Effects of a 250-mL Enema Containing Sodium Phosphate on ... · principles of the Declaration of Helsinki 11 and the Guidelines for ... occurred in a serum electrolyte concentration

VOLUME 67, NUMBER 5, SEPTEMBER/OCTOBER 2006

Effects of a 250-mL Enema Containing Sodium Phosphate on Electrolyte Concentrations in Healthy Volunteers: An Open-Label, Randomized, Controlled, Two-Period, Crossover Clinical Trial Bel~n S~daba, MD, PhD1; Jos~ R. Azanza, MD, PhD1; Miguel A. Campanero, PharmD1; Emilio Garcfa-Quetglas, MD, PhD1; Maria Jos~ Mufioz, PhD1; and Santiago Marco, PhD 2

7 Clinical Pharmacology Service, University Hospital of Navarra, School of Medicine, Pamplona, Spain; and 2Laboratorios Casen Fleet S.L., Zaragoza, Spain

ABSTRACT Background: Enemas are used by indiv iduals wi th const ipat ion and are of-

ten required before certain medical diagnostic procedures and surgical interven- t ions. However, abnormal i t ies in serum electrolyte concentrat ions have been associated wi th enema use.

Objective: The aim of this study was to determine the changes in serum electrolyte concentrations (phosphorus, calcium, sodium, and potassium) and urinary phosphorus elimination after the administration of a sodium phosphate enema.

Methods: Healthy volunteers aged 35 to 70 years were eligible for this open- label, randomized, controlled, 2-period, crossover clinical trial at the Clinical Research Unit of the University Hospital of Navarra, Pamplona, Spain. The s tudy comprised 2 one-day periods separated by a 7-day washout. All subjects were randomly assigned in a 1:1 ratio to 1 of 2 study sequences: (1) a single dose of Enema Casen ® 250 mL in the first period followed by no treatment (control) in the second period, or (2) no treatment in the first period followed by a single dose of the study drug in the second period. The sequence of treatment was assigned using a randomization table that was prepared before the beginning of the study. Serum concentrations of phosphorus, sodium, potassium, and calcium were measured in both periods. Urinary phosphorus elimination was measured for 12 hours after enema administration (Ae0_12) in a subset of the subjects in the second period. Adverse events (AEs) were monitored by the investigators throughout the study. Normal ranges for the electrolytes were as follows: phosphorus, 2.5 to 5 mg/dL; calcium, 8.5 to 10.5 mg/dL; sodium, 135 to 145 mEq/L; and potassium, 3.5 to 5 mEq/L.

Results: Twenty-four subjects (12 men, 12 women; mean [SD] age, 47.8 [9.6] years [range, 36-68 years]) participated in the study. All of the subjects

This study was presented in part as an abstract at the XIXth Spanish Clinical Pharmacology Society (Sociedad Espa~ola de Farmacologfa Clfnica-SEFC), October 27-30, 2004, Santander, Spain. Accepted for publication August 1 I, 2006. doi:l 0.1016/j.curtheres.2006.10.004 Reproduction in whole or part is not permitted. 0011-393X/06/$19.00

334 Copyright © 2006 Excerpta Medica, Inc.

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were white and none were smokers . Twelve hours after enema administrat ion, mean se rum p h o s p h o r u s and sodium concen t ra t ions increased by a mean of 1.18 mg/dL and 1.32 mEq/L, respec t ive ly (both, P < 0.001). Mean se rum phosphorus concen t ra t ions were above the upper limit of normal (5 mg/dL) at 30 and 60 minutes after enema administrat ion. In all subjects the values re turned to normal within 4 hours after enema administrat ion; a meal was provided after a 3-hour fast. Four subjects (16.7%) had >1 se rum p h o s p h o r u s concen t ra t ion me a su re me n t >7 mg/dL, a value that is cons ide red ser ious hype rphospha temia . A stat ist ically significant corre la t ion was found be tween p h o s p h o r u s Cm~ x and enema re tent ion t ime (r 2 = 0.452; P < 0.001). No abnormal se rum concen t ra t ions were obta ined for the o ther e lec t rolytes measured. P h o sp h o ru s Ae0_12 was increased after enema adminis t ra t ion by 86% (P < 0.001). No ser ious AEs were observed , a l though 13 AEs were r epor t ed in 9 subjects . None of the changes in se rum elect rolyte concen t ra t ions were assoc ia ted with clinical symptoms .

C o n c l u s i o n s : Administrat ion of an enema containing 250 mL of sodium phospha t e was assoc ia ted with se rum p h o s p h o r u s concen t ra t ions of >7 mg/dL in 16.7% of the hea l thy subjects who par t ic ipa ted in the study; however, none of those subjects exper ienced hypocalcemia . Enema re tent ion t ime was significant ly cor re la ted with the degree of phosphatemia . (Curr Ther Res Clin Exp. 2006;67:334-349) Copyright © 2006 Excerpta Medica, Inc.

Key words: phosphatemia , e lectrolyte modifications, sodium phospha te enema, phosphatur ia , absorpt ion.

INTRODUCTION Const ipat ion is a c o m m o n condi t ion in the general popula t ion and occurs with a par t icular ly high preva lence in e lder ly patients. 1 Up to 30% of hea l thy elder ly individuals need chronic t r ea tmen t with laxatives, and even then they might require the use of evacuat ing solut ions because of fecal impaction. Evacuating solut ions must also be adminis tered before many diagnostic s tudies and surgical in tervent ions . Therefore , these solut ions are widely used both at home and in medical centers .

Generally, evacuat ing solut ions do not contain p roduc t s tha t have sys temic pharmacolog ic effects; their mechan ism of action is based on water diffusion to the intestinal lumen by osmosis . When a saline solut ion is administered, the sodium concen t ra t ion in the intestinal lumen increases, result ing in an increase in fluids in the intestinal lumen and the de t ach m en t of fecal materials from the colonic mucosa. Moreover, the monosod ium and disodium salts of o r thophos - phor ic acid increase peristalsis by stimulating ne rve endings, result ing in the total elimination of stools. 2

Enema Casen ® (Labora tor ios Casen Fleet S.L., Zaragoza, Spain) is an enema that contains 16 g of monobas ic sodium pho sp h a t e m o n o h y d r a t e and 3.7 g of sodium per 100 mL of solution. Rectal adminis t ra t ion of the solut ion has been assoc ia ted with adverse events (AEs) after a single administrat ion, such as

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CURRENT THERAPEUTIC RESEARCH

hype rphospha temia , hypocalcemia , and hyperna t remia , general ly in pat ients with impaired renal function, hemolysis , t umor lysis syndrome, or chronic use of p h o s p h o r u s supplements . 3

There is little information in the l i terature (MEDLINE search wi thout year or language restr ict ion; key terms: e n e m a AND hyperphosphatemia or e n e m a AND electrolyte) about changes in se rum electrolyte concen t ra t ions after the use of sodium phospha t e enemas. In a double-blind s t u d y 4 compar ing a sodium phospha te enema (n = 22) with a water enema (n = 20) and a po lye thy lene glycol e lec t rolyte lavage solut ion (n = 24), a significant increase in se rum p h o s p h o r u s concen t ra t ion was obse rved in the sodium phospha t e enema group compared with the o ther 2 groups, wi thout changes in o ther e lect rolyte concen t ra t ions (P < 0.001). Serum p h o s p h o r u s concen t ra t ions after adminis t ra t ion of the sodium phospha t e enema remained within the normal range in all but 1 patient . The pat ient se rum p h o s p h o r u s after enema adminis t ra t ion was 5.8 mg/dL. In an observa t iona l p rospec t ive s t udy 5 33% of pat ients (5/15) had se rum p h o s p h o r u s concen t ra t ions that exceeded the upper limit of normal (ULN). Some o ther s tudies 6-1° have d iscussed impor tan t changes in e lectrolyte concent ra t ions after the adminis t ra t ion of different oral sodium phospha t e preparat ions; however, due to the oral me thod of administrat ion, their results cannot be ex t rapola ted to enema administrat ion.

The small amounts of data available regarding p h o s p h o r u s pharmacokinet - ics after rectal adminis t ra t ion of phospha t e enemas are controversial ; some data show p h o s p h o r u s modification, while o thers do not. There are also few da ta on the impact of p h o s p h o r u s on o ther e lec t ro ly te concen t ra t ions . Therefore , this was the first s tudy designed to de te rmine the changes in se rum p h o s p h o r u s concen t ra t ions after the adminis t ra t ion of 250 mL of an enema containing sodium phospha te . As a s e c o n d a r y end point, var ia t ions in sodium, potass ium, and calcium were de termined, along with ur inary p h o s p h o r u s elimination for 12 hour s (Ae0_12) af ter enema adminis t ra t ion or t ime 0. In addit ion, the influence of other factors (age,creatinine clearance, and enema retention time) on changes in e lect rolyte concen t ra t ions were assessed.

SUBJECTS AND METHODS This open-label, randomized, control led, 2-period, c rossover clinical trial was carr ied out in the Clinical Research Unit of the University Hospital of Navarra, Pamplona, Spain. The s tudy pro tocol was approved by the Clinical Research Ethics Commit tee of Navarra and the Spanish Agency of Medicines and Heal thcare Produc ts in 2004. The s tudy was carr ied out in conformi ty with the principles of the Declarat ion of Helsinki 11 and the Guidelines for Good Clinical Practice. 12

The individuals who were asked to vo lun teer for this s tudy were existing pat ients included in a da tabase at our research unit. The subjects were paid for their part icipat ion.

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Individuals were eligible for the s tudy if they were aged 35 to 70 years , had a body mass index ranging from 20 to 28 kg/m 2, were nonsmoker s or smoked <10 cigaret tes a day, had nei ther organic nor psychia t r ic illness, and were able to follow instruct ions. Each vo lun teer p rovided a medical h i s to ry and under- went a physical examination, e l ec t roca rd iography (ECG), and analytical test ing (hematology, clinical chemistry, urine analysis, se rum hepat i t is B surface anti- gen, hepat i t is C antibody, and human immunodef ic iency ant ibody) pr ior to par- t icipation in the study. All subjec ts provided wri t ten informed consen t before initiation of the study.

The s tudy compr i sed 2 periods. Patients were randomly assigned in a 1:1 ratio to one of two 1-day s tudy sequences : (1) a single dose of Enema Casen 250 mL in the first period followed by no t reatment (control) in the second period, or (2) no t reatment in the first period followed by a single dose of the s tudy drug in the s e c o n d per iod . The s e q u e n c e of t r e a t m e n t was ass igned using a ran- domizat ion table tha t was p repared before the beginning of the study. A 7-day washou t was es tabl ished be tween periods.

In bo th per iods of the study, b lood samples were ex t rac ted before and 10, 20, 30, 40, and 60 minutes, and 2, 4, 6, and 12 hours after enema adminis t ra t ion or t ime 0 (ie, the s ta r t t ime of the control period) . Subjects were asked to retain the e ne m a for as long as possible . Subjects fas ted for 3 hour s af ter en em a administrat ion or t ime 0.

Urine was co l lec ted dur ing the following intervals : 0 to 90 minutes ; 90 min- u tes to 3 hours ; 3 to 7 hours ; and 7 to 12 hour s af ter e n e m a admin is t ra t ion or t ime 0.

Normal ranges for the electrolytes were as follows: phosphorus , 2.5 to 5 mg/dL; calcium, 8.5 to 10.5 mg/dL; sodium, 135 to 145 mEq/L; and potassium, 3.5 to 5 mEq/L. Serum calcium and p h o s p h o r u s concen t ra t ions were measu red using a color imetr ic procedure . 13,14 Calcium concen t ra t ions were de te rmined using the reagent a rsenazo III (SPINREACT, S.A. Sant Esteve D'en Bas, Gerona, Spain) in a neutral environment , and p h o s p h o r u s concen t ra t ions were de te rmined in an acidic env i ronment using ammonium molybdate . Urine samples were acidi- fied with 10% hydroch lor ic acid. These analyses were carr ied out in an auto- matic analyzer (Vitalab Viva, Dade Behring, Spankeren, The Nether lands) . Serum potass ium and sodium concen t ra t ions were measured using a select ive e lec t rode by potent iometry . These assay p rocedu re s were carr ied out in the LX-20 and CX3 automat ic analyzers (Beckman Coulter, Fullerton, California). For all analyses, the technician responsib le was bl inded to the per iod of the s tudy during which the samples were obtained.

A n u m b e r of p a r a m e t e r s were ca lcu la ted for the e l ec t ro ly tes ( p h o s p h o r u s , calcium, sodium, and po tass ium) . Cma x was d e t e r m i n e d when an increase o c c u r r e d in a s e rum e lec t ro ly te c o n c e n t r a t i o n after e n e m a admin is t ra t ion or t ime 0. Cmh ~ was d e t e r m i n e d when a d e c r e a s e o c c u r r e d in a s e ru m e lec t ro ly te c o n c e n t r a t i o n after admin i s t ra t ion of the so lu t ion or t ime 0. Both Tm~ and Tmh ~ were d e t e r m i n e d d i rec t ly from the data. In t hose cases in which the

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s a m e va lues of Cma x or Cmh ~ were o b s e r v e d m o r e t han once , the first occur - r ence of the va lue was to be u sed for a s s e s s m e n t . The s e r u m AUC was calcu- la ted us ing the t r a p e z o i d a l m e t h o d f rom e n e m a a d m i n i s t r a t i o n or t ime 0 to t ime t (AUCo_t), w h e r e t c o r r e s p o n d e d to each of the s ampl ing t imes. The to ta l AUC (AUC0_12) was m e a s u r e d until 12 h o u r s af ter admin i s t r a t i on or t ime 0. The a c c u m u l a t e d p h o s p h o r u s quan t i t y in ur ine (Ae0_t) was d e t e r m i n e d f rom t ime 0 to t ime t. Ae0_12 was a lso m e a s u r e d .

In bo th s t u d y per iods , sit t ing b lood p re s su re and hear t ra te were r eco rded at base l ine and at 30 minutes and 4 and 12 hours . At least 24 hour s after the second period, each vo lun tee r u n d e r w e n t a final examinat ion, which included a phys ica l examinat ion , ECG, and b lood and urine analyses .

All AEs, bo th those r epo r t ed by the sub jec t s and those o b s e r v e d by the inves t igators , were recorded . Signs of AEs were mon i to red con t inuous ly by the inves t igators . According to s t u d y protocol , any sub jec t who had abno rma l b lood p res su re (systol ic b lood p res su re >140 m m Hg or diastolic b lood p res su re >90 m m Hg) or hea r t ra te (>100 bpm) m e a s u r e m e n t s or a ca rd iovascu la r AE was to undergo ECG immediately. The re la t ionship of AEs to s t u d y t r e a t m e n t was a s s e s s e d as "not re lated" or "unlikely, .... possibly, .... probably," or "definitely" re la ted using the Karch-Lasagna modif ied criteria. 15

Statistical Analysis Based on a s t u d y 16 of a popula t ion similar to our sub jec t s (mean age, 47 years ;

bo th sexes with creat inine c lea rance >70 mL/min), in w h o m the mean basel ine s e r u m p h o s p h o r u s concen t ra t ion was 3.56 (0.51) mg/dL, it would be n e c e s s a r y to include a min imum of 20 sub jec t s to de tec t a difference of 15% in s e r u m phospha t e concen t r a t ion at an c¢ level of 0.05 and a 1~ level of 0.90. The var iabi l i ty of base l ine da ta for calcium, sodium, and p o t a s s i u m was <15%16; therefore , the power of the analysis was higher than 90%.

AUC0_12 , AUC0_t, Cmax, Cmin, and the concen t ra t ion at each t ime t of each elec- t rolyte were ana lyzed in relat ion to t r e a t m e n t using the t tes t for paired sam- pies. P h o s p h o r u s Aeo_12 values were also c o m p a r e d using the t tes t for inde- p e n d e n t samples , as this informat ion was ob ta ined only in the s e c o n d per iod of the s t u d y in s o m e subjec ts .

By m e a n s of l inear least s qua re s regress ion analysis, the poss ib le relat ion of e n e m a re tent ion time, age, and creat inine c lea rance with the AUCo_12 of each e lec t ro ly te and with the Aeo_ t of p h o s p h o r u s were explored.

The re la t ionship be tween t r e a t m e n t and h igher - than-normal s e r u m electrolyte concen t r a t i ons was a s s e s s e d using the Z 2 test.

After check ing the cond i t i ons of app l i ca t ion of the t e s t s (ie, d i f fe rences in h o m o g e n e i t y for pa i red t t e s t or v a r i a n c e in h o m o g e n e i t y for ana lys i s of vari- ance) , o t h e r quan t i t a t i ve da t a o b t a i n e d f rom the ana ly t ica l t e s t s and mea- s u r e m e n t s of b lood p r e s s u r e and h e a r t ra te we re ana lyzed us ing the t t e s t for m a t c h e d da ta or ana lys i s of va r i ance . P < 0.05 was c o n s i d e r e d s t a t i s t i ca l ly s ignif icant .

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RESULTS Twenty-four sub jec t s (12 men and 12 women; mean [SD] age, 47.8 [9.6] yea r s [range, 36-68 years ] ) were included in the s t u d y (Table I). All of the sub jec t s were whi te and were nonsmoke r s . Twelve sub jec t s were admin i s t e red the e n e m a in the first per iod, with the o the r 12 act ing as a control; the 12 control sub jec t s from the first per iod were admin i s t e red the e n e m a in the s econd period.

Tab le II shows a significant increase in the mean Cm~ for p h o s p h o r u s and sod ium (both, P < 0.001), and a significant dec rea se in the mean Cm~ n for po tas - s ium (P = 0.020) after e n e m a admin is t ra t ion c o m p a r e d with the un t rea ted per iod. The dec r ea s e in mean s e r u m calc ium concen t ra t ion was not significant. In t hose cases in which the s a m e va lues of Cm~ and Cm~ n were o b s e r v e d more than once, the first o c c u r r e n c e of the value was to be used for a s se s smen t . This occu r r ed more f requent ly in sub jec t s during the un t rea ted per iod than dur ing the t r e a t m e n t per iod. The value o b s e r v e d under base l ine condi t ions was not found to be the m a x i m u m or min imum mean value in any of our cases .

All of the s e r u m p h o s p h o r u s concen t r a t i ons were significantly higher in the sub jec t s who rece ived e n e m a s than in the un t rea ted subjec ts , excep t at t ime 0 and 6 and 12 hours . Therefore , the s e r u m p h o s p h o r u s concen t ra t ions were similar at the beginning of bo th pe r iods of the s t u d y and were inc reased for up to 4 hours after e n e m a admin is t ra t ion (Figure 1). The mean increase in s e r u m p h o s p h o r u s concen t r a t ion after e n e m a admin is t ra t ion was 1.18 mg/dL.

Table I. Baseline demographic and clinical characteristics of healthy volunteers (N = 24).

Characteristic Value

Age, y Mean (SD) 47.8 (9.6) Range 36-68

Weight, kg Mean (SD) 70.4 (13) Range 53-98.5

Height, cm Mean (SD) 168.4 (9.6) Range 155-188

BMI, kg/m 2 Mean (SD) 24.7 (2.6) Range 20.2-27.9

CICr, mL/min Mean (SD) 92.8 (22.2) Range 59.2-131.2

BMI = body mass index; ClCr = creatinine clearance.

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Table II. Pharmacokinetic parameters for serum concentrations of phosphorus, sodium, potassium, and calcium and for urinary phosphorus elimination in subjects administered Enema Casen ® 250 mL and those not treated (N = 24).

Pharmacokinetic Treatment No Treatment Parameter Period Period P*

Serum phosphorus C . . . . mg/dL

Mean (SD) 5.6 (1.3) 3.7 (0.5) <0.001 Range 3.6-8.5 2.7-4.6

Tmax, h 0.3 0.3 NS Range 0-2.0 0.17-2.0

AUC0_12 , mg/dL, h Mean (SD) 48.9 (6.7) 42.4 (4.9) <0.001 Range 34.4-63.4 31.8-50.3

Serum sodium C . . . . mEq/L

Mean (SD) 141.4 (1.7) 140.2 (1.4) <0.001 Range 138.8-146.4 137.2-143.3

Tmax, h 0.6 0.6 NS Range 0.1 7-2.0 0.17-2.0

AUC0_12 , mg/dL, h Mean (SD) 1682.5 (1 7.9) 1673.5 (16.0) 0.002 Range 1655.2-1 738.2 1638.4-1 710.0

Serum potassium Cmin, mEq/L

Mean (SD) 3.7 (0.8) 3.9 (0.9) 0.02 Range 3.64.4 3.5-4.5

Tmin, h 0.7 0.7 NS Range 0-2.0 0.2-2.0

AUC0_12 , mg/dL, h Mean (SD) 47.2 (2.1) 48.1 (2.6) 0.049 Range 43.8-51.9 43.1-52.8

Serum calcium Cmin, mg/dL

Mean (SD) 8.8 (0.3) 8.7 (0.4) NS Range 8.3-9.4 7.4-9.2

Tmin, h 0.7 0.5 NS Range 0.3-2.0 0.2-2.0

AUC0_12 , mg/dL, h Mean (SD) 108.7 (3.2) 110.1 (3.7) 0.023 Range 104.1-114.8 105.0-119.3

Urine phosphorus t Aeo_12 , mg

Mean (SD) 621.04 (151.6) 334.4 (75.1) <0.001 Range 333.7-815.3 212.1-402.2

AUC012 = serum concentration between 0 and 12 hours; Ae 012 = accumulated quantity of phosphorus in urine between 0 and 12 hours. *Treatment period versus untreated period. tData were available for only 9 subjects during the treatment sequence and 9 during the untreated sequence of the second period.

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Figure 1.

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Mean (SE) serum phosphorus concent ra t ions a f ter the admin i s t ra t i on of Enema Casen ® 250 mL and w i t h no t r ea tmen t . Solid lines ind icate the serum phosphorus normal range. *P < 0.001 versus no t rea tmen t ; tp = 0.004 versus no t r ea tmen t .

As a result of the se rum p h o s p h o r u s data obta ined during the first per iod of the study, urine samples were obta ined from 18 subjec ts during the second per iod (9 per s tudy sequence) . This was a modification of the initial p ro tocol and required the approval of the ethics commit tee .

Serum p h o s p h o r u s concen t ra t ions above the ULN (5 mg/dL) were o b se rv ed in 14 (58.3%) of the 24 subjects be tween 10 minutes and 2 hours after enema t rea tment ; none of the unt rea ted subjects had abnormal ly high concen t ra t ions (P< 0.001).

Mean se rum p h o s p h o r u s concen t ra t ions were above the ULN at 30, 40, and 60 minutes after enema administrat ion, with concen t ra t ions ranging from 3.4 to 8.5 mg/dL. In the un t rea ted period, the concen t ra t ions for the same per iod ranged from 2.5 to 4.2 mg/dL. The concen t ra t ions in the t rea ted subjects subse- quent ly dec reased to normal in all of the subjec ts within 4 hours of enema administrat ion.

Four subjects had >1 se rum phosphorus concent ra t ion >7 mg/dL, values con- s idered to be serious hyperphospha temia . These values were isolated and limited in time, at 40 and/or 60 minutes after enema administration. The mean (SD) retent ion t ime in these 4 subjects was significantly higher than that of the entire group (29 [11.7] vs 15.3 [11.5] min; P = 0.006).

A statist ically significant corre la t ion was found be tween p h o s p h o r u s Cm~ x and enema retent ion t ime (r 2 = 0.452; P < 0.001) (Figure 2). Similarly, a statisti-

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0 2 4 6 8 10

Cmax ( m g / d L )

C o r r e l a t i o n b e t w e e n e n e m a r e t e n t i o n t i m e and p h o s p h o r u s a f t e r t h e ad- m in i s t r a t i on of Enema Casen ® 250 mL.

cally significant corre la t ion was found be tween p h o s p h o r u s Tm~ and re tent ion t ime (r 2 = 0.432; P < 0.001). Nei ther age nor creat inine c lea rance was cor re la ted with the Tm~, Cm~, or AUC0_12 of s e r u m p h o s p h o r u s .

Ur inary p h o s p h o r u s e l iminat ion was inc reased for 12 hou r s af ter e n e m a admin i s t r a t ion (Figure 3). After e n e m a adminis t ra t ion , p h o s p h o r u s elimina- t ion inc reased by 85% in relat ion to the no - t r ea tmen t g roup (P < 0.001). Only e n e m a re ten t ion t ime was s ignif icant ly co r re l a t ed with p h o s p h o r u s Ae0_12 (P < 0.001).

None of the o the r s e r u m elect rolyte concen t r a t i ons (ie, sodium, po tass ium, ca lc ium) ob ta ined during the s t u d y fell ou ts ide of the normal ranges (Table If).

Mean s e r u m sod ium concen t r a t i ons were significantly higher after e n e m a adminis t ra t ion than after no t r ea tmen t at 30 and 60 minutes, and at 4 hours (P = 0.031, P = 0.036, and P = 0.017, respec t ive ly) (Figure 4). No corre la t ion was found be tween Cm~ values and re tent ion time, age, or creat inine c learance . The mean increase in s e r u m sod ium concen t r a t ion after e n e m a admin is t ra t ion was 1.32 mEq/L.

There were no significant differences in mean s e r u m calc ium concen t r a t i ons be tween the t r ea ted and un t rea ted sub jec t s (Figure 5).

Mean s e r u m p o t a s s i u m concen t r a t i ons were significantly lower (P = 0.026) at 40 minu tes after e n e m a admin is t ra t ion c o m p a r e d with the no - t r ea tmen t per iod (Figure 6).

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0 2 4 6 8 ll0 12

Time (h)

Figure 3. Mean (SE) accumula ted quan t i t y of phosphorus e l im ina ted in ur ine t h r o u g h o u t the 12 hours a f ter the admin i s t ra t i on of Enema Casen ® 250 mL and w i t h no t r ea tmen t .

E c- o , m

e-

c -

O U

145 • Enema treatment O No treatment

140

135

t I I I I I I I

0 2 4 6 8 10 12 Time (h)

Figure 4. Mean (SE) serum sod ium concent ra t ions a f ter the admin i s t ra t i on of Enema Casen ® 250 mL and w i t h no t r ea tmen t . *P < 0.05 versus no t r ea tmen t .

343


1 0 -

• Enema treatment © No treatment

E c- O °m

4~

4~ e-

c- O

U

9 -

8

I I

i i i i i i ll2 0 2 4 6 8 10

Time (h)

Figure 5. Mean (SE) serum calcium concentrations after the administration of Enema Casen ® 250 mL and wi th no t reatment . *P < 0.05 versus no t reatment .

4.5

E c- O ° m

4~

= 4.0 0

U

5.0 • Enema treatment © No treatment

3.5 I I I I I I I

0 2 4 6 8 10 12 Time (h)

Figure 6. Mean (SE) serum potassium concentrations after the administration of Enema Casen ® 250 mL and wi th no treatment. *P< 0.05 versus no treatment.

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B. S/ldaba et al.

No ser ious AEs were observed , a l though 13 AEs were r epor t ed in 9 subjects (Table llI). The sever i ty of the AEs was assessed as mild in each case. None of the subjects had abnormal vital signs (blood pressure and hear t rate), and no pat ients unde rwen t ECG because of AEs. Medical t r ea tmen t was n e c e s s a r y for 2 ep isodes of headache ( t rea ted with parace tamol and ibuprofen) and 1 ep isode of back pain ( t rea ted with topical diclofenac). The remainder of the AEs did not require t r ea tment because the subjects r ecove red spontaneously . The results of the analysis of the blood samples drawn the day after the last per iod showed some values outs ide of the reference range, but none of these abnormal values had clinical consequences . No clinically significant changes were o b se rv ed in physical examinat ion findings, ECG proper t ies , b lood pressure, hear t rate, res- p i ra to ry rate, or t empera ture .

DISCUSSION The results of this s tudy suggest tha t after the adminis t ra t ion of Enema Casen 250 mL, p h o s p h o r u s and sodium were abso rbed systemically, so that mean se rum p h o s p h o r u s concen t ra t ion was increased by 1.18 mg/dL and mean se rum sodium concen t ra t ion was increased by 1.32 mEq/L. In a 2006 observa- tional p rospec t ive study, 5 15 patients, mean aged 73 years , were adminis tered 2 or 3 Enema Casen 250 mL enemas the night prior to colonoscopy. All the pat ients had higher se rum p h o s p h o r u s concen t ra t ions after enema administration (0.9 mg/dL of difference, P = 0.002), a l though the t ime the final b lood sam- ple was obta ined was not repor ted . It is possible tha t se rum concen t ra t ions measu red in the first hour after enema adminis t ra t ion would have been higher and more similar to our observa t ions .

Table III. Reported adverse events (AEs) and their relationship to the study medication. AEs occurred in 1 subject unless otherwise noted.

Relation to the Study Medication AE

Not related Headache (3 subjects) Allergic stigmas and asthenia Back pain Hematochezia Right submandibular adenopathy Slight increase in transaminase activities

Dizziness Headache

Abdominal cramping Abdominal pain and sensation of coldness

Sensation of coldness and general malaise

Unlikely

Probable

Possible

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Our resul ts might have smal le r changes than those o b s e r v e d after the adminis t ra t ion of o the r sod ium p h o s p h a t e laxative p r o d u c t s b e c a u s e those p roduc t s were admin i s t e red orally. 17 Also, the quant i ty of e lec t ro ly tes in the oral products is higher than tha t in the rectal p roduc t s , 18 and rectal ab so rp t i on might be more erra t ic than abso rp t i on via o ther routes . 19 In our study, the s e r u m phos- p h o r u s concen t r a t i ons of 58% of the sub jec t s were above no rma l va lues at 30, 40, and 60 minutes after e n e m a adminis t ra t ion . This increase was self-limited, b e c a u s e p h o s p h o r u s u r ina ry el imination after e n e m a admin is t ra t ion was 85% grea te r than tha t o b s e r v e d in the un t rea ted per iod. This higher u r ina ry elimina- t ion made accumula t ion of p h o s p h o r u s imposs ib le in b lood up to 6 hour s after adminis t ra t ion .

Enema re tent ion t ime in the intest inal lumen was a decis ive factor in the increase in p h o s p h o r u s Tm~, as has been sugges t ed in p rev ious s tudies . 2°,21 During our s t u d y the sub jec t s were asked to pro long the e n e m a re tent ion t ime as m u c h as possible . According to the p rod uc t descr ip t ion, 2 Enema Casen usu- ally works in 2 to 5 minutes . The re tent ion t ime was ex tended in this s t u d y to a s s e s s wha t oc cu r s when the e n e m a does not cause the des i rab le effect and therefore , it was not expel led and remained in the bowel more than desirable . In our s t u d y popula t ion, the high s e r u m p h o s p h o r u s concen t r a t i ons might have been physiologica l ly regula ted by an increase in renal e l iminat ion of p h o s p h o - rus, as o b s e r v e d by others . 22 The increases in s e r u m p h o s p h o r u s concen t ra - t ion and the renal el imination of p h o s p h o r u s we o b s e r v e d were not cor re la ted with age, as desc r ibed previously, 23 or with creat inine c lea rance ( p r o b a b l y because our vo lun tee r s had va lues up to 25 mL/min). 21

The s e r u m calc ium concen t r a t i ons did not change significantly dur ing the 12-hour s t u d y per iod in the t r ea ted subjec ts , with all va lues remaining within the normal range. In a p ro spec t i ve study, 5 s e r u m calc ium concen t r a t i ons were be low the lower limit of normal in 27% of cases; however , t hose pa t ien ts rece ived 2 or 3 enemas . Cases of toxici ty tha t have been desc r ibed have generally been a resul t of d e c r e a s e s in s e r u m calc ium concen t ra t ion , s o m e t i m e s with fatal ou t comes . 2~4° In these cases , the e n e m a s might have been admin i s t e red to ill pat ients , children, or pa t ien ts with m o d e r a t e to seve re renal or hepa t ic failure. The package inser t indicates tha t the e n e m a is con t ra ind ica ted in such pa t i en t s or should be used with caut ion. 2 During this s t u d y no changes in s e r u m calc ium concen t r a t i ons were obse rved , sugges t ing tha t the p h o s p h a t e m i a ob- s e r v e d dur ing the s t u d y was no t cl inical ly r e l evan t b e c a u s e it was not a sso- c ia ted with hypoca lcemia .

Because s e r u m concen t r a t i ons of sod ium and p o t a s s i u m remained within the normal range t h r o u g h o u t the study, they were cons ide red clinically irrele- vant . The e n e m a s were genera l ly well to le ra ted in this popula t ion of hea l thy subjec ts .

A l imitation of this s t u d y was tha t it might not be poss ib le to general ize the findings to a wider pa t ien t popula t ion. The s t u d y was c o n d u c t e d in hea l thy subjects, while m o s t AEs as soc ia t ed with e n e m a use occur in pa t ien ts with under-

346

B. S/ldaba et al.

lying medica l p rob lems . 3 However, while severa l s tud ies have examined changes in s e r u m concen t r a t i ons with sod ium p h o s p h a t e p r epa ra t i ons admin- i s tered orally, 6-1°,17 little da ta are avai lable regarding the effects of e n e m a s on s e r u m elect rolyte concen t r a t i ons in hea l thy sub jec t s or individuals with heal th p rob lems . In an a t t e m p t to make the resul ts appl icable to a wider popula t ion, sub jec t s as old as 70 yea r s were eligible for the study, b e c a u s e age is one of the p red ic to r s of h y p e r p h o s p h a t e m i a after the use of oral sod ium p h o s p h a t e p repa ra t ions . 16

CONCLUSIONS The admin is t ra t ion of a 250 mL e n e m a containing sod ium p h o s p h a t e was asso- c ia ted with s e r u m p h o s p h o r u s concen t r a t i ons ~7 mg/dL in 16.7% of the hea l thy sub jec t s who pa r t i c ipa ted in the study; however , none of t hose sub jec t s expe- r ienced hypoca lcemia . Enema re tent ion t ime was significantly cor re la ted with the degree of p h o s p h a t e m i a obse rved .

ACKNOWLEDGMENT This s t u d y was s u p p o r t e d (Zaragoza, Spain).

by grants from Labora to r ios Casen Fleet S.L.

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Acute hyperphosphatemia induced by enemas [in Spanish]. Med Clin (Barc). 1998; 110:805.

2. Enema Casen [package insert]. Zaragoza, Spain: Laboratorios Casen Fleet S.L.; 2004. 3. Shiber JR, Mattu A. Serum phosphate abnormalities in the emergency department.

J Emerg Med. 2002;23:395-400. 4. Cohan CF, Kadakia SC, Kadakia AS. Serum electrolyte, mineral, and blood pH changes

after phosphate enema, water enema, and electrolyte lavage solution enema for flexi- ble sigmoidoscopy. Gastrointest Endosc. 1992;38:575-578.

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6. Ainley E J, Winwood P J, Begley JP. Measurement of serum electrolytes and phosphate after sodium phosphate colonoscopy bowel preparation: An evaluation. Dig Dis Sci. 2005;50:1319-1323.

7. Ell C, Fischbach W, Keller R, et al, for the Hintertux Study Group. A randomized, blinded, prospective trial to compare the safety and efficacy of three bowel-cleansing solutions for colonoscopy (HSG-01*). Endoscopy. 2003;35:300-304.

8. Seinela L, Pehkonen E, Laasanen T, Ahvenainen J. Bowel preparation for colonoscopy in very old patients: A randomized prospective trial comparing oral sodium phosphate and polyethylene glycol electrolyte lavage solution. Scand J Gastroenterol. 2003;38:216-220.

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9. Poon CM, Lee DW, Mak SK, et al. Two liters of polyethylene glycol-electrolyte lavage solution versus sodium phosphate as bowel cleansing regimen for colonoscopy: A prospective randomized controlled trial. Endoscopy. 2002;34:560-563.

10. Mathus-Vliegen EM, Kemble UM. A prospective randomized blinded comparison of sodium phosphate and polyethylene glycol-electrolyte solution for safe bowel cleansing. Aliment Pharmacol Ther. 2006;23:543-552.

11. World Medical Association Declaration of Helsinki: Recommendations Guiding Medical Doctors in Biomedical Research Involving Human Subjects [WMA Web site]. Ferney-Voltaire, France: WMA; 1989. Available at: http://www.wma.net. Accessed June 18, 2004.

12. European Agency for the Evaluation of Medicinal Products, International Conference on Harmonisation-World Health Organization. Guideline for Good Clinical Practice [EMEA Web site]. ICH Topic E6. Geneva, Switzerland: WHO; 2002. Available at: http://www.emea.eu.int. Accessed June 18, 2004.

13. Calcio Arsenazo III. Colorimetric [in Spanish]. Available at: http://www.spinreact.com/ uploads/pdf/BSDTT09%20CALCIUM-A%20III.pdf. Accessed October 13, 2006.

14. Fosforo. Fosfomobildato. Colorimetric [in Spanish]. Available at: http://www.spinreact. com/uploads/pdf/BSDTT15%20PHOSPHORUS%20-UV.pdf. Accessed October 13, 2006.

15. Karch FE, Lasagna L. Toward the operational identification of adverse drug reactions. Clin Pharmacol Ther. 1977;21:247-254.

16. Gumurdulu Y, Serin E, Ozer B, et al. Age as a predictor of hyperphosphatemia after oral phosphosoda administration for colon preparation. J Gastroenterol Hepatol. 2004; 19:68-72.

17. Curran MP, Plosker GL. Oral sodium phosphate solution: A review of its use as a colo- rectal cleanser. Drugs. 2004;64:1697-1714.

18. Tan HL, Liew QY, Loo S, Hawkins R. Severe hyperphosphataemia and associated electrolyte and metabolic derangement following the administration of sodium phosphate for bowel preparation. Anaesthesia. 2002;57:478-483.

19. van Hoogdalem E J, de Boer AG, Breimer DD. Pharmacokinetics of rectal drug administration, part II. Clinical applications of peripherally acting drugs, and conclusions. Clin Pharmacokinet. 1991;21:110-128.

20. Schuchmann GD, Barcia PJ. Phosphate absorption from fleet enemas in adults. Curr Surg. 1989;46:120-122.

21. Gutierrez E, Gonzalez E, Hernandez E, et al. Acute hyperphosphatemia secondary to phosphate administration for bowel preparation [in Spanish]. Nefrologia. 2004;24: 283-287.

22. Grosskopf I, Graff E, Charach G, et al. Hyperphosphataemia and hypocalcaemia induced by hypertonic phosphate enema--an experimental study and review of the literature. Hum Exp Toxicol. 1991;10:351-355.

23. Marin Gabriel JC, Rodriguez Munoz S, de la Cruz Bertolo J, et al. Electrolytic distur- bances and colonoscopy: Bowel lavage solutions, age and procedure. Rev Esp Enferm Dig. 2003;95:863-875.

24. Nir-Paz R, Cohen R, Haviv YS. Acute hyperphosphatemia caused by sodium phosphate enema in a patient with liver dysfunction and chronic renal failure. Ren Fail. 1999;21:541-544.

25. Soumoy MP, Bachy A. Risk of phosphate enemas in the infant [in French]. Arch Pediatr. 1998;5:1221-1223.

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26. Helikson MA, Parham WA, Tobias JD. Hypocalcemia and hyperphosphatemia after phosphate enema use in a child. J Pediatr Surg. 1997;32:1244-1246.

27. Ehrenpreis ED, Wieland JM, Cabral J, et al. Symptomatic hypocalcemia, hypomagne- semia, and hyperphosphatemia secondary to Fleet's Phospho-Soda co]onoscopy preparation in a patient with a jejunoilea] bypass. Dig Dis Sci. 1997;42:858-860.

28. Sutters M, Gaboury CL, Bennett WM. Severe hyperphosphatemia and hypocalcemia: A dilemma in patient management. J A m Soc Nephrol. 1996;7:2056-2061.

29. Wilmanns C, Bernschneider T, Schoffel U, Farthmann EH. Enema-induced hyperphosphatemia in ileus of the small and large intestine [in German]. Zentralbl Chir. 1995;120:981-983.

30. Fass R, Do S, Hixson LJ. Fatal hyperphosphatemia following Fleet Phospo-Soda in a patient with colonic ileus. Am J Gastroenterol. 1993;88:929-932.

31. Korzets A, Dicker D, Chaimoff C, Zevin D. Life-threatening hyperphosphatemia and hypocalcemic tetany following the use of fleet enemas. J Am Geriatr Soc. 1992;40: 620-621.

32. Wason S, Tiller T, Cunha C. Severe hyperphosphatemia, hypocalcemia, acidosis, and shock in a 5-month-old child following the administration of an adult Fleet enema. Ann Emerg Med. 1989;18:696-700.

33. Biberstein M, Parker BA. Enema-induced hyperphosphatemia. Am J Med. 1985;79: 645-646.

34. Rohack J J, Mehta BR, Subramanyam K. Hyperphosphatemia and hypocalcemic coma associated with phosphate enema. South Med J. 1985;78:1241-1242.

35. Reedy JC, Zwiren GT. Enema-induced hypocalcemia and hyperphosphatemia leading to cardiac arrest during induction of anesthesia in an outpatient surgery center. Anesthesiology. 1983;59:578-579.

36. Haldimann B, Vogt K. Hyperphosphatemia and tetany following phosphate enema [in French]. Schweiz Med Wochenschr. 1983;113:1231-1233.

37. Sotos JF, Cutler EA, Finkel MA, Doody D. Hypocalcemic coma following two pediatric phosphate enemas. Pediatrics. 1977;60:305-307.

38. Davis RF, Eichner JM, Bleyer WA, Okamoto G. Hypocalcemia, hyperphosphatemia, and dehydration following a single hypertonic phosphate enema. JPediatr. 1977;90: 484-485.

39. Martin RR, Lisehora GR, Braxton M Jr, Barcia PJ. Fatal poisoning from sodium phosphate enema. Case report and experimental study. JAMA. 1987;257:2190-2192.

40. Ma KK, Ng CS, Mui LM, et al. Severe hyperphosphatemia and hypocalcemia following sodium phosphate bowel preparation: A forgotten menace. Endoscopy. 2003;35:717.

Address correspondence to: Bel6n S~daba, MD, PhD, Servicio de Farmacologia CHnica, Clinica Universitaria de Navarra, 36 Avda. de Pio XII, 31008 Pamplona, Spain. E-mail: [email protected]

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Effects of a 250-mL Enema Containing Sodium Phosphate on ... · principles of the Declaration of Helsinki 11 and the Guidelines for ... occurred in a serum electrolyte concentration