently. Therapeutic peaks are described as between 4-15mg/L, while trough concentrations should be kept to less than 2mg/L. Current approaches to dosing aminoglycosides involve estimating patient pharmacokinetic parameters to in i t iate therapy. In centres where the f a c i l i t i e s and expertise are available, subsequent dosage adjustments are based on serum concentrations of the drug, which are 9 used to establish individual pharmacokinetic parameters. When individualized methods are not ut i l i zed, assumptions regarding the Vd have demonstrated to be a primary source of error (65). In order to improve our accuracy in obtaining therapeutic peak concentrations a less variable Vd in "normal" patients (those with no extrinsic factors known to alter gentamicin Vd) needs to be established. Once a Vd has been established in "normal" patients, one wil l be able to more precisely determine the effect of individual disease states on gentamicin Vd. An intr ins ic factor known to alter Vd is obesity (51,66-68). If the effects of leanness or obesity on the Vd of gentamicin were known, the accuracy of our estimation of Vd would be increased, as estimations of body composition are readily available in the c l in ica l setting. This knowledge would also provide a more accurate description of the "normal" patient population and serve as a better comparison for future studies. Optimal efficacy from gentamicin is related to obtaining therapeutic peak concentrations as soon as possible. This can be realized i f one is able to estimate a patient's Vd of gentamicin accurately. 10 1.5 OBJECTIVES: 1. To accurately describe the gentamicin Vd in "normal" patients. 2. To determine i f there is a continuous relationship between gentamicin Vd and percent body fat, through lean, normal and obese groups. 3. To determine i f the association between volume of distribution of gentamicin and body composition can be attributed to changes in extracellular f lu id volume. 4. To develop a c l i n i ca l l y useful formula for estimating Vd using c l i n i ca l l y available measurements (height and weight) which wil l accurately predict Vd for a l l body weights, in similarly selected patients. 1.5.1 VOLUME OF DISTRIBUTION IN "NORMAL" PATIENTS Currently, 0.25-0.26L/kg is the assumed Vd of gentamicin used to predict dosage requirements in adult patients of average weight (51,52). HEALTHY VOLUNTEERS: Regamey et al. (38) studied Vd when gentamicin was given either IV or IM in 4 healthy volunteers. They found that Vd after IV injection was 30.8±3.4%(SD) of total body weight and after IM injection was 27.9+3.9%(SD) of body weight. These values were not s ignif icantly different. Wilson et al. in 1973 (44) examined Vd in 7 young adults with normal renal and hepatic function, using t r i t i a ted gentamicin, and found i t to be 28%±1.2 (SEM) of the body weight. 11 PATIENTS: Gentamicin volume of distribution was i n i t i a l l y found to be similar to inulin (6). In 1972, Cutler et al. (42) described gentamicin Vd as being 24% of body weight. More recently, large variations in gentamicin Vd have been reported in patients. Barza and co-workers in 1975 (69) found that the apparent Vd varied six fold from 12-70% of body weight in 21 patients studied. In that same year Siber et al. (70) reported that Vd varied from 14.6 to 46.9% of body weight. Zaske, Cipolle, and Strate in 1980 (53) looked at 242 surgery patients. They reported Vd's ranging from 0.06-0.63L/kg of actual body weight. This is a tenfold variation. Zaske and co-workers (71) examined kinetics in 1640 patients with gram-negative infections and found, in patients with normal renal function, the Vd varied from 0.04 to 0.74L/kg. The average Vd was 0.19±0.08L/kg. These studies, while reporting large variations in gentamicin Vd, did not exclude patients with conditions or factors now known to alter the Vd of gentamicin. Cl in ical experience of the investigators indicates that large variations in gentamicin Vd are not seen in individuals presenting with an absence of factors known to alter the Vd of gentamicin. As yet, the Vd of gentamicin in these "normal" patients has not been firmly established. It is necessary to define the Vd in "normal" patients so that the effects of disease states (ie. sepsis) can be examined and compared to a less variable standard. 1.5.2 RELATIONSHIP BETWEEN GENTAMICIN VD AND PERCENT BODY FAT EFFECT OF OBESITY: As early as 1964 i t was noted by Erlanson and Lundgren (72) that obesity alters the Vd of aminoglycoside 12 antibiot ics. Since that time several investigators (51,66-68) have examined the relationship between obesity and gentamicin Vd. These investigators have demonstrated that the Vd for obese patients is smaller per kg of actual body weight (ABW) as compared to normal weight individuals. Hull and Sarubbi (51) looked at 40 patients, 10 of whom were defined as obese. In their study obese was described as 5.0kg above ideal body weight (IBW), (defined by Geigy's sc ient i f i c tables (73)). They were able to decrease the error associated with their predictions of peak plasma concentrations by using IBW, instead of ABW to calculate Vd for obese subjects. Schwartz and co-workers (66) examined gentamicin pharmacokinetics in 6 obese (ie. more than 30% above lean body weight as defined by Geigy's sc ient i f ic tables (73)) and 6 normal volunteers. Their obese volunteers were on average 76% overweight. They reported a Vd for obese individuals as 0.185L/kg (ABW), while Vd for their normal weight volunteers was 0.244L/kg (ABW). Korsager in 1980 (67) confirmed the findings of Schwartz et a l . (66). This t r i a l looked at 17 markedly obese patients (average of 82.7% overweight as defined by Geigy's sc ient i f i c tables (73)), and 10 normal weight patients (average of 4.5% overweight). The apparent Vd in their normal patients was 0.232±0.05L/kg (ABW), while in the obese patients the apparent Vd was 0.177±0.028L/kg (ABW). In 1981 Sketris et a7. (68) studied the effects of obesity on gentamicin pharmacokinetics. Their patients included 30 normal weight patients (within 20% of IBW), and 30 obese patients (ie. more 13 than 30% above IBW) with an average of 51% above IBW. IBW was based on tables produced by Katch et a7.(74). The apparent mean Vd of gentamicin in their obese group was 0.15L/kg (ABW) compared to 0.19L/kg (ABW) in their control group. These studies demonstrate a decreased Vd L/kg (ABW) for obese individuals compared to normal weight patients. Schwartz et a7. (66), Korsager (67), and Sketris et a7. (68) proposed that gentamicin, being a polar compound distributes into extracellular f lu id in both lean body mass and adipose tissue. Adipose tissue contains 12-13% extracellular f lu id (75). EFFECT OF LEANNESS: The relationship between weight and gentamicin Vd is less well defined in lean patients. Pediatrics: Bravo et a7. in 1982 (76) described the Vd in 10 malnourished infants as 0.46±0.02L/kg, while in their eutrophic infants (n=7) the Vd was 0.39+0.02L/kg. This was in close agreement with the mean Vd reported by Buchanan et a7. (77) for 6 children with kwashiorkor. Buchanan et a7. (77) found upon admittance to hospital the average Vd of gentamicin was 0.45L/kg. Adults: Counts et a7. (78) assuming a Vd of 0.26L/kg, reported they overpredicted peak serum levels, in 10/13 patients receiving gentamicin who were 10 to 35kg below their estimated IBW (Geigy's sc ient i f i c tables (73)). Tointon and co-workers in 1987 (79) retrospectively examined the charts of patients receiving gentamicin. Fifty-one patients were c lass i f ied as lean (below IBW as determined from Devine's formulas 14 (80)), while 20 patients formed the control group. There were 9 patients in the lean group and 6 patients in the control group who received gentamicin. Amikacin or tobramycin had been given to the other patients. In the lean population the Vd was found to be 0.30±0.07L/kg (IBW), the range was 0.15-0.53L/kg. The control group had an average Vd of 0.25±0.04L/kg (IBW), the range was 0.17-0.34L/kg. These studies in lean patients indicate that the apparent Vd of gentamicin is expanded compared to normal weight individuals. The patient population being treated with gentamicin is usually comprised of patients with serious infections and/or severe diseases. Therefore, i t is not uncommon to find them malnourished. Several previous studies have indicated that lean patients, constitute a signif icant portion of hospitalized patients (81-84). Willard et al. (84) reported on 200 hospital-admitted patients, 30.5% of the population studied were malnourished. In a recent study (85) comprising of 112 patients receiving gentamicin in community hospitals, the percentage of patients whose ABW was less than IBW was 30.3%, confirming that lean patients constitute a signif icant portion of the patients receiving this drug. Studies to date indicate in the obese population the Vd in L/kg (ABW) is decreased compared to normal weight individuals. Conversely in lean patients the Vd in L/kg (ABW) is increased. In this study patients c lass i f ied as lean, normal weight, and obese, were examined to determine i f a relationship between volume of distribution and 15 body composition exists, in the absence of other factors known to alter Vd. 1.5.3 CORRELATION BETWEEN GENTAMICIN VD AND CHANGES IN ECFV Gyselynck et al. in 1971 (6) found the Vd of gentamicin to be comparable to the space that inulin distributes into. Inulin is used to measure the extracellular f lu id volume. These investigators concluded that the Vd was similar to the ECFV. Several authors have since determined the Vd in varying patient populations and found i t to be 24-31% of total body weight, and concluded that this is similar to the ECFV (38,42,44). The studies which have examined the effects of body composition and disease states on gentamicin Vd have assumed that deviations from normal were due to changes in the ECFV. To date there is only one study (6) that has examined the relationship between gentamicin Vd and ECFV d irect ly, by simultaneously measuring both compartments. In order to demonstrate that alterations in gentamicin Vd are associated with ECFV fluctuations, measurements of both gentamicin Vd and total body water (TBW) were performed on each subject. ECFV was assumed to be a constant fraction of total body water. 1.5.4 FORMULA FOR ESTIMATING GENTAMICIN Vd Several methods of predicting dosage requirements are available. Studies have shown that calculating dosages based on individually determined pharmacokinetic parameters, such as volume of distr ibution, clearance, and ha l f - l i f e wil l best predict serum levels 16 ( 4 0 , 6 5 , 8 6 - 8 9 ) . However, t h i s m e thod r e q u i r e s t h a t d o s e s be g i v e n , b l o o d s a m p l e s d r a w n , and s e r u m g e n t a m i c i n l e v e l s d e t e r m i n e d . I n d i v i d u a l i z i n g a p a t i e n t ' s d o s i n g r e q u i r e m e n t s t a k e s t i m e and r e q u i r e s a k n o w l e d g e o f k i n e t i c s . In many c e n t r e s t h e f a c i l i t i e s and e x p e r t i s e a r e n o t a v a i l a b l e t o p e r f o r m t h i s m e t h o d . When i n d i v i d u a l i z e d p a t i e n t p a r a m e t e r s a r e n o t u t i l i z e d , as i s t h e c a s e when t h e r a p y i s i n i t i a t e d , a s s u m p t i o n s r e g a r d i n g t h e Vd h a v e d e m o n s t r a t e d t o be a p r i m a r y s o u r c e o f e r r o r when m a k i n g d o s a g e p r e d i c t i o n s ( 5 3 , 6 9 . 8 9 ) . When e v a l u a t e d , i t was f o u n d t h a t p r e d i c t i v e m e t h o d s c u r r e n t l y e m p l o y e d t e n d t o u n d e r d o s e p a t i e n t s w i t h s e v e r e i n f e c t i o n s 5 0 % o f t h e t i m e ( 6 5 ) . As w e l l , a p p r o x i m a t e l y 2 0 % o f t h e p a t i e n t s d o s e d w i t h t h e s e m e t h o d s had s e r u m c o n c e n t r a t i o n s o f g e n t a m i c i n t h a t a r e a s s o c i a t e d w i t h an i n c r e a s e d r i s k o f b o t h o t o t o x i c i t y and n e p h r o t o x i c i t y . W i t h few e x c e p t i o n s t h e s e nomograms assume a c o n s t a n t v a l u e f o r Vd, and do n o t a c c o u n t f o r v o l u m e c h a n g e s r e s u l t i n g f r o m d i f f e r e n c e s i n body c o m p o s i t i o n . In t h o s e nomograms w h i c h do make v o l u m e a d j u s t m e n t s b a s e d on body c o m p o s i t i o n , o b e s i t y i s a c c o u n t e d f o r b u t n o t l e a n n e s s . I f l e a n p a t i e n t s h a v e a l a r g e r Vd [ L / k g ( A B W ) ] t h a n n o r m a l w e i g h t p a t i e n t s , f o r any d o s e g i v e n , t h e se r u m l e v e l o b t a i n e d w i l l be l o w e r . T h i s l e a v e s l e a n p a t i e n t s e x p o s e d t o a g r e a t e r r i s k o f t r e a t m e n t f a i l u r e b e c a u s e t h e r a p e u t i c c o n c e n t r a t i o n s a r e l e s s l i k e l y t o be o b t a i n e d e a r l y i n t h e r a p y . 17 SUMMARY: It is the intent of the study to: 1. accurately describe a volume of distribution for gentamicin in "normal" patients; 2. determine i f the relationship between gentamicin volume of distribution and body composition is s ignif icant; 3. determine i f this relationship is associated with extracellular f lu id alterations; and 4. develop a predictive formula for estimating gentamicin dosage requirements. With this information c l in ic ians should be able to use this drug more effect ively, maximizing its efficacy and minimizing its tox ic i t ies . 18 2.0 METHODS Patients, with no extraneous factors known to alter gentamicin Vd, were selected from those receiving gentamicin at St. Paul's Hospital. Once informed consent was obtained, five blood samples were drawn, around one steady-state dose of gentamicin. Steady-state was assumed to have been obtained i f , 5 hal f - l ives of the drug had elapsed since therapy was init iated and the patient was stable in the previous 24 hours. A one-compartment model was used to calculate Vd. Tr it iated water measurements conducted simultaneously provided estimates of total body water, and lean body mass. Anthropometric measurements provided a second estimate of body composition. Together, these values were used to examine the relationship between gentamicin Vd and body composition. 2.1 SITE The study was conducted at St. Paul's Hospital, Vancouver, B.C.. St. Paul's Hospital is a 550 bed, acute care teaching hospital. As part of i ts services St. Paul's offers a drug measurement service (90). This service provides interpretations and recommendations for aminoglycoside therapy. 2.2 SELECTION CRITERIA A l i s t of a l l patients receiving gentamicin was generated daily by the pharmacy department. From this l i s t patients were screened to determine e l i g i b i l i t y . The selection c r i te r i a was as follows: 19 a. Absence of conditions known to alter the pharmacokinetic parameters (ie. congestive heart fa i lure, amputation, l i ver fa i lure, pregnancy or postpartum, patients less than 72 hours post-operative, and sepsis), as determined from the health records and from discussion with the attending physician. b. Patients had normal values for the following laboratory indices: 1. Creatinine Clearance (CrCl) (60 - 120ml/min/72Kg), estimated from Scr using the equation developed by Cockcroft and Gault (91); 2. BUN (8-22mg/dl); c. Normal Fluid Balance, identif ied by a combination of the following: 1. Normal specif ic gravity (urine) 1.003 to 1.030; 2. Normal f lu id balance = 0 - 1500ml/24h; and 3. Absence of signs and symptoms of dehydration, overhydration, edema, ascites, and vomiting or diarrhea. d. Able to complete . a series of physical measurements, including; height, weight, and skinfold measurements. e. Absence of concurrent medication known to interfere with the analysis of gentamicin (ie. heparin, t i c a r c i l l i n , carbenic i l l in or piperaci11 in). 2.3 GENTAMICIN DOSAGE AND ADMINISTRATION 20 MATERIALS: Gentamicin sulphate was supplied by Schering Canada Inc. Travenol Canada Ltd. manufactured the 100ml minibags of normal saline. EQUIPMENT: Balance (Mettler PC 440); balance (Sartorius -model 1601AMP8-1); pharmaceutical weights (Henry Troemner Inc.); volumetric pump (IVAC 580 Starflow); infusion tubing (IVAC S9870). METHODS: Gentamicin dosage requirements were determined by the attending physician in conjunction with the c l in ica l pharmacokinetic consultation service (90). The dose of gentamicin sulphate was measured using a syringe. The syringe was weighed immediately before and after use to determine the weight of gentamicin, and thus the dose of gentamicin administered. The gentamicin was then added to a 100ml minibag of normal saline. The infusion of the solution was supervised by the investigator, and controlled by an IVAC infusion pump. The infusion was given over a 60 minute period, and the exact time of the infusion was noted by the investigator. After the infusion was complete the minibag and tubing were immediately flushed with three, 15ml solutions of normal saline. The tubing contained approximately 14ml of solution. A sample of the solution remaining in the tubing was collected and frozen at -20°C until analyzed for i ts gentamicin content. 2.4 BLOOD SAMPLING 21 EQUIPMENT: Vacutainers K (Becton Dickinson SST 10ml clotted non-heparinized). METHODS: Blood samples were drawn by a phlebotomist and timed by the investigator. Samples were drawn from the arm contralateral to the site of injection. A total of f ive samples were drawn per patient according to the following schedule: BLOOD SAMPLING SCHEDULE SAMPLE TIME* VOLUME TESTS (#) (min) (ml) -30 120 210 300 360 10 10 10 10 10 gentamicin, 3-H20 gentamicin, 3-H20 gentamicin, 3-H20 gentamicin, 3-H20 gentamicin, 3-H20 * Relative to the start of the 60 minute infusion. 2.5 GENTAMICIN SERUM LEVEL DETERMINATIONS MATERIALS: Reagents (EMIT, Syva Co., Palo Alto, CA). EQUIPMENT: Centrifuge (Western Scient i f ic-S i lencer H-103NA series); spectrophotometer (C0BAS B-10, Roche Analytical Instruments Inc. Nutley, NJ) f i t ted with a DENS (Data evaluation of non-linear standard curves) option. 22 METHODS: Samples were allowed to c lot, then spun at 3000rpm for 15 minutes. The serum was stored at -20°C until the assay was performed. Reagent preparation involved some modification of the manufacturer's instructions (92). 2.6 GENTAMICIN PHARMACOKINETIC PARAMETER CALCULATIONS EQUIPMENT: SPSS:X2 (Statist ical package for the social sciences) (92). METHODS: a) ELIMINATION RATE CONSTANT: Linear regression analysis of the log concentration versus time data, obtained during the elimination phase (samples Cj-C^), was used to determine the patient's elimination rate constant (K^). Patients were only considered for s tat i s t ica l evaluation i f the correlation coeff icient for the post-dose serum gentamicin levels (C^ -C4) was greater than 0.95. b) VOLUME OF DISTRIBUTION: A single compartment model was used to determine the volume of distr ibution. EQUATION: Once steady-state had been achieved, the Vd was calculated using information obtained from the serum gentamicin 23 levels and the following equation (94): Vd (L)= K o ( l - e ' K d T ) Kd[C p -C 0 (e - K d t ) ] Where: Ko = infusion rate (mg/h) C 0 = pre-dose concentration (mg/L) Cp = peak serum concentration (mg/L) - determined by back extrapolation of the elimination curve, to the time of the end of the infusion. Kd = elimination rate constant (h~*) T = infusion time (h) t = time interval between CQ and the end of the infusion (h) 2.7 ACTUAL BODY WEIGHT MEASUREMENTS EQUIPMENT: Single beam balance METHODS: Measurements of body weight were taken within four hours of the start of the infusion. Patients wore only a hospital gown for this measurement. 2.8 IDEAL BODY WEIGHT CALCULATIONS EQUIPMENT: Metric measuring tape; f la t edge. METHODS: Height was determined using a metric measuring tape and a f l a t edge. Patients stood erect, barefoot, heels together against a wall. Measurements were made to the nearest 1.0cm. 24 EQUATIONS: Calculations for IBW are based on formulas that incorporate sex and height (80). The formulas used to calculate IBW (kg) are: Males = 50 + 2.3(height (in.) - 60) Females = 45 + 2.3(height (in.) - 60) 2.9 BODY COMPOSITION - ANTHROPOMETRIC MEASUREMENTS EQUIPMENT: Skinfold calipers (HarpendenR, Brit ish Indicators Inc). METHODS: The skinfold measurements were performed by the investigator, using skinfold cal ipers. The following anatomical sites were used; triceps, biceps and subscapular. Measurements were made in t r ip l i ca te and the median values to the nearest 0.1mm were recorded. EQUATIONS: Employing age-specific formulas, established by Durnin and Womersley (95), skinfold measurements were used to determine total body fat. 2.10 BODY COMPOSITION - TRITIATED WATER MEASUREMENTS MATERIALS: Trit iated water (DuPont); Trichloroacetic acid (Fisher Sc ient i f i c ) ; PCS-phase contrast system (Amersham); and xylene (Fisher Sc ient i f i c ) . 25 EQUIPMENT: Vortex mixer (Scientif ic Industries Inc.- model K-550-G); centrifuge (International Equipment Co.- model HN-S); automatic pipette (Clay Adams-Selectapette, 1ml volume); glass counting vials (Fisher Sc ient i f i c ) ; balance (Sartorius-Model 1601 AMP8-1); l iquid sc int i l l a t ion counter (Beckman Instruments I n c -Beckman LS9800). METHODS: Percent adiposity was determined from total body water which was calculated from an isotope di lut ion equation. Tr it iated water (300uCi) was administered oral ly to the patient. Serum drawn for gentamicin determinations was also used for tritium counting. Sample preparation: Proteins were precipitated from the serum using a method employing 10% trichloroacetic acid, as described by Langham in 1956 (96). The tritium was counted on a Beckman counter. Each sample was counted in t r ip l i ca te , 10 minutes each time. The average of the last two counts for each sample was used in calculations. Counting efficiency averaged 35%. Standards were prepared in the same manner as the samples and counted at the same time. Urine samples were prepared in the same manner as the serum samples. EQUATIONS: Total Body Water was calculated from the isotope 26 dilution equation described below: TBW = C_L C F Where: TBW = Total body water (ml) Cj = Activity of administered test substance (dpm) Cp = Activity of the test substance (dpm/ml) after equilibrium has occurred. Percent Adiposity was then calculated from TBW based on the following equations (97): Lean Body Mass(LBM)= TBW x 100/732 Percent Adiposity = (ABW - LBM)/LBM x 100 2.11 DATA COLLECTION For each patient al l measurements were performed within a 12 hour period. Al l information was recorded on standardized data col lection forms (see Appendix 1). 2.12 STATISTICAL ANALYSIS Stat ist ica l analysis was performed using the Stat ist ica l Package for the Social Sciences, version X2 (93). Pearson correlation coefficients for Vd [L/kg(IBW)] versus percent body fat (determined by skinfold cal iper, and total body water measurements) were calculated. 27 Analysis of Vd (L) versus TBW was completed using linear regression analysis. A stepwise multiple regression analysis was used to determine the relative contribution of the following predictive factors; weight, height, age, sex, SCr and percent adiposity, to the measured volume of distribution (L). Stat ist ical significance for a l l tests was set at p<0.05. 28 3.0 RESULTS 3.1 DESCRIPTION OF SCREENED/EXCLUDED PATIENTS Over a 26 week period, between March 1987 and January 1988, 666 patients receiving gentamicin were screened to determine e l i g i b i l i t y . Of the 45 patients who were e l ig ib le to participate in the study, 22 refused; 23 patients were entered and of these, 20 patients were e l ig ib le for data analysis. Of the 3 remaining patients, 2 did not complete the t r i t i a ted water measurements, and 1 did not meet the c r i te r i a for normal CrCl. Weights were obtained for 489/666 patients. They are c lass i f ied according to body composition in Table 1. Table 1 - PATIENTS CLASSIFIED ACCORDING TO BODY COMPOSITION LEAN (%) NORMAL (%) OBESE (%) TOTAL SCREENED 53 (11.0%) 304 (62%) 132 (27%) 489 RECRUITED 2 (3.8%) 12 (3.4%) 9 (6.8%) 23 A categorical description of excluded patients is presented in Table 2. 29 TABLE 2 - PATIENTS EXCLUDED REASON FOR EXCLUSION TOTAL(%) LEAN NORMAL OBESE UNKNOWN Factors known to alter ECFV: CrCl <60ml/min/72kg < 72h POST-OPERATIVE FLUID STATUS ABNORMAL ABNORMAL LFT AMPUTEE SEPTIC ALBUMIN LOW 145(22.4) 122(18.9) 52 (8.1) 24 (3.7) (1-6) (0.9) (0.3) 10 6 2 11(21.6) 2 (0.3) 7(13.7) 5 (9.8) 0 1 (2.0) 0 65(22.3) 51(17.5) 26 (8.9) 8 (2.7) (1.4) (1.0) (0.7) 35(28.5) 24(19.5) 12 (9.7) (5.7) 34(19.2) 45(25.4) 7 0 1 0 (0.8) 7 4 6 1 0 (4.0) (2.3) (3.4) (0.6) Factors not known to alter ECFV, but prevented patient participation: BLOOD AND BODY FLUID 27 (4.2) 7(13.7) 13 (4.5) 2 (1.6) 5 (2.8) PRECAUTIONS NEUTROPENIC/ANEMIC/ 26 (4.0) 4 (7.8) 16 (5.5) 3 (2.4) 3 (1.7) THROMBOCYTOPENIC REFUSED 22 (3.4) 4 (7.8) 10 (3.4) 8 (6.5) 0 WEIGHT NORMAL 22 (3.4) 0 22 (7.5) 0 0 NOT ORIENTATED 18 (2.8) 1 (2.0) 8 (2.7) 2 (1.6) 7 (4.0) UNABLE TO STAND 6 (0.9) 1 (2.0) 4 (1.4) 1 (0.8) 0 DID NOT SPEAK ENGLISH 4 (0.6) 0 2 (0.7) 1 (0.8) 1 (0.6) Technical reasons for exclusion: ICU/CCU/CCR/EMERG 78(12. •1) 3 (5.9) 22 (7. .5) 7 (5.7) 46(25.4) DISCHARGED/DISCONTINUED 33 (5. • 1) 3 (5.9) 17 (5. 8) 5 (4.1) 8 (4.5) TIMING OF DOSES 12 (1. • 9) 0 6 (2, .1) 5 (4.1) 1 (0.6) COULD NOT CONTACT MD 8 (1. •2) 0 4 (1. • 4) 3 (2.4) 1 (0.6) DRUG NOT GIVEN IV 8 (1. • 2) 1 (2.0) 2 (0. • 7) 1 (0.8) 4 (2.3) CENTRAL LINE 7 (1 .1) 1 (2.0) 4 (1 • 4) 0 2 (1.1) UNKNOWN 11 (1 .7) 0 3 (1. .0) 6 (4.9) 2 (1.1) TOTAL 643 51 292 123 177 30 A demographic description of the patients e l ig ib le for data analysis is provided in Table 3. Table 3 - PATIENTS ELIGIBLE FOR DATA ANALYSIS BODY COMPOSITION AGE (years) SEX (M/F) Lean x = 52 SD = 8 (46 & 57) 2/0 Normal T= 43 SD = 19 (22-75) 5/5 Obese x = 55 SD = 18 (23-82) 4/4 ALL PATIENTS T = 49 SD = 18 (22-82) 11/9 3.2 GENTAMICIN PHARMACOKINETIC PARAMETERS The data used to estimate gentamicin volume of distribution and Ke (h _ 1 ) for each patient are displayed in Table 4. A representation of the serum concentration versus time curve is displayed in Figure 1. 3.3 BODY COMPOSITION ESTIMATES Anthropometric measurements used to estimate percent body fat according to Durnin and Womersley's formulas (95) are reported in Table 5. The mean value for percent body fat was 22.7±0.3% (8.9%-43.0%). 31 TABLE 4 - GENTAMICIN PHARMACOKINETIC PARAMETERS I n i t i a l s Sex Age Dose I n f u s i o n Gentamicin Serum Level D e t e r m i n a t i o n s ( y e a r s ) (mg) Time (h) CO TO CI TI C2 T2 C3 T3 C4 T4 R Ke t l / 2 Vd (C=mg/L; T0=h predose; Tl-T4=h postdose) (h-1) (h) (L) PW M 57 114.11 0.87 1.8 0.17 5.3 2.50 3.4 3.75 2.5 4.92 1.8 6.44 0.99 0.27 2.6 15.7 TM M 46 89.45 0.97 2.1 0.12 3.6 2.64 2.7 3.72 1.8 5.22 1.4 6.72 0.99 0.23 3.0 22.5 LT P 29 92.03 0.95 0.6 0.55 4.2 2.02 3.2 3.05 1.6 5.03 1.3 5.87 1.00 0.31 2.2 14.2 DL M 49 134.30 0.85 0.8 0.23 4.0 2.28 2.5 3.55 1.9 4.50 1.2 6.05 1.00 0.32 2.2 21.3 JD M 38 90.83 0.53 1.1 0.05 2.6 2.31 1.7 3.73 1.3 4.90 1.1 5.64 1.00 0.26 2.7 27.6 co DV P 33 103.73 1.00 1.1 0.05 3.1 2.90 2.3 3.78 1.7 5.12 1.3 6.03 1.00 0.27 2.6 21.5 ™ AW M 75 92.56 0.83 0.5 0.53 2.9 2.00 2.0 3.31 1.5 4.36 1.2 5.83 0.99 0.23 3.0 25.6 KE F 24 90.65 0.85 0.7 0.08 2.5 2.33 1.6 3.45 1.1 4.77 0.6 7.30 0.99 0.28 2.5 27.1 MS M 22 89.59 0.90 0.8 0.03 3.6 2.13 1.9 4.01 1.4 4.97 1.0 6.47 0.99 0.30 2.3 18.0 RE F 51 68.65 0.90 1.4 0.43 3.5 2.15 2.5 3.58 1.9 4.67 1.2 6.08 1.00 0.27 2.6 14.9 RG M 73 115.04 0.93 2.7 0.33 6.1 2.10 4.4 3.58 3.8 4.41 2.5 6.08 0.99 0.22 3.2 17.5 DP F 33 91.94 0.90 0.1 0.83 4.1 1.70 1.9 3.03 1.1 4.27 0.5 5.77 1.00 0.51 1.4 12.4 FJ M 65 157.35 1.01 1.8 0.21 6.1 2.04 3.3 3.74 2.8 4.74 2.2 6.18 0.97 0.24 2.9 23.7 AM M 44 156.42 0.88 1.6 0.88 3.9 2.15 2.0 3.61 1.6 4.53 0.9 6.03 0.99 0.37 2.3 26.4 SS F 63 113.31 0.88 1.5 1.05 4.4 2.25 3.1 3.38 1.8 4.86 1.5 5.93 0.99 0.30 2.3 17.4 LR F 23 92.69 0.93 1.1 0.25 3.1 2.88 1.8 4.10 1.2 5.38 0.9 6.28 1.00 0.36 1.9 14.9 PJ F 82 72.65 0.88 1.8 1.17 5.0 1.96 3.7 3.38 2.9 4.91 2.5 6.71 1.00 0.18 3.9 14.4 EL M 66 90.74 0.88 0.5 0.42 3.4 1.85 2.0 3.28 1.4 4.26 0.9 5.91 1.00 0.33 2.1 18.9 MY F 56 89.10 1.02 2.1 0.13 5.4 1.85 3.4 3.40 2.5 4.87 1.9 5.87 1.00 0.25 2.8 15.8 AA M 41 90.21 0.88 0.8 0.35 2.4 2.2 1.8 2.76 1.0 4.86 0.5 5.91 1.00 0.39 1.8 21.8 Figure 1 - Plot of Mean Log Concentration versus Time Log Gentamicin Concentration (mg/L) El m I I I I I L -1 0 1 2 3 4 5 Time relative to start of infusion (h) 33 TABLE 5 - BODY COMPOSITION - ANTHROPOMETRIC MEASUREMENTS INITIALS Sex Age HT ABW IBW Ratio (cm) (kg) (kg) ABW/IBW FH M 57 172 40.3 67.8 0.59 TM M 46 184 61.4 78.6 0.78 LT F 29 170 53.8 60.5 0.89 DL M 49 175 73.4 70.0 1.05 JD M 38 195 81.6 88.1 0.93 DV F 33 164 51.4 55.5 0.93 AW M 75 175 68.0 70.5 0.97 KE F 24 165 54.8 56.6 0.97 MS M 22 172 66.2 68.0 0.97 RE F 51 163 59.5 54.2 1.10 RG M 73 158 57.0 54.6 1.04 DP F 33 164 55.8 55.7 1.00 FJ M 65 172 85.4 67.3 1.27 AM M 44 171 86.9 66.8 1.30 SS F 63 161 74.5 52.8 1.41 LR F 23 164 73.8 55.5 1.33 PJ F 82 148 58.5 40.6 1.44 EL M 66 174 79.5 69.6 1.14 MY F 56 160 81.5 51.8 1.57 AA M 41 172 82.0 67.3 1.22 MEAN 49 169 67.3 62.6 1.10 SD 18 10 12.9 10.5 0.23 MIN 22 148 40.3 40.6 0.59 MAX 82 194 86.9 88.1 1.57 Skinfold Thickness Dumin/Womersley Triceps Biceps Subscapular Percent body fat (mm) (mm) (mm) 2.8 2.8 4.5 8.9 N/A N/A N/A N/A 9.4 3.0 6.2 17.0 14.4 8.3 7.1 23.5 5.1 3.5 8.8 17.0 2.9 6.3 8.1 18.1 10.9 4.5 12.9 19.7 9.8 5.8 9.0 21.4 5.1 12.7 13.5 16.9 11.9 8.8 12.4 30.9 10.3 3.3 6.4 14.4 14.8 13.6 8.2 27.8 13.5 8.5 6.2 24.2 8.8 5.8 11.1 21.4 31.0 24.7 27.1 40.4 19.6 10.2 38.5 36.3 23.4 12.1 18.1 33.9 15.8 9.7 4.3 25.1 16.6 34.2 31.1 43.0 9.2 5.2 1.9 15.0 22.7 10.3 0.0 43.0 34 Trit iated water measurements ut i l ized in the estimation of LBM and percent body fat are shown in Table 6. The mean value for percent body fat using this method was 29.1±24.2% (-5.6%-78.9%). 3.4 VOLUME OF DISTRIBUTION IN "NORMAL" PATIENTS The gentamicin volumes of distribution for each patient in [L/kg(ABW), L/kg(IBW), L/kg(LBM)] are reported in Table 7. The mean Vd [L/kg(ABW)] was 0.30+0.08L/kg. The mean Vd [L/kg(IBW)] was 0.31+0.06L/kg. The mean Vd [L/kg(LBM)] was 0.36±0.07L/kg. 3.5 RELATIONSHIP BETWEEN GENTAMICIN Vd AND PERCENT BODY FAT The relationship between Vd (L) and ABW, IBW, and LBM are depicted in Figures 2,3 and 4 respectively. Correlation coefficients calculated for these three measurements of weight, indicate that LBM correlated best with Vd (r=0.739, p<0.001), followed by IBW (r=.617, p<0.01) and ABW (r=.404, p<0.05). In the c l in i ca l setting measurements of LBM are not pract ical , therefore estimates of body composition were compared to Vd [L/kg(IBW)] to determine i f the predictive ab i l i ty of IBW could be improved upon. The calculated values for percent body fat (as determined by skinfold caliper (95) and t r i t i a ted water measurements (97)) are presented in Table 8. A s ta t i s t i ca l l y significant correlation between gentamicin Vd [L/kg(IBW)] and percent body fat (estimated 35 TABLE 6 -BODY COMPOSITION - TOTAL BODY WATER MEASUREMENTS TRITIUM SPECIFIC ACTIVITY INITIALS ABW BKGD SERUM STND TBW LBM PERCENT (kg) (DPM) (DPM) (DPM) (L) (kg) BODY FAT FW 40.3 54 10301 213534 31.25 42.7 -5.6 TM 61.4 43 7418 213534 43.42 59.3 3.5 LT 53.8 53 8808 215846 36.97 50.5 6.5 DL 73.4 57 7444 215765 43.80 59.8 22.7 JD 81.6 44 5349 213534 60.36 82.5 -1.1 DV 51.4 48 8081 193824 36.18 49.4 4.0 AW 68.0 59 6796 192580 42.86 58.6 16.1 KE 54.8 52 8506 192580 34.16 46.7 17.4 MS 66.2 48 8748 192580 33.19 45.4 46.0 RE 59.5 43 10526 186785 26.72 36.5 63.0 RG 57.0 50 9777 186785 28.80 39.3 44.9 DP 55.8 60 10324 215765 31.52 43.1 29.6 FJ 85.4 49 5909 213534 54.65 74.7 14.4 AM 86.9 72 5860 215765 55.90 76.4 13.8 SS 74.5 45 8394 186785 33.55 45.8 62.6 LR 73.8 49 7263 186785 38.83 53.0 39.1 PJ 58.5 51 11035 186785 25.50 34.8 67.9 EL 79.5 44 6670 186785 42.29 57.8 37.7 MY 81.5 48 8708 192580 33.35 45.6 78.9 AA 82.0 51 6513 214440 49.77 68.0 20.6 MEAN 67.2 39.15 53.4 29.1 SD 12.9 9.63 13.1 24.2 MIN 40.3 25.50 34.8 -5.6 MAX 86.9 60.36 82.4 78.9 36 TABLE 7 - VOLUME OF DISTRIBUTION DESCRIBED AS A FUNCTION OF WEIGHT BODY INITIALS Ratio Vd COMPOSITION ABW/IBW (L) LEAN FW 0.59 15.1 TM 0.78 16.7 MEAN 0.69 15.9 SD 0.09 0.84 LT 0.89 15.3 DL 1.05 22.9 JD 0.93 31.6 DV 0.93 23.8 AW 0.97 25.9 KE 0.97 27.9 MS 0.97 16.4 RE 1.10 16.5 RG 1.04 16.4 DP 1.00 16.7 MEAN 0.99 21.3 SD 0.06 5.6 FJ 1.27 26.0 AM 1.30 29.3 SS 1.41 16.7 LR 1.33 16.9 PJ 1.44 15.0 EL 1.14 20.2 MY 1.57 15.1 AA 1.22 35.7 MEAN 1.34 21.8 SD 0.13 7.2 ALL PATIENTS MEAN 21.0 SD 6.4 MIN 15.1 MAX 29.3 Vd Vd Vd [L/kg(IBW)] [L/kg(ABW)] [L/kg(LBM)] 0.23 0.39 0.37 0.29 0.37 0.38 0.26 0.38 0.38 0.03 0.01 .00 0.23 0.26 0.28 0.30 0.29 0.36 0.31 0.34 0.34 0.39 0.42 0.43 0.36 0.38 0.44 0.48 0.49 0.58 0.26 0.27 0.40 0.28 0.25 0.41 0.32 0.31 0.44 0.22 0.22 0.29 0.32 0.32 0.40 0.07 0.08 0.08 0.35 0.28 0.32 0.40 0.30 0.35 0.33 0.23 0.38 0.27 0.20 0.28 0.35 0.25 0.41 0.27 0.24 0.33 0.31 0.19 0.35 0.32 0.27 0.32 0.33 0.25 0.34 0.04 0.04 0.04 0.31 0.30 0.37 0.06 0.08 0.07 0.22 0.19 0.28 0.48 0.49 0.58 37 30 25 20 15 10 Figure 2 - Plot of Vd (L) versus ABW (kg) Volume of Distribution (L) y-0.145x • 9.79 r-0.404 p<0.05 20 40 60 80 100 Actual Body Weight (kg) 38 30 25 20 15 10 Figure 3 - Plot of Vd (L) versus IBW (kg) Volume of Distribution (L) y - 0 . 2 7 x • 2 . 4 8 r - 0 . 617 p<0.01 20 40 60 Ideal Body Weight (kg) 39 30 25 20 15 10 Figure 4 - Plot of Vd (L) versus LBM (kg) Volume of Distribution (L) y - 0 . 2 6 x • 5 .59 r - 0 . 7 3 9 p<0.001 20 40 60 Lean Body Mass (kg) 40 TABLE 8 - GENTAMICIN VOLUME OF DISTRIBUTION VERSUS PERCENT BODY FAT PERCENT BODY FAT INITIALS Vd(I) DURNIN/WOMERSLEY PACE/RATHBUN [L/kg(IBH>] (skinfold caliper) (tritiated water) FW 0.23 8.9 -5.6 TM 0.29 N/A 3.5 LT 0.23 17.0 6.5 DL 0.30 23.5 22.7 JD 0.31 17.0 -1.1 DV 0.39 18.1 4.0 AW 0.36 19.7 16.1 KE 0.48 21.4 17.4 MS 0.26 16.9 46.0 RE 0.28 30.9 63.0 RG 0.32 14.4 44.9 DP 0.22 27.8 29.6 FJ 0.35 24.2 14.4 AM 0.40 21.4 13.8 SS 0.33 40.4 62.6 LR 0.27 36.3 39.1 PJ 0.35 33.9 67.9 EL 0.27 25.1 37.7 MY 0.31 43.0 78.9 AA 0.32 15.0 20.6 CORRELATION R=.0030 R=-.0703 COEFFICIENTS p >.05 p >.05 41 from either anthropometric or t r i t i a ted water measurements) could not be demonstrated (Figures 5 & 6). When the groups (lean, normal and obese) were compared with respect to Vd measured in L/kg (ABW, IBW, or LBM) using a Mann Whitney U test, the only significant difference found was between the lean and obese group when volumes were reported as L/kg(ABW),(p<.05, two ta i led) . 3.6 CORRELATION BETWEEN GENTAMICIN Vd AND ECFV Linear regression analysis of gentamicin Vd (L) versus TBW produces a correlation coefficient of r=.739 (p<0.001). See Figure 7. 3.7 A PREDICTIVE EQUATION FOR GENTAMICIN Vd A stepwise multiple regression analysis of gentamicin Vd (L) versus height, weight, age, sex, SCr, found height to be the only signif icant predictive variable (r^=0.36,F=10.29(df 1,18)). A stepwise multiple regression analysis of gentamicin Vd (L) versus IBW, age, sex, SCr, found IBW to be the only predictive variable (r 2=0.36,F=ll.35,(df 1,18)). 42 Figure 5 - Plot of Vd |L/kg(IBW)] versus PBF (%) PBF determined from Tritiated Water Measurements Volume of Distribution [L/kg(IBW)] 0.6 y -0 .00018x + 0.32 r—0.07 p>0.05 S _ ra * 0 -20 0 20 40 60 80 Percent Body Fat 43 Figure 6 - Plot of Vd [L/kg(IBW)] versus PBF (%) 0 PBF determined from Skinfold Caliper Measurements Volume of Distribution [L/kg(IBW)] y-0.00002x * 0.32 r-0.003 p>0.05 1 3 El fCi £3 H El i i 0 10 20 30 40 50 Percent Body Fat 44 Figure 7 - Plot of Vd (L) versus TBW (L) 30 25 20 15 10 Volume of Distribution (L) y-0.36x + 5.59 r-0.739 p<0.001 10 20 30 40 50 Total Body Water (L) 45 4.0 DISCUSSION 4.1 METHODS The major d i f f i cu l t y encountered in the study was patient recruitment. In particular the number of recruited lean patients was s ignif icantly lower than the number of e l ig ib le normal weight or obese patients. A larger percentage of the lean patients were excluded because of f lu id volume alterations, blood and body f lu id precautions, abnormal l i ver function tests and neutropenia, anemia, or thrombocytopenia compared to the normal weight or obese groups. This may indicate that the larger volumes that are noted c l i n i c a l l y in lean patients are to due factors other than weight. The d i f f i cu l t i e s encountered in recruiting patients, and thus the small sample size l imit the conclusions that can be drawn from this study. It was necessary to have the s tr ic t selection c r i te r i a which eliminated approximately 70% of the e l ig ib le patients, in order to meet our objectives. Therefore, ways in which recruitment could have been increased are: 1) have a larger population to sample patients from or 2) increase the recruitment of e l ig ib le patients, perhaps by having their physician discuss the study with them. 4.2 GENTAMICIN VOLUME OF DISTRIBUTION IN "NORMAL" PATIENTS This study was designed to demonstrate that a less variable, more precise, volume of distribution for gentamicin could be described, through the elimination of factors known to alter 46 gentamicin Vd, in hospitalized patients. This would allow one to better estimate i n i t i a l dosage requirements in the uncomplicated patient population, as well as serve as a baseline for evaluation of the effect of factors which alter gentamicin Vd. Our results indicate that the volume of distribution of gentamicin in this population was 0.30±0.08L/kg(ABW). It is known that gentamicin Vd is best described by a three compartment model (44-46). In this study we have used a one compartment model to describe gentamicin Vd. Assuming a one compartment model may lead to an over-estimation of Vd (98). However, i t is the model which is most practical in a c l in i ca l setting and, therefore, most frequently used to estimate volumes in various patient populations. Gentamicin Vd in this study was calculated based on serum gentamicin concentrations which were assayed by EMIT. An excellent correlation between this methodology and other assays has been described (99-101), although differences have been noted (102). Therefore, the results of this study may not be s t r i c t l y comparable with studies that have used other methods of analysis. INTERPRETATION: This mean value is similar to that reported for normal healthy volunteers (38,44), but di f fers from those obtained by Zaske et al.(1980,1982) where 242 (53) and 1640 (71) patients respectively had serum gentamicin levels monitored. In these large 47 patient populations, the mean Vd described was 0.195L/kg (ABW) and 0.19±0.08L/kg (ABW). Rotschafer et al.(102) has demonstrated that RIA (method of gentamicin analysis used by Zaske et a l . (53,71)) consistently measured serum concentrations higher than EMIT. They found the calculated Vd of gentamicin was 25% lower when serum levels were measured using RIA compared to EMIT. This may explain the observed difference between Zaske et a l ' s (53,71) reported mean Vd and the mean Vd reported in this study. Tr ia ls which have examined the correlation of the newer assays (EMIT, RIA, and fluorescent immunoassay) a l l have demonstrated excellent correlations with the disc diffusion technique (99). When the studies that described a relationship between gentamicin serum concentrations and response (16-19) were conducted, gentamicin serum concentrations were assayed by either by disc diffusion or radioenzymatic assay. As concentration-response information is not available from patients who have had serum levels assayed by EMIT, or RIA, we cannot determine which of these assays wil l provide the most accurate or c l i n i ca l l y applicable measurement of serum gentamicin levels. Selecting patients who had no factors known to alter gentamicin Vd did not decrease the reported var iab i l i ty in gentamicin Vd, hence, the source of var iab i l i ty in gentamicin's Vd remains to be described and explained. 48 In this study we have reported a Vd for gentamicin in a highly selected group of patients, that is larger than is currently used to determine i n i t i a l dosage requirements. This larger Vd may be due either to, the method of gentamicin analysis, or the selection of patients, or a combination of the effects of both of these factors. It would be therapeutically advantageous to base i n i t i a l dosing regimens on this larger Vd. The support for this statement arises from two facts. F irst , there are more known factors that increase gentamicin Vd in hospitalized patients as compared to the number of factors known to decrease gentamicin Vd. Without being able to accurately estimate the changes in gentamicin Vd due to disease states, we wil l be able to achieve serum concentrations within the therapeutic range for the majority of patients by u t i l i z ing the larger Vd in our calculations of dosage requirements. Second, underdosing the patient, which may occur as a result of assuming a smaller Vd, may expose the patient to a greater risk of treatment fa i lure. In the minority of patients who would receive excessive doses using this larger volume, the use of serum level monitoring would minimize their risk of developing toxic i t ies associated with aminoglycoside therapy. RECOMMENDATIONS: The mean Vd for gentamicin described here, in this highly selected group of patients, is larger than is currently used to base empiric dosing recommendations. Therefore, in this patient population we should use this larger Vd and consequently larger doses in order to achieve therapeutic concentrations ear l ier in therapy. 49 To describe the var iab i l i ty in volumes due to al l causes one would need to conduct a controlled prospective t r i a l , calculating gentamicin Vd's in a large number of patients, using minimal selection c r i t e r i a . Patients with similar conditions could be categorized and s imi lar i t ies and differences between and within groups noted. 4.3 RELATIONSHIP BETWEEN GENTAMICIN VOLUME OF DISTRIBUTION AND PERCENT BODY FAT This study was designed to determine i f the relationship between gentamicin Vd and percent body fat is continuous, throughout the lean, normal weight, and obese population. It was demonstrated that estimates of LBM provide the best estimates of gentamicin Vd (L). However since these estimates are not practical in the c l in ica l setting estimates of IBW provide the next best estimate of gentamicin Vd (L). Measurements of percent body fat were not able to increase the accuracy of prediction of that relationship. Recruitment of an adequate sample size in this study was hindered by the selection processes. The s t r i c t selection c r i te r i a determined that the majority of patients receiving gentamicin were excluded. Of the patients screened, only 7% were e l ig ib le and half of those refused to participate. 50 The other d i f f i cu l t y encountered in attempting to determine the relationship between gentamicin Vd and percent body fat, was the inherent error associated with the measurement of obesity. Estimates of obesity by methods currently available al l incur some degree of error. Previous studies ut i l ized Geigy's sc ient i f i c tables (73) for a description of IBW. These values were based on weights at which mortality was lowest in adults who had bought l i f e insurance. Therefore, they are not necessarily representative of the entire population, nor ref lect a physiologic ideal body weight. Our methodology in assessing percent body fat also had errors associated with i t . When skinfold calipers or TBW measurements are used to estimate percent body fat an underlying assumption is that fat is a constant density. This has been disproven in recent cadaver studies (103). In addition skinfold caliper measurements suffer from several other d i f f i cu l t i e s . They are useful in assessing one individual over a period of time. However, when comparing individuals, several factors can decrease their usefulness. It has been demonstrated that individuals d i f fer with respect to: the compressibility of fat (103), skin thickness (103), internal to external adiposity ratios (103), adipose tissue composition and distribution (103), a l l which are assumed to be constant when using skinfold calipers to estimate percent body fat. INTERPRETATION: Investigators that have examined, and found a relationship between obesity and gentamicin Vd have defined obese as 51 being at least 30% over lean body weight. Schwartz and co-workers in 1978 (66) reported a volume of 0.185±0.027L/kg(ABW);n=6. Their obese patients were 30% over IBW as defined by Geigy's sc ient i f i c tables (73). In 1980 Korsager (67) found the volume in obese patients (50% over IBW as defined by Geigy's sc ient i f i c tables (73)) to be 0.177±0.028L/kg(ABW);n=17. The most recent study (1981) was conducted by Sketris et a l . (68). Their obese patients demonstrated a Vd=0.15±0.04L/kg(ABW);n=30. In their study obese was 30% above IBW as defined by Katch (74). They were a l l able to show a s ta t i s t i ca l l y significant difference between their normal weight and obese patients. Lean patients have also been shown to have an increased volume of distribution [L/kg(ABW)] compared to normal weight patients. Siber et a l . (70) f i r s t suggested that lean adults have larger calculated extracellular f lu id volumes. He also noted decreased peak concentrations in these individuals compared to the normal weight individuals they studied. Counts et a l . in 1982 (78) also found, when they based dosage requirements for lean patients (ABW-IBW=-35 to -lOKg) on a Vd=0.26L/kg, that they overpredicted peaks in 10/13 patients. The most recent findings (1987) reported by Tointoin were the results of a retrospective study. In their lean patients (ABW < IBW, as defined by Devine (80)), they reported a Vd=0.30±0.07L/kg(IBW) which was s ta t i s t i ca l l y different from the volume noted in their normal weight population. While i t was noted that IBW was the best predictor of gentamicin Vd, which indicates that body composition does influence 52 gentamicin Vd, we were not able to demonstrate that estimations of body composition improved the correlation between gentamicin Vd and IBW. There are several reasons that may be postulated as to why this relationship could not be detected in this study. F i r s t , the number of patients examined may not have been large enough to detect the relationship between percent body fat and gentamicin Vd. Second, we may not have been able to detect a relationship due to the low var iab i l i ty of percent body fat in our patient population. In this study obese was defined as any weight 10% above their IBW, and lean as any weight 10% below their IBW. The studies which have previously examined this relationship have used populations at greater extremes of weight. Martin et al.(103) have found that the fat content of adipose tissue varies depending on the quantity of adipose tissue. This may indicate that the relationship between ECFV and percent adiposity and thus, gentamicin Vd is not l inear but rather curvi l inear. If this were so, the relationship between gentamicin Vd and percent body fat may be only of importance in those patients at extremes of body weight, rather than those who are close to normality. Another reason we may not have been able to detect a relationship between percent body fat and gentamicin Vd may l i e in the characteristics of this particular patient population. The variation caused by changes in body composition were not as important, or as large, as other factors that cause f lu id alterations 53 in hospitalized patients. We attempted to exclude patients who would have abnormal f lu id distributions, however changes in volume of up to 10% may occur and not be c l i n i ca l l y detectable (104). Measurements of body compartments using radioactive tracers conducted since the 1950's have demonstrated a relationship between percent body fat and extracellular f lu id volume (105,106). The information obtained from studies which have examined the relationship between Vd and body weight, also indicate that the relationship between gentamicin Vd and percent body fat exists and is continuous (66-68,76-79). The results of this study suggest, that either the relationship between gentamicin Vd and percent body fat is not l inear, or our methodology of assessing leanness and obesity could not detect l inear i ty. This study also indicates that even i f one can detect a l inear relationship in healthy adult volunteers, there are many variables that alter gentamicin Vd in hospitalized patients. Thus, i t appears that leanness and obesity, except at extremes of weight are not important determinants of gentamicin Vd in hospitalized patients. RECOMMENDATIONS: When dosing patients empirically we should continue to use the correction factor suggested by Schwartz et al.(66). Although i t may not be c l i n i ca l l y important to include this factor until a patient is 30-40% above their IBW, for convenience and standardization i t would be useful to use this correction factor for al l patients whose ABW is greater than IBW. 54 For extremely lean patients a Vd for gentamicin has not been described. There are indications that i t is indeed larger, although i t has not been quantified. Until this information is available one should empirically dose gentamicin on the basis of IBW, since IBW has been demonstrated to correlate better with gentamicin Vd compared to ABW. Serum levels should be monitored promptly to ensure the therapeutic range has been obtained. The Vd in the lean patient remains to be described in patients with an absence of factors known to alter Vd. Presently, i t appears to be of greater c l in ica l importance to pursue the characterization of the var iab i l i ty of gentamicin Vd in hospitalized patients, for extrinsic variables, rather than weight. 4.4 CORRELATION BETWEEN ECFV AND GENTAMICIN VOLUME OF DISTRIBUTION It was the intention of this study to demonstrate a relationship between TBW and gentamicin Vd, in patients where the relationship between ECFV and TBW was normal and stable. This could then be used to reinforce conclusions previously made that gentamicin distributes into the ECFV (6,38,42,47). We were able to demonstrate a correlation between gentamicin volume of distribution and total body water (r=0.739;p<0.001). In this study TBW was measured. ECFV was assumed to be a constant proportion of TBW, and within normal l imits. Patients with 55 c l i n i c a l l y detectable variations in the ratio between ECFV and TBW were excluded. Since we did not measure both ECFV and TBW we cannot conclude that the ratio was normal and constant. Gyselynck et a l . (6) performed simultaneous measurements of ECFV (using inulin) and gentamicin Vd. They found there was no s ta t i s t i ca l l y significant difference between mean inulin and gentamicin volumes (n=10,T=0.745,p>0.3). A correlation coeff ic ient, calculated from their data was 0.146, which may indicate that in their patients ECFV was not predictive of gentamicin Vd. Siber et a l . (70) calculated ECFV for their adult patients based on equations established by Skrabal and co-workers (107). Siber et a l . (70) found the ECFV was inversely related to peak concentrations obtained after giving 17 patients a gentamicin dose of lmg/kg (r=-.74,p<0.05). Our results are similar to those reported in the above studies. INTERPRETATION: If gentamicin is distributed only into the ECFV, the theoretical correlation between gentamicin Vd and ECFV would be r=l. Only Gyselynck et a l . (6) have direct ly examined that relationship, and in order to confirm their results, i t is necessary to repeat the experiment. Siber's values (70) for ECFV may be subject to inaccuracies because they are calculated values. Our methodology assumes that the relationship between total body water and ECFV is normal, which we did not confirm in the patients studied. 56 Since the time that Gyselynck's ar t ic le (6) was published, there are reports in the l i terature which indicate that gentamicin may not only distribute freely within the ECFV, but may concentrate in tissues as the result of either an active transport mechanism (108), or pinocytosis (109). Gentamicin has been shown to concentrate in renal tissue (110,111) and in perilymph (112). Therefore, i t appears that although gentamicin may distribute primarily into the ECFV, a better understanding of i ts transport mechanisms would assist us in identifying and quantifying changes observed in disease states. RECOMMENDATIONS: Few guidelines exist to assist in the empiric dosing of acutely i l l patients, therefore i t is necessary to note when f lu id volumes have deviated from normal. In these patients, a best estimate of the deviated volume must be made on the basis of c l i n i ca l l y available information. This is especially important in patients who have expanded f lu id volumes, as underdosing of these patients may result in treatment fa i lure. The lack of our ab i l i ty to accurately estimate gentamicin Vd reinforces the need to monitor serum levels, to ensure they are maintained within the therapeutic range. The relationship between gentamicin Vd and ECFV remains to be quantified in patients with an absence of factors known to alter ECFV. In order to establish the relationship between gentamicin Vd and ECFV one would need to measure the ECFV d irect ly, this would avoid errors in assumptions made either through calculations of ECFV, 57 or measurements of total body water. This information would provide a baseline to which the effect of diseased states could be identi f ied, compared, and quantitated. 4.5 DEVELOPING A CLINICALLY APPLICABLE PREDICTIVE FORMULA It was the intention of this study to develop a formula for calculating gentamicin Vd, using c l i n i ca l l y available information, which would improve our ab i l i ty to estimate gentamicin Vd. This would enable c l in ic ians to prescribe doses which are more l ike ly to provide therapeutic concentrations within the f i r s t 24 hours of therapy. Multiple regression using a stepwise approach of gentamicin Vd with IBW, SCr, age, and sex provided the following predictive equation, Vd(L)=0.27(IBW)+2.5L. The predictive formula we have established is based on information obtained from a highly selected population which is not necessarily representative of the population who are usually prescribed gentamicin. INTERPRETATION: We have described a formula which wil l calculate a larger volume of distribution than is currently used to estimate empiric dosing regimens for gentamicin. Current recommendations estimate Vd as follows: Vd=0.25L/kg(ABW) (52). We have also described an intercept in our predictive formula, which has not previously been reported. 58 Through the elimination of factors known to alter ECFV we have described a predictive formula for patients that is similar to that reported for healthy adult volunteers. This may be due to the elimination of these factors, or to differences in assay methodology. It is thought that the intercept noted in this formula indicates the relationship between gentamicin Vd and weight is not l inear through al l ranges of weights. This is reinforced by the knowledge that in infants, ECFV consists of a larger proportion of their body weight (113,114). For example, in a 3 month old fetus, ECFV accounts for 65% of body weight (113). At term gestation, the percentage has decreased to 35-44% (113). At 12 months of age the ECFV comprises 26-30% of body weight (113). After the f i r s t year ECFV decreases slowly until adult values are attained at puberty (113). Thus the relationship between ECFV and body weight may not be l inear, as has previously been described, but rather curvi l inear. If this formula were used to estimate dosing requirements, in the "normal" patient, larger volumes would be calculated. Therefore larger doses would be administered. The resulting dosing regimens for gentamicin would allow more patients to obtain therapeutic serum levels within the f i r s t 24 hours. RECOMMENDATIONS: For this predictive formula to be c l i n i c a l l y useful i t would be important to simplify i t . To calculate dosing requirements in adult patients with no known factors which may alter Vd, Vd should be estimated as = 0.30L/kg(dosing weight). When ABW is 59 >IBW, the dosing weight should be calculated as follows: DW=0.40(ABW-IBW)+IBW (66). Presently, in cases where ABW < IBW, ABW is used as the dosing weight. This study has found that IBW is a better predictor of gentamicin Vd than ABW. This is in agreement with results reported by other authors (51,78). Therefore i t seems appropriate at this time to empirically dose lean patients based on IBW until their Vd can be described in a larger patient population. This would result in larger doses being administered, thus decreasing the r isk of underdosing this important sector of the hospitalized population. This predictive formula needs to be tested prospectively, in order to demonstrate that i t does provide better estimations of gentamicin Vd, in similarly selected patients. This formula wil l s t i l l not adequately estimate gentamicin Vd for the majority of hospitalized patients, therefore our efforts to describe and quantitate variations in volumes in gentamicin Vd should continue. 60 5.0 CONCLUSIONS 5.1 VOLUME OF DISTRIBUTION IN "NORMAL" PATIENTS We have described a Vd for gentamicin, in a highly selected group of patients, that is larger than is currently used to base empiric dosage regimens on. Since response to this antibiotic is related to serum concentrations of the drug, i t would be therapeutically advantageous to use this larger Vd to determine i n i t i a l dosing recommendations. 5.2 RELATIONSHIP BETWEEN GENTAMICIN Vd AND PERCENT BODY FAT This study could not detect a l inear relationship between gentamicin Vd and percent body fat. It is thought that this relationship may be curvi l inear, and as such i t may be an important variable in hospitalized patients who are at extremes of weight. Studies should be conducted to determine the Vd in extremely lean patients, as the volume changes in this population have not been quantified. 5.3 CORRELATION BETWEEN ECFV AND GENTAMICIN Vd A strong relationship between TBW and gentamicin Vd was noted. We excluded patients in whom ECFV could not be assumed to be a constant and normal fraction of TBW. Thus, indirectly we have demonstrated a strong relationship between gentamicin Vd and ECFV. 61 Although the relationship is strong, i t does not account for al l of the var iab i l i ty of gentamicin Vd. Therefore, a better understanding of gentamicin's distribution characteristics would allow us to better predict the Vd in "normal" and diseased patients. 5.4 DEVELOPMENT OF A CLINICALLY APPLICABLE PREDICTIVE FORMULA The data gathered on these patients suggest that the Vd for uncomplicated patients should be calculated as follows: Vd=0.30L/kg(Dosing Weight) Where dosing weight equals: IBW, when ABW < IBW, or 0.4(ABW-IBW)+IBW, when ABW > IBW. This predictive formula must be tested prospectively before one can conclude that i t provides better estimations of gentamicin Vd in similarly selected patients. There are several areas which s t i l l need to be explored. F i rs t , the relative association between gentamicin eff icacy, toxic ity and serum concentrations or AUC needs to be further c l a r i f i ed . Second, gentamicin's distribution characteristics have yet to be accurately described and quantitated. 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Equations for the prediction of normal values for exchangeable sodium, exchangeable potassium, extracellular f lu id volume and total body water. Br Med J 1973;2:37-38. 108. Kluwe WM, Hook JB. Analysis of gentamicin uptake by rat renal cortical s l ices. Toxicol Appl Pharmacol 1978;45:531-539. 109. Si lverblatt FJ, Kuehn C. Autoradiology of gentamicin uptake by the rat proximal tubule c e l l . Kidney Int 1979;15:335-345. 110. Edwards CQ, Smith CR, Baughman KL, Rogers JF. Concentrations of gentamicin and amikacin in human kidneys. Antimicrob Agents Chemo 1976;9:925-927. 111. Luft FC, Yum MN, Walker PD, Kleit SA. Gentamicin gradient patterns and morphologic changes in human kidneys. Nephron 1977;18:167-174. 112. Stupp H, Kupper K, Lagler F, Sous H, Quante M. Inner ear concentrations and ototoxicity of different antibiotics in local and systemic application. Audiology 1973;12:350-363. 113. Friis-Hansen B. Changes in body water compartments during growth. Acta Paediatr Scand 1957;46(Suppl 110):1-68. 114. Cheek DB. Extracellular f lu id volume: its structure and measurement and the influence of age and disease. J . Pediatr. 1961;58:103-125. 115. Prentice TC, S ir i W, Berlin NJ, et a l . Studies of total body water with tr it ium. J Clin Invest 1952;3:412-418. 71 7.0 APPENDICES 7.1 APPENDIX 1 - DATA COLLECTION FORMS 7.1.1 - DATA COLLECTION FORM - SCREENING PATIENTS NAT.E WARD KT WT IB; AGE D I A G N O S I S : PHYSICIAN 5 C R CRCL BUN S ALE HCE FLUID BALANCE URINE S.C. DOSE 72 7.1.2 DATA COLLECTION FORM - ENROLLED PATIENTS DATA COLLECTION FORM ? t . Kane ID Sex B t . Wt. SCREENING CRITERIA: AGE: [DIAGNOSIS: SURGERY: YES MO Xf•yes when FLUID BALANCE: , Intake/Output r a t i o Urine S p e c i f i c C r a v i t y Any i n d i c a t i o n s of f l u i d Imbalance i e edema, dehydration, overhydration,ascites v o m i t i n g , d i a r r h e a . TEMPERATURE: i e l e s s than 37.5C f o r the pact 24 hours. Yes No SCr CrCl Serum Albumin BUN Hemoglobin CONCOMM1TTENT MEDICATION 73 DATA COLLECTION FORM - PAGE 2 WEIGHT OF DRUG AND SYRINGE WEIGHT OF SYRINGE WEIGHT OF DRUG ADMINISTERED MG OF DRUG ADMINISTERED (44.35mg/ml) SKINFOLD CALIPER MEASUREMENTS: TRICEPS:  BICEPS:  SUBSCAPULAR SUPRAILEAC THIGH CALF GIRTH MEASUREMENTS TRICEPS  CHEST  ABDOMEN THIGH CALF DRUG ADMINISTRATION: START: „„„„ ADMINISTRATION TIME: STOP : RADIOACTIVE NUCLIDE ADMINISTRATION: Time: Nuclides Administered: BLOOD SAMPLING TIME HR PD LEVEL BRE- DOSE (1) POST DOSE (2) POST DOSE (3) POST DOSE (4) POST DOSE (5) URINE COLLECTIONS: TIME HR PD ML COUNTED SA PRF.DOSE (1) POST DOSE (2) POST DOSE (3) POST DOSE (ti) POST DOSE (5> TOTAL VOLUME COLLECTED 74 7.2 APPENDIX 2 - STANDARDIZATIONS A. GENTAMICIN SERUM LEVEL DETERMINATIONS 1. Calibration of Mettler PC 440 balance A Mettler PC 440 balance was used at St. Paul's Hospital to weigh syringes and thus determine the dose of gentamicin administered. This balance was calibrated using a set of pharmaceutical weights (Henry Troemner Inc.) and two other balances (Sartorus model AMP8-1). The recordings for the various weights are recorded below: Pharmaceutical Sartorius Sartorius Mettler Weight Set Balance Balance Balance 0.050 0.0501 0.0501 0.050 0.100 0.0997 0.0996 0.103 0.200 0.2006 - 0.2006 0.200 0.500 0.4986 0.4989 0.500 1.000 1.0031 1.0031 0.003 2.000 2.0021 2.0021 2.001 5.000 5.0038 5.0039 5.003 10.000 10.0106 10.0109 10.010 20.000 19.9970 19.9970 19.997 50.000 50.0156 50.0160 50.020 2. Gentamicin Serum Assay Serum samples were frozen at -20°C until assayed. A standard curve was constructed dai ly, based on six serum samples (0, 1, 2, 4, 8, and 16 mg/L) and one control (6mg/L). Day to day coefficients of variation for the hospital assay are 6.0% at 2.1mg/L and 3.6% at 6.32mg/L. 75 B. TRITIATED WATER MEASUREMENTS 1. Measurement of dose of t r i t i a ted water The dose of t r i t i a ted water was measure in a 1 cc tuberculin syringe. Prentice et a l . (115) determined gravimetricall ly the variation in the volume of water delivered by a tuberculin syringe and found the maximum error was 2%. 2. Calibration of automatic pipette (Clay Adams, Selectapette; lml volume) The pipette was tested at three increments (0.5, 0.9 and 1.0ml). At each increment i t was f i l l e d with d i s t i l l ed H2O ten times and the volume delivered weighed on a Sartorius balance (model AMp8-1). The results of those weighings are presented below: Pipette Setting Weights Mean Std Dev 0. 5ml 0. 9ml 1. 0ml 0. 4927 0. 9092 0. 9990 0. 5006 0. 9119 1. 0038 0. 4935 0. 9124 1. 0055 0. 4910 0. 9193 1. 0210 0. 4923 0. 9100 0. 9902 0. 4906 0. 9146 1. 0142 0. 4988 0. 9078 1. 0083 0. 4933 0. 9118 0. 9976 0. 4880 0. 9057 1. 0068 0. 4877 0. 9048 0. 9590 0. 4928 0. 9107 1. 0054 +0.004 +0.004 +0.017 3. Liquid Sc int i l lat ion Counting A Beckman LS 9800 l iquid sc int i l l a t ion counter was used to determine the act iv ity of the patients serum. Five serum samples were counted in t r ip l i ca te for each patient. Channel were set at 0 76 and 400 nanometers. Quench correction is computed automatically using a 1 3 7 C s source and an unquenched 3H sample. The quench l imits were 24 to 347. Al l samples fe l l within this range. Counting eff iciency ranged between 34 and 38%, the mean value was 35%. 77 APPENDIX 3 - INFORMED CONSENT GENTAMICIN - VOLUME O F DISTRIBUTION i n v e s t i g a t o r s ? Ms. M. Boyce S c . ( C l i n i c a l Pharmacy) c a n d i d a t e , U n i v e r s i t y o f B.C. D r . R. Ensom, F a c u l t y o f P h a r m a c e u t i c a l S c i e n c e s , U n i v e r s i t y o f B.C. Dr. R. R o s e n b e r g , Head o f C l i n i c a l C h e m i s t r y , S t . P a u l ' s H o s p i t a l Dr. A. B e l z b e r g , D i r e c t o r o f N u c l e a r M e d i c i n e , S t . P a u l ' s H o s p i t a l PURPOSE OF STUDY? To d e t e r m i n e t h e r e l a t i o n s h i p between t h e amount o f a n t i b i o t i c i n y o u r b l o o d s t r e a m and t h e amount o f body f a t you h ave. BENEFITS OF THE STUDY? The s t u d y w i l l i m p r o v e our f u t u r e a b i l i t y t o p r e d i c t t h e e x a c t dose o f t h i s a n t i b i o t i c t h a t p a t i e n t s w i l l need t o p r o d u c e t h e most b e n e f i c i a l e f f e c t . WHAT PROCEDURES WILL YOU HAVE TO UNDERGO? (1) N o r m a l l y when t h e s e d r u g s a r e used i n p a t i e n t s a t S t . P a u l ' s H o s p i t a l t h e amount t h a t a p p e a r s i n t h e b l o o d s t r e a m i s a l w a y s measured t o i n s u r e s a f e and e f f e c t i v e amounts a r e p r e s e n t . T h i s p r o c e d u r e i n v o l v e s t a k i n g a t l e a s t two b l o o d s a m p l e s (o r v e n e p u n c t u r e s ) . I n o r d e r t o i m p r o v e t h e a c c u r a c y o f o u r s t u d y two more v e n e p u n c t u r e s may need t o be t a k e n i n e x a c t l y t h e same manner. (2) We w i l l a l s o d e t e r m i n e y o u r h e i g h t and w e i g h t and, u s i n g s k i n f o l d c a l i p e r s , y o u r body f a t measurement w h i l e i n h o s p i t a l . (3) A n o t h e r method o f m e a s u r i n g body f a t w i l l a l s o be e m p l o y e d . T h i s i n v o l v e s d r i n k i n g a g l a s s o f t r i t i a t e d w a t e r ( r a d i o a c t i v e ) and h a v i n g t h e c o n c e n t r a t i o n i n t h e b l o o d measured a t some t i m e a f t e r w a r d s . The t r i t i a t e d w a t e r t e c h n i q u e has been u s e d f o r s e v e r a l y e a r s i n d i f f e r e n t h o s p i t a l s f o r v a r i o u s s t u d i e s . The r a d i o a c t i v i t y o f t h e w a t e r used i s 100 t i m e s weaker t h a n an X - r a y . T h e r e a r e no known h a r m f u l e f f e c t s a s s o c i a t e d w i t h t h i s t e c h n i q u e . One o f t h e b l o o d s a m p l e s t a k e n t o measure t h e amount o f d r u g i n t h e b l o o d s t r e a m w i l l a l s o be u s e d t o measure t h e t r i t i a t e d w a t e r c o n c e n t r a t i o n . HOW MUCH TIME I S REQUIRED? S k i n f o l d measurements a r e c o m p l e t e l y p a i n l e s s and w i l l t a k e a b o u t f i f t e e n m i n u t e s o f y o u r h o s p i t a l t i m e . 78 l«i MO« mmnt M C j K i i a i i i M w»a«T 30 p a t i e n t s t o t a l d i v i d e d i n t o 3 weight groups: — _ ~ J 1* 1 0 normal (• 20% o f i d e a l body weight) HP. -mn M ) . c t . T ( 2 ) j 0 e b e f e 2 £ ) % o y e r l d # a l ^ weight) i i ) 10 l e a n (< ? n * « M . r Kr>*y M » ? g n 12 ane M i n g r e e r u i t a f l ana anat arc tna e n tar (a f o r tna<r aa taction? The otudy p o p u l a t i o n w i l l c o n s i s t o f i n p a t i e n t s a t S t . P a u l ' s H o s p i t a l who • r e r e c e i v i n g gentamicin i n t r a v e n o u s l y and, (a) have reached a steady s t a t e blood l e v e l o f the drug i n the body, (b) are p o s o l o g i c a l l y and p h y s i o l o g i c a l l y s t a b l e w i t h r e s p e c t to f a c t o r s known to i n f l u e n c e aminoglycoside pharmacokinetics and (c) have pharmacokinetic data a v a i l a b l e from the Drug Measurement S e r v i c e a t S t . Paul's H o s p i t a l . 13 a n a t a u o j a e t i a i l l b a a » e i u o a o f r o * p a M i c i p a t i o n ? E x c l u s i o n s w i l l be an important p a r t of our s e l e c t i o n process and w i l l i n c l u d e those p a t i e n t s : (a) unable t o stand f o r heigh t , weight and s k i n f o l d t h i c k n e s s measures, (b) wi t h f a c t o r s known to a f f e c t the Vd of aminoglycoside a n t i b i o t i c s i n c l u d i n g (i) p a t h o l o g i c a l i n c r e a s e s i n body f l u i d such as edema, a s c i t e s , burns, e t c . ( i i ) compromised r e n a l f u n c t i o n with c r e a t i n i n e c l e a r a n c e l e s s than 70 mL/min. ( i i i ) c e r t a i n drugs (c) w i t h c o n d i t i o n s or treatments known to a f f e c t the accuracy of s e r a -c o n c e n t r a t i o n d e t e r m i n a t i o n s . n H O . » r « t r * a u e j a e t t O a i n g r a c r u ' t a o ' * ( I f i n i t i a l c o n t a c t <• Oy l a l t a ' o r i f a r a c r u < t a * " t n o i <ct i t t o p a p o t t o s , a t t a c n a c o p y ) NOTE t n a t use pet i c y p r o n i p i t t i n i t i a l c o n t a c t Oy t a i a p n o n a P a t i e n t s w i l l be i d e n t i f i e d as r e c e i v i n g gentamicin from the r e c o r d s of the Drug Measurement S e r v i c e , a t St. Paul's H o s p i t a l . The p a t i e n t w i l l then be approached by one of the c o - i n v e s t i g a t o r s i n person to d e s c r i b e the study and s o l i c i t p a r t i c i p a t i o n . IS I f r e r u n a r . i n v o w a s . a n a i f t n a . r a a ' a c t i o n a n a / o r r » e r u i t a » n t O l f f a r t f r o - t n a a o o v a . p r o . ' O . o a t * n o . Not a p p l i c a b l e . 81 gttCtt'TlPN Or tTWOPOLOCr t —PefBUQIS i t * l u a i r y o f e e t n o o e i o e y a n a p r o c e a u r e e . I n e i u o a o a t a i l a o f a n y a p e d n e • a n i s u i a t t o n a : t y r » Quantity t o rout* o f a o a i n f a t r a t f e n o f o r u g a o r r e f l a t i o n , o p e r a t i o n s , t o a t a : waa o f o e a i c e l o e v i c e t t n a t e r e . - o t o t y p e o r a t t o r o a f r a o t h o a a <n c l i n i c a l u a a : I n t e r v f a a a o r e p e a t l o n n e i r e i . P a t i e n t * r e c e i v i n g gentamicin f o r moderate t o severe i n f e c t i o n s are monitored by the Drug Measurement S e r v i c e a t S t . Paul's H o s p i t a l to assure t h e r a p e u t i c , non-toxic b l o o d l e v e l s . A standard p r o t o c o l i s fo l l o w e d . P a t i e n t s p e c i f i c pharmacokinetic i n f o r m a t i o n i s c a l c u l a t e d which w i l l be a v a i l a b l e f o r our study. P a t i e n t s w i l l be s e l e c t e d by e x c l u d i n g a l l those w i t h known f a c t o r s a f f e c t i n g Vd. Assessment o f percent body f a t w i l l be undertaken by anthropometric methods. Skin f o l d t h i c k n e s s w i l l be determined u s i n g s k i n f o l d t h i c k n e s s c a l i p e r s (Harpenden R). S i x anatomical s i t e s w i l l be measured (three measurements per s i t e ) and value s obtained w i l l be converted t o a percentage body f a t d e t e r m i n a t i o n u t i l i z i n g the a p p r o p r i a t e equations. Height and weight w i l l be determined by c o n v e n t i o n a l s c a l e s and measuring tape. Both measurements w i l l be undertaken by the experimenter, w i t h the p a t i e n t standing t o reduce p o t e n t i a l v a r i a t i o n i n r e s u l t s . A data c o l l e c t i o n form, w i l l be implemented to rec o r d a l l p e r t i n e n t i n f o r m a t i o n r e g a r d i n g p a t i e n t s h e i g h t , weight, percentage body f a t and pharmacokinetic v a r i a b l e s . 17 a n e r e a i l l t n a p r o j e c t b a c o n o u c t o a ( r o o o o r a r e a ) S t . P aul's H o s p i t a l ward area s . i t Who a l l I a c t u a l l y c o n d u c t t n a a t u o y ? Ms. X. lo/ce If I H I »*octpu»t> pcKt ia tP fsovt n t L I I H I D IS tHl E 2 5 fouotnws. ouitf. c x c » THI 4» » t a » « i * n |Q»<») #NC m> TO m a BI IEli W I I IHli l i I*K t>H. BSij TH{ o t i c i m i aapTQCOL *x owl £o»i SLIP 11 JBE a i t n e r a a a i o f b t a o o ^ a V I e s a a i n e t i o n o f a o a i c a l r e e o r o i a n a / o r r e c o r o e a O a t a Q u a a o f a e e c i a a n t a c q u i r e d n o n - i n v a i i v e l y a » o f a a t a r i a l a n o r e a l l y • l e c e r e e a Q t h e p r o j e c t t a a e o o i f i c a t l o r . o f t n a t a p p r o v e d u n d e r c l i n i c a l p r o t o c o l I 82 ' \ t M i <s known a b o u t t h e n e k » a n a M n t d t i o f t h e p r o p o t e a m u ' e M Oo y o u have e o o t t t e n e i g « m W l a n t h i * l e e u e T * » a l l p rocedures d e s c r i b e d ( e x c l u d i n g s k i n f o l d t h i c k n e s s determinat ions ) r e t y p i c a l o f the med i ca l management p a t i e n t s v i l l r e c e i v e when t r e a t e d f o r moderate t o severe g r a n - n e g a t i v e i n f e c t i o n s , no a d d i t i o n a l r i s k to the p a t i e n t w i l l be appa ren t . On ly p a t i e n t s who are o rde red gentamic in by t h e i r p h y s i c i a n w i l l be admi t ted t o the s tudy . The b e n e f i t of t h i s r e s e a r c h i s e x p l a i n e d i n s e c t i o n 16. 30 » n a t e o c o a t f O M * r i n c a p a c i t y e r e t h e e u c j e c t a l i k e l y t e e n o u ' * a * • r e s u l t e f t h e e a p e r i a e n t a i '. p r o c e e v r a o T P a t i e n t s who a r e t o r e c e i v e gen tamic in t y p i c a l l y undergo venepunctures to a s c e r t a i n serum l e v e l s o f the drug b e f o r e and a f t e r a d m i n i s t r a t i o n . < The expe r imen ta l p rocedures d e s c r i b e d w i l l not r e s u l t i n any a d d i t i o n a l d i s c o m f o r t o r i n c a p a c i t y . The d e t e r m i n a t i o n o f p e r c e n t body f a t u s ing s k i n f o l d c a l i p e r s i s not a s s o c i a t e d w i t h any d i s c o m f o r t o r i n c a p a c i t y . J i P r e v i a * O e t e H s o f any known t i e * e f f e c t s w h i c h e a r r e e u l t f r o * t h e u p t n a t n t t l t r e a t m e n t The a d m i n i s t r a t i o n o f gentamic in i n t r a v e n o u s l y i s a s s o c i a t e d w i th p o t e n t i a l s i d e e f f e c t s . However, f o r the purposes o f t h i s s tudy , a l l p a t i e n t s i n v o l v e d w i l l be r e c e i v i n g t h i s drug f o r i n d i c a t i o n s independent o f the study p r o t o c o l . 23 e n a t p r - o c e o w r e o i n t m a p r o j e c t i n v o l v e a n e * D « r i » * - \ t a i u o f H C f i i n t h a t t h e r e •*> De t r e a t m e n t o p t i o n s o i c t a t e e Dy t n e p r o t o c o l r a t n e r t h e n e r t r e a i e e n t - e f - c h o i c e a e c i e i o n * A l l p a t i e n t s admi t ted to the study w i l l undergo i d e n t i c a l procedures w i th r e s p e c t to venepunctures and s k i n f o l d t h i c k n e s s d e t e r m i n a t i o n s . No v a r i a t i o n i n t reatment o p t i o n s d i c t a t e d by p r o t o c o l w i l l o c c u r . 21 B"h*i p r e v i t i o n o e r e a e o e t c D r * e « t n e c o o * e f • O e v i O l e - D l i n o s t u O y T Who n e t t h e c e o * ? The study w i l l not be d o u b l e - b l i n d . » 4 t f e o n e t e r y c o n v e n a a t t o n te t e De o f f e r e e t n e e u t o j e c t e . p r o v t o e a e i e t l * o f a a o u n t s . a n a p e y a e n t : e c n e o u i e s . Ro monetary compensat ion w i l l be o f f e r e d to the s u b j e c t s . t t NO* ouch t 1 a * v i i i a e u e j e c t n e v e t e a e o i c a t e t e t n e p r o j e c t D e y e n a t h a t n e e a e a f a r t r a a t a e n t ? Sr»oetime a f t e r r e a c h i n g a s t a b l e c l i n i c a l c o n d i t i o n , s k i n f o l d t h i c k n e s s , jht and.weight measurements w i l l be taken f o r each s u b j e c t , r e q u i r i n g K H O V a u e n t i a e w i l l a n e r a e i v o l u n t e e r ( I f a n y ) h a v e t e o e e i c a t e t e t n e p r o j e c t ? •one. 83 j i T M C w i n h a v a o c c e s s t e t n e d a t a ? Only the i n v e s t i g a t o r s mentioned i n 11 and 12. 21 MOW « < " c o n f i d e n t l a ! i t y e f t h e d a t e be e a i n t e i n t e d 7 Ho B a n e s o r i d e n t i f y i n g numbers o f s u b j e c t s t r i l l be l i s t e d i n p u b l i c a t i o n s r e s u l t i n g f rom t h i s s tudy . I d e n t i f i c a t i o n o f s u b j e c t s w i l l be l i m i t e d on l y t o p r o f e s s i o n a l pe r sonne l d i r e c t l y i n v o l v e d i n the s tudy .  it Whet t w o t n e p l e n a f o r f u t u r e uae e f t h e o e t a ( P e y o n e t h a t d e s c r i b e e i n t h i s p r o t o c o l ) ? Ho p r e s e n t p l a n s e x i s t f o r the f u t u r e use o f the d a t a . )0 M i l l a n y o e t a w h i c h i d e n t i f i e s I n d i v i d u a l s be a v a i l a b l e t e p e r s o n s o r e g e n c i e s o u t « 1 0 * t h e U n i v e r s i t y ? No data w i l l s p e c i f i c a l l y i d e n t i f y i n d i v i d u a l s except t o h o s p i t a l a d m i s s i o n number. The i n f o r m a t i o n w i l l not be a v a i l a b l e to persons o r a g e n c i e s o u t s i d e the U n i v e r s i t y . I W OfCC C O N S C M ? 11 a n i l t h e g^euo o f S u b j e c t s have any p ' o e ' e n i g i v i n g m f c - e e o c o n t e n t a n t h e i r own o e n a i r ? C o n » . o « -p n y t i c a l o r a e n t a i e o n c i t i o n . a g * . l a n g u s p * . o r o t n e ' p e r n o r s A l l s u b j e c t s w i l l be capab le o f g i v i n g informed consent on t h e i r own b e h a l f . 1 I f t h e e u b j e c t s e r e no t c o m p * i * n t t o g . v * f u l l y i n f o r e e o c o n t e n t , who w i l l c o n t e n t e n t h e ' r b e n * 1 f ? Not a p p l i c a b l e . S J use e e l i c y r e o u i r e t » f t t u - c o n t e n t i n a n c a t a i P l e a t * c n e c . a a c n t t e e i n t h e f o l t e v i n g 1111 b e ' o r e • u M n n o r o f t h i t f o r e t o m i u ' t t h a t t n e w r i t t e n c o n t e n t f o r e e t t e c n e s c o n t a i n s a l l n e c e s s a r y i t e m 53 T ' " e o f p r o j e c t JJS l o e n t i f i c e t i o n o f i n v e s t i g a t o r s 3 d | n i ' p u t c o a c i e t * D e s c r i p t i o n I N L » ' laNGUAGC o f t h e p u r p o s e o f t n e e x p e n a e n i ana o f e n e * p * r i a * n t a i p r o c e o u r e s V\ S t e t e a e n t o f e n k n o . n a i d e e f f e c t s w i t h e n e s t i a e t e o f t h e p r o b a b i l i t y o f t h e i r o c c u r r e n c e ) Q a s s u r a n c e thet i d e n t i t y o f t h e e u b j e c t w i l l be k e p t e o n f i o e n t i a i o n e D e s c r i p t i o n o f n o . t h i s e m be e c c o a p i i e n e a o Q S t e t e n e n t o f t h e t o t a l e e e u n t o f t l a * t h e t e i l l De r e o u i r e d o f a s u b j e c t b e y o n e t ha t neeoea f o r t r e a t a e n t 99 D e t a i l s o f e o n e t e r y c o m p e n s a t i o n , i f a n y . t e be o f f e r e d t e s u b j e c t s 99 a n o f f e r t o answer any I n o u i r l t i c o n c e r n i n g t h e p r o c e o u r e s t e e n s u r e t h a t t h e y e r e f u l l y u n d e r s t o o d by t h e s u b j e c t a n u n a m b i g u o u s s t s t e w e n t t h e t t h e e u b j e c t a e y See 11ne t e e n t e r e r w i t h d r e w f ree t n e p a p e r l e a n t a t a n t T I M e i t h e w t any e o n s e o v e n c e t t o c o n t i n u i n g a a o i c a l c e r e 99 S i g n a t u r e e f e u b j e c t C O N S E M T I M C t e p a r t i c i p a t e I n t n e r e s e a r c h p r o j e c t . i n v e s t i g a t i o n o r s t u d y , a n a » C K N O « L I D C I M C r e c e i p t e f e c o p y e f t n e c o n t e n t f o r e i n c l u d i n g e n e t t e c n e e n t s * P 9 S i g n a t u r e o f a w i t n e s s 84 ar* aoewwrs 114 C n e c k K m a t t a c h e * t e t h i s e u o a i s t i o n i f a p p l i c a b l e ( I n c o w K t i l u M i n l o n i > i n n e t t » , „ „ „ 3 ] • l e t t e r e f i n i t i a l c o n t a c t ( i t e m 14) O a o v e r t n e e e n t f o r v o l u n t e e r s u b j e c t s d t e * H) 13 e u b j e c t c o n t e n t f o r e ( i t e a 1 1 ) • n o r o a i e u b j e c t c o n t e n t f o r * O f d i f f e r e n t f r o * a b o v e ) Q Q u e s t t o n n e m e t . t e s t e . I n t e r v i e w s . e t c • e t h e r , s p e c i f y MOT! TWA.T ATTACHMENTS SHOULD IC tEST»ICTED TO THE atOVE «OOITION«L SUTEt!*L eenvlDED (IncluOino o-„o coapeny protocols I VI LL BE ADDED TO THE FILE «UT VI LL Sfil •£ D1STSJPUTED TO THE »EVIEV COWWITTEt I S U s e t h i s s p e c * t o p r o v i o e i n o ' M i i e " v n i e r you ' e t i v t l l be n e i p f u l t o t n e r e v i e » c o w t u i i oc t : c o n t i n u e any i t e m f o r v m c n e u f ' t c i e n t s c s c t ne t a v a i l e d * 85 T H E U N I V E R S I T Y O F B R I T I S H C O L U M B I A 114t EAST MALL VANCOUVER. B.C.. CANADA V6T 1W5 FACULTY OF PHARMACEUTICAL SCIENCES MEMORANDUM C84-212 To: C l i n i c a l Screening Committee f o r Research and Other S t u d i e s I n v o l v i n g Human Sub j e c t s Froir,: Dr. Robin Ensom, P r i n c i p a l I n v e s t i g a t o r F a c u l t y of Pharmaceutical Sciences T i t l e : Gentamicin Volume of D i s t r i b u t i o n (Vd) Study - R e l a t i o n Between A c t u a l Vd and Percent Body Pat Number: C84-212 Date: Kay 13, 19B5 Dr. A. B e l z b e r g , D i r e c t o r of Nuclear Medicine at S t . P a u l ' s H o s p i t a l , w i l l be j o i n i n g our study as a C o - I n v e s t i g a t o r . In a d d i t i o n , the f o l l o w i n g changes i n t h i s study are submitted f o r e t h i c a l review by the C l i n i c a l Screening Committee: DESCRIPTION OF METHODOLOGY fc PROCEDURES 16. Summary of methodology and procedures . ( I n c l u s i o n ) T o t a l body water w i l l be determined by the t r i t i a t e d water d i l u t i o n method. From t h i s v a l u e body f a t can be d e r i v e d . The s u b j e c t w i l l have a b a s e l i n e blood sample, f o l l o w e d by the o r a l a d m i n i s t r a t i o n of 300 uC of t r i t i a t e d water and another blood sample approximately 2 hours l a t e r . Measurement of t r i t i u m a c t i v i t y i n serum w i l l be w i t h a s c i n t i l l a t i o n c ounter. 19. What i s known about the r i s k s and b e n e f i t s o f the proposed research? ( Inc lus ion) The sub jec t s w i l l r e c e i v e 300 uC of t r i t i a t e d water (3H-water) o r a l l y f o r the c a l c u l a t i o n of t o t a l body water con ten t . I t i s cons idered to be the t r a c e r of c h o i c e f o r 88 c a l c u l a t i o n of body water and was f i r B t de sc r i bed by Pace i n 1947. The average b i o l o g i c h a l f - l i f e o f the t r a c e r i s 11.5 days. The est imated r a d i a t i o n exposure i s 0.004 rads . A standard chest x - ray d e l i v e r s 0.4 rads . There are no known harmful e f f e c t s a s s o c i a t e d w i th t h i s techn ique . T h i s method i s expected to p rov ide an o b j e c t i v e means of c o r r o b o r a t i n g es t imates of body f a t determined by anthropometr ic measurements. 20. What d i scomfor t or i n c a p a c i t y are the sub jec t s l i k e l y to endure as a r e s u l t of the exper imenta l procedures? ( Inc lus ion) The t r i t i a t e d water d i l u t i o n method i s not expected to r e s u l t i n any d i scomfor t to the s u b j e c t s . Blood samples f o r measuring t r i t i u m a c t i v i t y are expected to be taken at the same t i n e that b lood i s drawn f o r gentamic in concen t r a t i on measurements. INFORMED CONSENT A r e v i s e d subjec t consent form i s a t t ached . 89 THE UNIVERSITY OF BRITISH COLUMBIA t l M HEALTH SCIENCES MALL V A N C O U V E R . B.C.. C A N A D A V6T 1W5 FACULTY OF PHARMACEUTICAL SCIENCES MEMORANDUM C 8 4 - 2 1 2 T O : C l i n i c a l S c r e e n i n g C o m m i t t e e f o r R e s e a r c h a n d O t h e r S t u d i e s I n v o l v i n g Human S u b j e c t s F R O M : D r . R o b i n E n s o m , P r i n c i p a l I n v e s t i g a t o r F a c u l t y o f P h a r m a c e u t i c a l S c i e n c e s T I T L E : G e n t a m i c i n V o l u m e o f D i s t r i b u t i o n ( V d ) S t u d y - R e l a t i o n B e t w e e n A c t u a l Vd a n d P e r c e n t B o d y F a t N U M B E R : C 8 4 - 2 1 2 D A T E : J u l y 2 1 / 8 6 T h e f o l l o w i n g c h a n g e s i n t h i s s t u d y a r e s u b m i t t e d f o r e t h i c a l r e v i e w b y t h e C l i n i c a l S c r e e n i n g C o m m i t t e e : DESCRIPTION OF METHODOLOGY AND PROCEDURES 1 7 . S u m m a r y o f m e t h o d o l o g y a n d p r o c e d u r e s . ( I n c l u s i o n ) T o t a l b o d y w a t e r a n d e x t r a c e l l u l a r f l u i d v o l u m e w i l l b e m e a s u r e d s i m u l t a n e o u s l y . T h e t o t a l b o d y w a t e r w i l l b e d e t e r m i n e d b y t h e t r i t i a t e d w a t e r d i l u t i o n m e t h o d . E x t r a c e l l u l a r f l u i d v o l u m e w i l l b e d e t e r m i n e d u s i n g a m e t h o d d e s c r i b e d by M o o r e i n 1 9 5 6 . T o t a l b o d y w a t e r m e a s u r e m e n t s w i 1 1 be u s e d t o c a l c u l a t e p e r c e n t a d i p o s i t y . E x t r a c e l l u l a r f l u i d v o l u m e i s a m e a s u r e o f Vd f o r g e n t a m i c i n . T h e b l o o d s a m p l e c u r r e n t l y u s e d f o r t h e a e n t a m i c i n t r o u g h l e v e l w i l l a l s o b e u s e d t o d e t e r m i n e t h e b a c k g r o u n d r a d i a t i o n f o r t h e t r i t i a t e d w a t e r a n d b r o m i n e m e a s u r e m e n t s . T h e t r i t i a t e d w a t e r a n d b r o m i n e w i l l b e g i v e n o r a l l y i n d o s e s o f 3 0 0 u C i a n d 2 5 u C i r e s p e c t i v e l y . T h e s e r u m b l o o d s a m p l e s d r a w n a f t e r t h e d o s e o f g e n t a m i c i n w i l l a l s o b e u s e d t o d o p l a s m a t r i t u m a n d b r o m i n e c o u n t s . S i m u l t a n e o u s u r i n e s a m p l e s w i l l be u s e d t o d e t e r m i n e t h e a m o u n t o f t r i t i u m a n d b r o m i n e e x c r e t e d 1n t h e u r i n e . A 2 4 h o u r u r i n e c o l l e c t i o n w i l l b e c a r r i e d o u t from t h e t i m e t h e t r i t i u m a n d b r o m i n e i s a d m i n i s t e r e d . A t t h e e n d of t h i s 24 h o u r p e r i o d a f i n a l b l o o d s a m p l e w i l l b e d r a w n t o d e t e r m i n e t h e t r i t i u m a n d b r o m i n e c o u n t s . M e a s u r e m e n t o f t h e t r i t i u m a n d b r o m i n e a c t i v i t y i n s e r u m w i l l b e w i t h a s c i n t i l l a t i o n c o u n t e r . 91 20. What i s known about the r i s k s and b e n e f i t s of the proposed research? ( I n c l u s i o n ) The subject s w i l l r e c e i v e 300uCi of t r i t i a t e d water (3H-water) o r a l l y f o r the c a l c u l a t i o n of t o t a l body water con ten t . It i s cons idered to be the t r a c e r of cho ice f o r the c a l c u l a t i o n of body water and was f i r s t de sc r i bed by Pace in 1947. The average b i o l o g i c h a l f l i f e of the t r a c e r i s 11.5 days. The est imated r a d i a t i o n exposure is 0.004 rads . 82-Bromine (25uci) w i l l be admin i s tered o r a l l y f o r the determinat ion of e x t r a c e l l u l a r f l u i d volume. The b i o l o g i c h a l f - l i f e of t h i s t r a c e r i s 36 hours. The est imated r a d i a t i o n exposure from t h i s t r a c e r i s .030 rads . There fore the t o t a l r a d i a t i o n exposure is .034 rads . A standard chest x - ray d e l i v e r s 0.4 rads . There are no known harmful e f f e c t s a s soc i a ted with t h i s techn ique . These methods w i l l prov ide us with o b j e c t i v e measurements of percent a d i p o s i t y and volume of d i s t r i b u t i o n of gentamic in . 21. What d i scomfor t or i n c a p a c i t y are the subject s l i k e l y to endure as a r e s u l t of the experimental procedures? ( I n c l u s i on ) The measurement ot t o t a l body water and e x t r a c e l l u l a r f l u i d volume should not r e s u l t in any d i scomfor t to the s u b j e c t s . One extra blood sample w i l l be drawn 24 hours a f t e r the t r a c e r s are admin i s te red . I n f o r m e d C o n s e n t A rev i sed informed consent form is a t tached . 92 

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