Feasibility study of short hydration using oral rehydration solution in cisplatin including chemotherapy of lung cancer

It was also determined that renal dysfunction could occur at high frequencies (28–36 %)
when including the slight impairments caused by ?50 mg/m
²
of CDDP administration, even when hydration and diuresis were conducted adequately
6], 7]. The renal dysfunction caused by CDDP was attributed to accumulation of CDDP in renal
tubules and associated tubular cell necrosis 8]. Hydration reduces renal dysfunction by diluting the urinary CDDP concentration,
as well as shortening the contact time in the renal tubule by early excretion. In
particular, the efficient dilution and excretion attributable to the hydration of
the CDDP free-form represented much of the early excretion (within 2 h after administration),
which was considered to be significant, as the form of CDDP not bound to proteins
in the blood has been implicated in glomerular toxicity 9]. Preservation of the early urine flow by the hydration seems to be required for prevention
of renal dysfunction during CDDP administration. Although hydration seemed beneficial
in general, there was some concern over whether renal dysfunction could be even further
reduced if the hydration increased the volume. The results of one study suggested
that increasing hydration volumes had no influence on the incidence of renal dysfunction
by showing no differences when hydration volumes during CDDP administration were more
than 2000 mL or not 10]. Some CDDP administration regimens with infusion volumes of approximately 2000 mL
have been termed short-term hydration, and have been investigated vigorously. Tiseo
et al. were the first to report the general idea of short-term hydration, suggesting
a total infusion volume of 2100 mL for 4.25 h in addition to chemotherapy including
?75 mg/m
²
of CDDP in lung cancer patients 1]. Five (4.6 %) of the 107 patients discontinued treatment due to renal dysfunction.
However, the definition of short-term hydration was not clear, and wide variations
in variables, including hydration volume, composition of the infusion, addition of
magnesium, rank order and the use of diuretics, were observed in subsequent studies.
Additionally, safety results from short-term hydration experiments performed in Japanese
prospective studies generally showed that grade ?2 renal dysfunction was detected
at a rate of less than 10 % 11], 12]. Therefore, we had designed a regimen including the combined use of ORS with existing
short-term hydration for the purpose of improving the safety issues associated with
renal dysfunction over prolonged infusion times.

Renal dysfunction, as evaluated by the sCre, was only observed to occur in two patients
and did not exceed grade 2 in any patient using our method combining ORS with an intravenous
infusion of an average of 1930 mL (4.7 h). On the other hand, there were more patients
(34.3 %) with grade 2 renal dysfunction after their last CDDP administration as evaluated
by eGFR when compared with sCre; however, this was not an unexpected finding, as there
were already 15 patients (42.9 %) with decreased renal function equal to grade 1 before
the first cycle. Importantly, most of the evaluated patients did not develop severe
renal dysfunction (grade ?3), and completed all four scheduled chemotherapy cycles.
The outcomes for the patients showing grade 2 renal dysfunction did not exhibit further
progression, and some of these patient even showed signs of recovery. The antiemetic
effect of this treatment seemed to be good based on the nausea grade, the number of
vomiting instances, and lack of effects on dietary intake. The high compliance and
tolerability of ORS drinking were confirmed, as all patients were available for 1000 mL
of ORS drinking on the first day. Side effects possibly attributable to ORS drinking
were only slightly observed as abdominal distension, nausea and diarrhea. It should
be noted, however, that these symptoms were considered as a side effect of the chemotherapy.

The safety of this regimen considered as follows. Nine of 47 patients who received
initial chemotherapy were not able to receive second cycle for a treatment-related
side effect. Also, reduction of CDDP was required for 40 % of patients after the second
cycle. Most of reasons were due to myelosuppression. The side effects such as the
myelosuppression occurred even if short hydration supplemented with ORS was used.
The initial chemotherapy should be carried out in hospitalization, and adequate attention
seemed to be required for side effects such as the myelosuppression in the subsequent
chemotherapy. It should also be noted, however, that some patients with renal dysfunction
up to grade 2 were observed even when ORS was used as a supplement to intravenous
transfusion in this study. Although our results were suggestive of the safety of this
regimen, the study was not sufficiently powered to conclude that supplementary use
of the ORS was able to relieve renal dysfunction due to CDDP. The mean age of the
study participants was comparatively high (65.7 years), and the 42.9 % of the patients
with 80 mL/min in eGFR at study entry may have influenced the study results. However,
improving the safety of CDDP for these patient groups remains an important goal for
those in clinical practice. Therefore, a modification of the hydration regimen was
thought to be necessary in order to further reduce the renal dysfunction associated
with the use of CDDP. The use of diuretics, such as mannitol or furosemide 13] and Na, Cl rich infusion 14], 15], as well as magnesium supplementation 16], have all been demonstrated as important for the prevention of renal dysfunction
due to CDDP. In this study, we used furosemide due to its rapid diuretic effect; however,
it was not administered before CDDP administration. It may be the case that use of
furosemide before CDDP administration may produce an earlier diuretic effect. Additionally,
maintenance infusion was used for hydration, and its Na and Cl quantity was 25 % saline.
It may have been more useful to employ higher amounts of saline for hydration. We
consider the factor which might influence the renal function of the patients as follows.
Patients with hypoalbuminemia in particular have been shown to experience renal dysfunction
rather easily as a result of CDDP treatment 10]. It should be noted, however, that hypoalbuminemia??3.0 g/dL was not detected in
the patient with sCre elevation of grade 2 in this study. Also, the poor PS might
influence renal function. However, the patients who received CDDP were all PS 1 in
this study. Therefore, it was thought that there was little effect of the PS on the
results. Combination use of nonsteroidal antiinflammatory drug (NSAIDs) was considered
as the factor which influenced renal dysfunction 17], 18]. Four patients used NSAIDs during duration of chemotherapy routinely. Three of four
patients had a grade aggravation evaluated by eGFR. Therefore, combination use of
NSAIDs might influence renal function in these patients. Renal function as evaluated
by sCre may result in underestimations because the biosynthesis of creatinine decreases
with the muscle degradation that accompanies the aging process (the so-called creatinine
blind). We used sCre, eGFR and BUN as parameter of renal function in this study to
investigate the complementarity of these results.

Oral hydration using ORS as a substitute for water was thought to be useful on the
initial CDDP administration day for at least two reasons. First, hydration is possible
before an infusion begins and can be administered anywhere. Secondly, the excretion
of the CDDP protein-free form, which exists at its highest levels in the early stage
of CDDP administration, was promoted pharmacologically due to its rapid water absorption.
ORS remained useful during the remainder of the CDDP regimen because it was available
for hydration in a non-intravenous manner, highly accessible in drug stores without
a prescription, low in cost and safe with rare side effects, including diarrhea.