VOLUME 23 䡠 NUMBER 10 䡠 APRIL 1 2005

JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T

Effects of Parenteral Hydration in Terminally Ill Cancer

From The University of Texas M.D.
Anderson Cancer Center, Houston, TX;
Hospital Eva Peron, Rosario, Argentina;
Instituto Nacional de Cancer, Santiago,
Chile; Clinica de Dolor, Fundacion
Santafe de Bogotá, Bogotá, Columbia;
and Centro Regional de Medicina,
Los Montalvos, Spain.
Submitted April 14, 2004; accepted
December 30, 2004.
Supported by the Brown Foundation,
Houston, TX; and the Tobacco Settle-
ment Foundation.
Presented in part at the 40th Annual
Meeting of the American Society of
Clinical Oncology, New Orleans, LA,
June 5-8, 2004.
Authors’ disclosures of potential con-
flicts of interest are found at the end of
this article.
Address reprint requests to Eduardo
Bruera, MD, Department of Palliative
Care and Rehabilitation Medicine, Unit
8, The University of Texas M.D. Anderson
Cancer Center, 1515 Holcombe Blvd,
Houston, TX 77030; e-mail: ebruera@
mdanderson.org.
© 2005 by American Society of Clinical
Oncology
0732-183X/05/2310-2366/$20.00
DOI: 10.1200/JCO.2005.04.069
Patients: A Preliminary Study
Eduardo Bruera, Raul Sala, Maria Antonieta Rico, Jairo Moyano, Carlos Centeno, Jie Willey,
and J. Lynn Palmer
A B S T R A C T
Purpose
Most patients with cancer develop decreased oral intake and dehydration before death. This
study aimed to determine the effect of parenteral hydration on overall symptom control in
terminally ill cancer patients with dehydration.
Patients and Methods
Patients with clinical evidence of mild to moderate dehydration and a liquid oral intake less
than 1,000 mL/day were randomly assigned to receive either parenteral hydration with 1,000
mL (treatment group) or placebo with 100 mL normal saline administered over 4 hours for 2
days. Patients were evaluated for target symptoms (hallucinations, myoclonus, fatigue, and
sedation), global well-being, and overall benefit.
Results
Twenty-seven patients randomly assigned to the treatment group had improvement in 53
(73%) of their 73 target symptoms versus 33 (49%) of 67 target symptoms in the placebo
group (n⫽22; P ⫽ .005). Fifteen (83%) of 18 and 15 (83%) of 18 patients had improved
myoclonus and sedation after hydration versus eight (47%) of 17 and five (33%) of 15
patients after placebo (P ⫽ .035 and P ⫽ .005, respectively). There were no significant
differences of improvement in hallucinations or fatigue between groups. When blinded to
treatment, patients (17 [63%] of 77) and investigators (20 [74%] of 27) perceived hydration
as effective compared with placebo in nine (41%) of 22 patients (P ⫽ .78) and 12 (54%) of
22 investigators (P ⫽ .15), respectively. The intensity of pain and swelling at the injection site
were not significantly different between groups.
Conclusion
Parenteral hydration decreased symptoms of dehydration in terminally ill cancer patients
who had decreased fluid intake. Hydration was well tolerated, and a placebo effect was
observed. Studies with larger samples and a longer follow-up period are justified.
J Clin Oncol 23:2366-2371. © 2005 by American Society of Clinical Oncology

always receive parenteral hydration in acute

INTRODUCTION
Decreased oral intake, a frequent complica-
tion of advanced cancer, results from vari-
ous causes, including profound anorexia,
odynophagia, oral cavity lesions, dysphagia,
nausea and vomiting, delayed gastric emp-
tying, bowel obstruction, cognitive impair-
ment, and severe mood disorders.1-4
Patients with advanced cancer who have de-
hydration or decreased oral intake almost
care facilities but almost never in hospices.3-5
In the past decade, the consequences of dehy-
dration in terminally ill cancer patients have
generated strong debate, with arguments for
and against fluid administration.5-7
The decision of whether to administer
fluids should be individualized, based on a
careful assessment of a patient’s clinical pre-
sentation, the potential advantages of paren-
teral fluids, and the patient’s and family’s

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Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
 Hydration in Terminally Ill Cancer Patients
wishes.6-8 Unfortunately, the decision-making process is
complicated by the absence of randomized controlled
trials focusing on the potential advantages and disadvan-
tages of parenteral hydration.9 However, retrospective
studies suggest that hydration can reduce neuropsychi-
atric symptoms such as sedation, hallucinations, myoc-
lonus, and agitation.10,11
Methods of fluid hydration for palliative care patients
include subcutaneous hydration or hypodermoclysis.6,12-14
This method has many potential advantages over other
methods of fluid replacement: it may be started and stopped
with no risk of thrombosis or bleeding; it is easier to manage
in the home setting, with administration performed by
family members or the patients themselves after minimal
training; infusions can be easily administered by gravity,
thereby avoiding the need for infusion pumps; and the same
infusion site can be used for many days.6,13
The purpose of this randomized, controlled, double-
blind study was to determine the effects of parenteral hy-
dration with 1,000 mL/d versus 100 mL/d of normal saline,
administered intravenously or subcutaneously, on overall
symptom control in patients with advanced cancer.
PATIENTS AND METHODS
Study Design
This study was conducted at The University of Texas M.D.
Anderson Cancer Center, Houston, TX; Hospital Eva Peron, Ro-
sario, Argentina; Instituto Nacional de Cancer, Santiago, Chile;
Clinica de Dolor, Fundacion Santafe de Bogotá, Bogotá, Colum-
bia; and Centro Regional de Medicina, Los Montalvos, Spain.
Patients had to meet the following inclusion criteria to be admitted
to the study: a diagnosis of advanced cancer, defined as locally
recurrent or metastatic, with no further treatment planned; an oral
intake of less than 1,000 mL/d, as determined by clinical assess-
ment; and evidence of mild to moderate dehydration, exhibited by
decreased turgor in the subclavicular region lasting more than 2
seconds. In addition, patients had to have one or more of the
following findings: dry mouth; thirst; decreased volume of urine
output, as reported by the patient; a darker color of urine than
usual, in the absence of reasons for jaundice or hematuria; and
laboratory values consistent with dehydration, such as an elevated
blood urea nitrogen to creatinine ratio of more than 20:1, when
this value was obtained within 24 hours of admission to the
study. Finally, patients had to be older than 16 years, able to
understand and give consent for participation in the study, and
able to tolerate parenteral treatment and the application of a
subcutaneous or intravenous cannula. Exclusion criteria in-
cluded a patient’s refusal to participate; the presence of severe
dehydration, defined as a decreased systolic resting blood pres-
sure of 30 mmHg or lower from the patient’s baseline value; low
perfusion of the limbs; no urine output for 12 hours or longer;
a decreased level of consciousness; or evidence of severe renal
failure or bilateral hydronephrosis.
The study was carried out after institutional review boards at
each study site approved the study and patients gave written in-
formed consent to participate. All participating investigators un-
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Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
derwent a 2-day training session at M.D. Anderson Cancer Center,
during which the protocol was reviewed, including the method of
administering hydration and the appropriate blinding of the type
of parenteral infusion given. Random numbers determining treat-
ment allocation were calculated at M.D. Anderson Cancer Center
and delivered to the investigators in sealed envelopes. The ran-
domization code was kept confidential at M.D. Anderson Cancer
Center until the completion of the study.
The study was randomized, controlled, and double blind.
Patients who met the inclusion criteria and agreed to participate
were randomly assigned to receive either 1,000 mL of normal
saline (treatment group) or 100 mL of normal saline (placebo
group) as an infusion over 4 hours for 2 days. Both types of
infusion were given parenterally (either intravenously or subcuta-
neously). Patients who already had an intravenous access device
(n ⫽ 12) received infusions intravenously, and patients with no
intravenous access device received infusions subcutaneously
(n ⫽ 37). One investigator at each institution was unblinded and
was responsible for preparing the saline, the droppers, and the
portable and nonportable pumps to maintain the blinding. The
investigator responsible for assessing the patient and the patient
himself or herself were not aware of the amount of fluid being
administered. In all cases, at least one test of blinding was con-
ducted before activation of the study at each institution.
Outcome Measures
No previously defined outcomes for our study existed be-
cause no previous randomized controlled trials of hydration had
occurred. We chose four target symptoms for hydration (sedation,
fatigue, hallucinations, and myoclonus) on the basis of retrospec-
tive studies10-12,14,15 and our clinical experience. These target
symptoms were found to be appropriate at a workshop at M.D.
Anderson that included the study investigators and six other non-
participating palliative care researchers from Houston. Patients
scored the presence of the four target symptoms on a numeric
scale of 0 (absent) to 10 (worst possible). The symptoms were
considered present whenever the score was 1 or greater, and im-
provement was defined as a decrease of one point or more. The
final scores were then added for the treatment (1,000 mL/d) and
the placebo (100 mL/d) groups.
The main outcome of the study for the purpose of sample size
calculation was the global assessment of the overall benefit of
hydration to the patient, as determined by the physician and
patient on day 2. The study was designed to detect a difference in
the proportion of patients in the two groups having any important
overall benefit. Parenteral hydration with 1,000 mL of normal
saline was considered successful if 75% of the patients were per-
ceived as having any important benefit (ie, a score of 3 or more) at
the end of 2 days of hydration. We expected that approximately
50% of the patients receiving only 100 mL of normal saline would
also be perceived as having an important benefit.
Our second proposed method of analysis was to test the
two groups separately to determine whether the proportion of
patients perceived to have some benefit was equal to 50% or
greater than 50%.
The planned sample size was calculated as 54 patients per
group to allow for the detection of differences, with an 80% power
and a one-sided significance level of .05.
Assessments
The following six assessments were performed before paren-
teral hydration began (baseline) and at the end of days 1 and 2,
2367
 Bruera et al

unless otherwise noted: (1) a history, physical examination, and

review of medications at baseline; (2) a Mini-Mental State Exam-
ination for assessment of cognitive function16 at baseline and on
day 2; (3) an evaluation for target symptoms of dehydration,
including hallucinations, myoclonus, fatigue, and sedation, dur-
ing the previous 24 hours was assessed by an investigator who was
unaware of the type of treatment that the patient received; these
four symptoms were assessed using a numeric scale of 0 (no
hallucination, no fatigue, and so on) to 10 (worst possible hallu-
cinations, worst possible fatigue, and so on); (4) an assessment of
the patient’s well-being performed by both the patient and inves-
tigator at baseline and on day 2 using a numeric scale of 0 (worst
possible) to 10 (best possible); (5) a global assessment of overall
benefit on day 2 performed by the patient and investigator using a
numeric scale of 1 (no important benefit) to 7 (greatly important
benefit); (6) an assessment for toxicity (eg, pain, swelling, or
leakage at the site of infusion) in each patient who received sub-
cutaneous hydration using a numeric scale of 0 (no toxicity) to 10
(worst toxicity).
After the assessments on day 2, the physician and patient were
free to choose to continue their preferred method of hydration.
The brief 2-day period of observation was established to allow the
treating physicians to provide their preferred method of hydration
Fig 1. Flow chart showing patient entry onto the study.
as rapidly as possible, after a sufficient time had passed for clini-
cally detectable changes to occur. If, in the opinion of the treating
physician, a patient experienced acute deterioration during the
According to our study design, if 75% of patients had
2-day period, the patient was removed from the study and pro-
vided standard care. any perceived important benefit at the end of 2 days of
hydration with 1,000 mL of normal saline, the treatment
would be considered successful. We achieved this goal, with
RESULTS

The planned sample size of this study was 108 patients. Table 1. Patient Characteristics and Type of Hydration Administered

However, because of difficulties in identifying patients with No. of Patientsⴱ

dehydration who had normal cognition and were willing to 1,000 mL of 100 mL of
Characteristic Saline Saline Total
participate in the study, the total accrual was only 51 pa-
Age, years
tients at the time of study closure. Twenty-eight patients
Median 65 60 63
were randomly assigned to the treatment group and 23 Range† 39-88 28-89 28-90
patients were randomly assigned to the placebo group (Fig Sex†
1). Only 49 (96%) of these patients were assessable; one Female 14 10 24
patient from each group did not complete the study because Male 14 13 27
Primary cancer site†
of family refusal in one case and dyspnea and rapid deteri- Breast 2 2 4
oration in the other. Genitourinary 4 2 6
Table 1 lists the characteristics of the patients admitted Gastrointestinal 9 10 19
to the study. All patients were receiving opioid analgesic Lung 6 3 9
Gynecologic 2 2 4
agents for pain management. Other 5 4 9
Table 2 lists the effects of hydration on the target symp- Performance status
toms. Fifty-three (73%) of 73 target symptoms experienced 0 0 0 0
by the treatment group improved, compared with 33 (49%) I 5 2 7
II 12 7 19
of 67 target symptoms in the placebo group (P ⫽ .006). III 8 11 19
Patients blindly perceived hydration as effective in 17 IV 3 3 6
(63%) of 27 cases in the treatment group and in nine (41%) Mini-Mental Status
Examination score
of 22 cases (P ⫽ .78) in the placebo group. Investigators, Mean 25.9 24.2
who were unaware of the type of hydration patients re- Standard deviation 3.5 4.6
ceived, perceived hydration as effective in 20 (74%) of 27 ⴱ
Unless otherwise specified.
cases in the treatment group and 12 (54%) of 22 cases †Of the 51 patients originally included in the study.
(P ⫽ .15) in the placebo group.

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Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
 Hydration in Terminally Ill Cancer Patients

Table 2. Improvement in Patient Score of Target Symptoms on Day 2

Treatment Group Placebo Group
Symptom Total No. Improvement % Total No. Improvement % P

Hallucinations 11 9 82 14 7 50 .208
Myoclonus 18 15 83 17 8 47 .035
Fatigue 26 14 54 21 13 62 .767
Sedation 18 15 83 15 5 33 .005
Total 73 53 73 67 33 49 .006

NOTE. A decrease of one point from the baseline determination on a 0 to 10 numeric scale was considered an improvement.

21 (78%) of 27 patients in the treatment group having a DISCUSSION

perceived important benefit of the treatment. However, 13
(59%) of 22 patients in the placebo group also had a per- In this randomized, controlled, double-blind study, we
ceived important benefit of the treatment, which was higher compared the effects of hydration with either 1,000 or 100
than the expected 50%. The difference in the proportion of mL of normal saline on target symptoms and overall per-
patients in the two groups who had a perceived important ception of treatment effectiveness by patients and investi-
benefit was not statistically significant (P ⫽ .16). We had a gators after 2 days of treatment. To our knowledge, this is
42% power to declare these proportions significantly differ- the first randomized controlled trial comparing hydration
ent with our reduced numbers of 27 and 22 patients per with placebo in patients with advanced cancer. Our results
group. Notably, if we had enrolled the original 54 patients suggested that hydration was able to improve the combined
per group and had found the same proportions (78% v target symptom score and decrease myoclonus and seda-
59%), we also would have had a reduced power of 61% to tion in the treatment group compared with the placebo
declare the difference in proportions statistically significant. group. A trend toward a perception of overall benefit for
Our second proposed method of analysis was to test the patients in the treatment group was also observed. Unfor-
two groups separately to determine whether the proportion tunately, these results are far from conclusive and need to be
of patients perceived to have some benefit was equal to 50% confirmed by other studies.
or greater than 50%. The results in the treatment group Patient enrollment in this study was much more diffi-
caused us to reject the null hypothesis (P ⫽ .0035), whereas cult than we had anticipated. At the time of their clinical
those in the placebo group did not (P ⫽ .20). In other dehydration and/or decreased oral intake, patients had
words, the proportion of patients in the treatment group frequently already developed delirium and were there-
judged by the treating physicians to have received a benefit fore unable to give consent for participation in the study.
was greater than 50%, with a significance level of .0035. In Future studies should attempt to obtain consent for
contrast, the proportion of patients in the placebo group
judged by the treating physicians to have received a benefit
was not significantly different from 50%.
The mean score (on a scale of 1 to 7) given by the Table 3. Scores Indicating Patients’ and Investigators’ Perceptions of
Patient Well-Being and the Overall Effectiveness of Treatment
investigators for their overall perception of the importance
of the treatment benefit was 4.5 ⫾ 2.3 in the treatment Treatment
Group Placebo Group
group and 3.4 ⫾ 2.4 in the placebo group (P ⫽ .13; Table 3).
Perception Mean SD Mean SD P
The mean score given by patients was 3.8 ⫾ 2.2 in the
*
treatment group and 3.6 ⫾ 2 in the placebo group (P ⬎ .2). Well-being
Patient score 1.4 4.1 0.8 3.1 .3
The mean scores for the perception of an overall sensation Investigator score 1.2 3.9 0.9 2.7 .4
of well-being are also provided in Table 3. Overall effectiveness†
With subcutaneous administration of saline, the mean Patient score 3.8 2.2 3.6 2 .2
intensities of pain at the injection site were 2.10 ⫾ 2.95 and Investigator score 4.5 2.3 3.4 2.4 .1
1.75 ⫾ 2.55 for the treatment (n ⫽ 20) and placebo17 group NOTE. Both patients and investigators were unaware of the type of
(P ⫽ .1), respectively; the mean scores for injection-site hydration patients received.
Abbreviation: SD, standard deviation.
swelling were 0.82 ⫾ 1.13 and 1.41 ⫾ 1.66 (P ⫽ .64). There *
Differences in scores ⫽ day 2 minus baseline, scored on a 0 to 10
were no significant differences in Mini Mental State Exam- numeric scale.
†Scored on a 1 to 7 scale; 1 ⫽ no important benefit, 7 ⫽ greatly
ination score at baseline and day 2 between treatment and important benefit.
placebo group.

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Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
 Bruera et al
participation before this complication occurs or use a
design that allows proxy consent in patients who have
already developed delirium.
Our findings suggested that double-blind studies are
feasible and that patients identified for such studies are
generally willing to give consent. One of the major chal-
lenges for such studies will be to obtain appropriate funding
for conducting these studies, which are unlikely to be of
interest to the pharmaceutical industry and so will have to
compete for the limited funding allocated by granting agen-
cies for clinical trials in palliative care.17
Some investigators were concerned about the possibil-
ity of clinical deterioration in the placebo group in a study
conducted over multiple days. Patients, without receiving
hydration, are likely to develop neurologic, renal, and car-
diovascular complications as a result of the rapid decrease
in intravascular volume. Clinicians who routinely adminis-
ter parenteral hydration and believe there are clinical ben-
efits from hydration have ethical concerns about randomly
assigning patients to a placebo group. Future clinical trials
of parenteral hydration should ideally be conducted in set-
tings where hydration is not routinely administered, such as
hospices. Therefore, the final assessment was conducted at
the end of the infusion on day 2, which meant that the final
assessment compared the differences between the treatment
and placebo groups over a period of less than 36 hours. It is
likely that much more significant differences will occur over
time. Because the outcomes of this study were mostly of a
neuropsychiatric nature, future studies should include more
investigator assessments, given that delirium is an extremely
frequent event in patients with advanced cancer and dehydra-
tion and that such patients may not be able to complete their
own assessments.18 Family assessments regarding neuropsy-
chiatric symptoms may be an important outcome as patients
become progressively unresponsive. The lack of changes in
cognition as measured by the Mini Mental State Examination
is not surprising because normal cognition was a criterion for
eligibility in these patients, and therefore there was very limited
room for improvement. The outcomes chosen for this study
were those found to be influenced by hydration in previous
retrospective studies.10-12,14 Dry mouth and thirst were not
included because previous research has shown that the associ-
ation between these symptoms and the hydration status of
patients with cancer is limited.19,20
The fact that 59% of patients in the placebo group per-
ceived important overall symptomatic benefit after less than 36
hours emphasizes the need for double-blind studies. Our
group has observed a large placebo effect in other symptom
control studies in advanced cancer patients.21-24 It is possible
that frequent contact with investigators results in improved
symptom expression. Findings of this study and our previous
experience21-24 suggest that a placebo control is very important
even for preliminary symptom control studies. Our findings
suggested that this blind perception of overall effectiveness
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Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
might not be sensitive enough to detect the effects of full
hydration compared with specific symptom assessments. The
most effective outcomes will need to be carefully defined in
future clinical trials. Prospective pilot studies of rehydration
conducted on an open basis may help better delineate target
symptoms for future randomized clinical trials.
Dehydration can cause various severe symptoms that
can be difficult to interpret in terminally ill cancer patients
because similar symptoms can be caused by the cancer itself
or by the drugs the patient is taking25; such symptoms
include dry mouth, cognitive failure, myoclonus, hallucina-
tions, hyperalgesia, and grand mal seizures.26,10 Dehydra-
tion can also result in fatigue, nausea, postural hypotension,
fever with no underlying infectious process, increased risk
for bedsores, and constipation.26-28 On the other hand,
parenteral hydration can increase the risk for edema and
respiratory distress and requires that patients remain at-
tached to an infusion device and undergo venipunctures. In
addition, intravenous hydration is costly and difficult to
maintain at home and, therefore, frequently requires pa-
tients to remain in the hospital until death.4-6
Our study found that hydration resulted in rapid de-
creases in the level of sedation, and myoclonus and a trend
toward a decreased level of hallucinations. These benefits may
have resulted from the hydration per se or simply from an
increased elimination of active opioid metabolites from our
patients, all of who were receiving opioids for their pain.15,18,25
This issue can be addressed in future studies by stratifying
patients according the use of opioid therapy. From a pragmatic
perspective, however, given that more than 80% of terminally
ill cancer patients receive opioids, future clinical trials should
focus mostly on patients such as those in our study.
Our findings suggest that clinical symptom improvement
can be observed with a volume of hydration of approximately
1,000 mL/d. Previous research has shown that patients treated
by palliative care teams receive significantly smaller volumes of
hydration compared with those admitted to cancer centers.29
Subcutaneous hydration with a total daily volume of approxi-
mately 1,000 mL can be easily achieved at home, can be admin-
istered by patients and family members independently,6,9,14
and—as our preliminary findings suggest— can result in mea-
surable symptomatic improvement.
Few areas of clinical care involve such disparity in
clinical practice, such passionate rhetoric, and such lack of
evidence as hydration near the end of life.5-9,15,20,26 Appro-
priately powered, randomized, double-blind studies with
longer follow-up periods and more investigator-measured
clinical outcomes than we used are required to help resolve
some of these issues.
■ ■ ■
Authors’ Disclosures of Potential
Conflicts of Interest
The authors indicated no potential conflicts of interest.
JOURNAL OF CLINICAL ONCOLOGY

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