Adrenocorticotropic Hormone Stimulation During Adrenal
Vein Sampling for Identifying Surgically Curable Subtypes
of Primary Aldosteronism
Comparison of 3 Different Protocols
Teresa M. Seccia, Diego Miotto, Renzo De Toni, Gisella Pitter, Franco Mantero,
Achille C. Pessina, Gian Paolo Rossi
Downloaded from http://hyper.ahajournals.org/ by guest on April 13, 2017
Abstract—Adrenocorticotropic hormone administration was proposed to overcome the biases associated with pulsatile
aldosterone secretion during adrenal venous sampling, but the usefulness of different protocols of stimulation was never
systematically assessed. We, therefore, compared the effects of a high dose (HD; 250 ␮g IV as a bolus), a very low dose
(VLD; 250 pg IV), and an intermediate dose (ID; 50 ␮g/h) of adrenocorticotropic hormone on the selectivity index (SI)
and the lateralization index in primary aldosteronism patients, using the diagnosis of aldosterone-producing adenoma,
based on pathology and follow-up data, as a reference. The HD (n⫽47) significantly increased plasma cortisol
concentration in infrarenal inferior vena cava (⫹79%) blood and the SI on both sides (SIRIGHT ⫹113% and SILEFT
⫹131%), as compared with baseline values. The ID (n⫽14) also markedly increased both plasma cortisol concentration
inferior vena cava (⫹93%) and the SI (SIRIGHT ⫹690% and SILEFT ⫹410%); the very low dose (n⫽6) had no effect on
either the plasma cortisol concentration or SI. In the patients with unilateral aldosterone-producing adenoma, the
increase of selectivity with the HD and ID was counterbalanced by a confounding effect on the correct identification
of the aldosterone-producing adenoma side, which was attributed to the wrong side in 3.0% and 12.5% with HD and
ID, respectively. In conclusion, the HD and the ID, but not the very low dose, adrenocorticotropic hormone stimulation
protocol facilitated the ascertainment of selectivity of adrenal vein catheterization. However, this favorable effect was
overridden by a confounding effect on the identification of lateralized aldosterone excess to the aldosterone-producing
adenoma side. Hence, we do not recommend adrenocorticotropic hormone stimulation. (Hypertension. 2009;53:00-00.)
Key Words: aldosteronism 䡲 adrenal venous sampling 䡲 adenoma 䡲 ACTH 䡲 cortisol
A
confound the identification of the side harboring the aldosterone-producing adenoma (APA).9,10 Nonetheless, if other
doses and protocols of ACTH administration5,7,8 had similar
effects or whether they might improve the diagnostic accuracy of AVS remained to be determined.
This study was, therefore, set up to prospectively compare
the effects of a very low dose (VLD), an intermediate dose
(ID), and a maximal ACTH dose administered during AVS
on the ratio between plasma cortisol concentration (PCC) in
the right or left adrenal vein and the infrarenal inferior vena
cava (IVC), herein termed selectivity index (SI), and the ratio
of plasma aldosterone concentration (PAC):PCC on the side
with the higher ratio over the contralateral PAC to PCC,
herein defined as the lateralization index (LI).9
drenal vein sampling (AVS) is considered the gold
standard for diagnosing the surgically curable subtypes
of primary aldosteronism.1,2 However, the pulsatile nature of
aldosterone secretion, which can even be augmented in
patients with hyperaldosteronism under the stressful condition occurring during AVS,3 can create artificial gradients
between the sides, particularly when the sequential blood
sampling technique is used, and, therefore, hamper the
diagnostic accuracy of AVS.
To overcome these potential biases, in 1979, Weinberger et
al4 introduced the stimulation with adrenocorticotropic hormone (ACTH), which was thereafter widely used,5– 8 even
without conclusive evidence for its advantages. Recent studies with bilaterally simultaneous AVS where baseline and
post-ACTH AVS data were compared head to head indicated
that a maximal (250 ␮g as an IV bolus) ACTH dose facilitates
the ascertainment of selectivity of catheterization during
AVS.9,10 They also suggested, however, that this dose can
Methods
Patient Selection
Among the patients referred for suspected primary aldosteronism
(PA) at the Specialized Centre for Hypertension in the Department of
Received December 27, 2008; first decision January 27, 2009; revision accepted March 11, 2009.
From the Department of Clinical and Experimental Medicine-Internal Medicine 4 (T.M.S., R.D.T., G.P., A.C.P., G.P.R.), Institute of Radiology (D.M.),
and Department of Medical and Surgical Sciences (F.M.), University of Padua School of Medicine, Padua, Italy.
Correspondence to Gian Paolo Rossi, DMCS-Clinica Medica 4, University Hospital, via Giustiniani 2, 35128 Padova, Italy. E-mail
[email protected]
© 2009 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.org
DOI: 10.1161/HYPERTENSIONAHA.108.128553
1
2
Hypertension
May 2009
Table 1. Clinical and Biochemical Features of Patients and Effects of
Adrenalectomy
Adrenalectomy
Variable
Before
After
P
Age, y
51⫾12
…
…
35/32 (52/48)
…
…
0.001
Gender (male/female), %
Systolic blood pressure, mm Hg
151⫾3
128⫾2
Diastolic blood pressure, mm Hg
96⫾2
84⫾2
0.001
Serum K⫹ levels, mmol/L
3.1⫾0.1
4.3⫾0.1
0.001
Supine PRA, ng/mL per h
0.38 (0.20 to 1.90)
0.82 (0.34 to 2.50)
NS
Supine aldosterone, ng/dL
23.1 (12.1 to 82.9)
10.1 (2.3 to 15.8)
0.014
ARR, ng/dL:ng/mL per h
61.6 (14.0 to 231.0)
9.4 (0.9 to 18.5)
0.017
…
…
Tumor size, mm
18 (10 to 75)
Data are mean⫾SE or median (range), as appropriate. . . . indicates no data; NS, not significant;
PRA, plasma renin activity; ARR, aldosterone: renin (PRA) ratio. To convert to SI units, multiply
picomoles per liter of aldosterone for 27.76.
Downloaded from http://hyper.ahajournals.org/ by guest on April 13, 2017
Clinical and Experimental Medicine of the University Medical
School of Padua from 2001 to 2007, those who had unequivocal
biochemical evidence of PA,11 no contraindications to surgery under
general anesthesia, and were willing to have laparoscopic adrenalectomy were offered AVS and recruited for this study. Exclusion
criteria were composed of coexisting heart failure or renal
insufficiency.
The patients were prepared from the pharmacological standpoint
by stopping diuretics, ␤-blockers, angiotensin-convertin enzyme
inhibitors, and angiotensin II receptor blockers ⱖ2 weeks before and
mineralocorticoid receptor antagonists ⱖ6 weeks before AVS, as
reported.11 AVS was undertaken after correction of hypokalemia, if
present, with oral or intravenous potassium ion supplementation. All
of the procedures followed the institutional guidelines, adhered to the
principles of the Declaration of Helsinki, and were approved by the
institutional review committee. An informed written consent was
obtained from each participant.
Plasma renin activity, aldosterone, cortisol, and ACTH were assayed,
as described.9 The diagnosis of APA was based on the “4 corners”
approach11 that required all of the following: (1) biochemical
diagnosis of PA; (2) lateralization of aldosterone secretion of AVS;
(3) evidence of adrenocortical adenoma at imaging, including computed tomography or magnetic resonance and/or pathology; and (4)
follow-up demonstration of correction of the hyperaldosteronism and
an unequivocal fall of blood pressure.14
AVS Procedure
Statistical Analysis
AVS was performed with bilateral simultaneous catheterization, eg,
by using 1 catheter for each adrenal vein, before and after stimulation
with synthetic ACTH (Synacthen, Novartis), as described.9 The
following protocols of ACTH administration were used: (1) a high
dose (HD; 250 ␮g as an IV bolus; n⫽47); (2) an ID (100 ␮g ACTH
as a priming dose followed by 50 ␮g/h of infusion; n⫽14); and (3)
a VLD (250 pg ACTH as a priming IV bolus followed by 0.5 pg/min
of infusion; n⫽6).
All of the AVS studies were performed by the same experienced
radiologist (D.M.) with the same methodology, as described.11 Blood
samples for the measurements of PAC and PCC were obtained from
the infrarenal IVC and the right and left adrenal veins by gravity at
baseline (t0) and again 30 minutes after ACTH stimulation (t30). On
the left side, the catheter remained in the adrenal vein during the
entire procedure. On the right side, it was withdrawn from the vein
after obtaining the t0 sample to avoid the risk of thrombosis; it was
thereafter repositioned in the vein to collect the blood sampling at
t30. Because of these differences, the effects of ACTH on the AVS
results of the left and right sides were analyzed separately to avoid any
bias associated with the repositioning.
Definitions
The SI was calculated as the ratio between PCC in the right or left
adrenal vein and the infrarenal IVC.9 The LI was assessed as the ratio
of PAC:PCC on the side with the higher ratio over the contralateral
PAC to PCC, as described.10 The cutoff value for ascertaining
selectivity of 1.1 was established previously using a receiver operator characteristic curve analysis.10,12 The fact that the right adrenal
vein shares egress in the IVC with hepatic accessory veins carrying
blood with a much lower PCC concentration in ⬇11% of the
patients13 justifies the selection of this seemingly low value.10,12 The
LI cutoff for diagnosing lateralization was similarly determined
using the diagnosis of APA as the referent.12 For the reasons detailed
previously,12 the LI was calculated only when SI values at t0 were
ⱖ1.1 on both sides.
Diagnostic Criteria
Results are expressed as mean⫾SEM or median and range, as
appropriate. Because of the skewed distribution of PAC and PCC,
values were examined after achievement of a Gaussian distribution
with log transformation. ANOVA and Bonferroni’s posthoc test
were used to compare variables across the groups; a paired t test was
used to compare baseline with ACTH-stimulated log-transformed
variables. Statistical significance was defined as P⬍0.05 (2 sided).
SPSS 16.0 for Windows (SPSS Italy, Inc) was used for the analysis.
Calculation of Power
A 2-group t test with a 0.05 2-sided significance level had a 94%
power to detect a difference between HD and ID means of 55,
assuming that the common SD was 50, given sample sizes of 47 and
14, respectively (nQuery Advisor 6.0, Statistical Solutions). With
similar assumptions, the study had a 77% power to detect a
difference between HD and VLD means with sample sizes of 47 and
6, respectively. With these sample sizes, the power to detect a
difference between t0 and t30 values using a paired t test was ⬎99%
for the HD versus ID comparison and ⬎90% for the HD versus VLD
comparison.
Results
Clinical Features of Patients
Sixty-seven consecutive consenting patients (33 men and 34
women; mean age: 51⫾12 years) met the inclusion criteria
and were recruited. Their main demographic and clinical
Seccia et al
characteristics (Table 1) were evidence of suppressed PRA
and elevated PAC, which translated in a prominent elevation
of the aldosterone:renin ratio. In computed tomography, the
median maximum diameter of the APA was ⬍20 mm.
ACTH Stimulation During Adrenal Vein Sampling
t 0 (baseline)
t 30 (30min after ACTH stimulation)
A
10000
P < 0.001
AVS Procedure
P < 0.001
SIRIGHT (%)
No adverse effects occurred during AVS. In 4 of the 67
patients, right adrenal vein cannulation was unfeasible at t30;
therefore, they were excluded from analyses concerning the
post-ACTH data.
Overall, after ACTH stimulation, 100% and 82% of the AVS
studies were selective on the left and on the right, respectively. The HD and the ID markedly stimulated cortisol
secretion from both sides, as evidenced by an increase of the
SI bilaterally (SIRIGHT ⫹113%, from baseline P⬍0.001;
SILEFT ⫹131%, P⬍0.001 with HD; SIRIGHT ⫹690%,
P⬍0.01; SILEFT ⫹410%, P⬍0.001 with the ID; Figure 1A
and 1B). Hence, both doses significantly increased PCC in
the infrarenal IVC (PCCIVC; ⫹79%, P⬍0.001; ⫹93%,
P⬍0.001, respectively, from t0 values). Although the percentage increase from baseline of PCC in the IVC did not differ
between the HD and the ID; Figure 2A), the increase of the SI
was significantly greater with the ID than with the HD on
both the right and the left (Figure 1).
Compared to t0 values both the HD (⫹87%; P⬍0.0001) and
the ID (⫹129%; P⬍0.001) significantly increased PACIVC,
without significant differences between the 2 doses (Figure
2B). By contrast, the VLD did not significantly increase the
SI on both sides (Figure 1A and 1B), the PCCIVC (Figure 2A)
and the PACIVC (Figure 2B).
ACTH Doses for the Identification of Lateralized
Aldosterone Secretion
To assess the outcome of the ACTH administration protocols
on the identification of the APA side, we used APA diagnosed with tight criteria as referent.11 Because the VLD did
not affect PCCIVC and PACIVC appreciably, this analysis was
confined to the HD and ID protocols. We found that neither
dose increased the LI (Figure 3); the HD actually lowered it
significantly, likely because the larger sample size in this
group decreased the spread of the values and, thus, enhanced
the statistical power.
P < 0.001
NS
10
B
1000
High
Intermediate Very Low
ACTH Dose
P < 0.001
P < 0.001
P < 0.001
SILEFT (%)
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Effects of the Different ACTH Protocols
1000
100
Baseline AVS Results and Effect of Adrenalectomy
At baseline, AVS was selective in 98% and 77% of the cases
on the left and on the right, respectively. Thirty-eight patients
(60%) with a lateralized aldosterone secretion were presumed
to harbor an APA. Of them, 35 patients underwent laparoscopic adrenalectomy and could be followed-up. All showed
complete correction of the hyperaldosteronism at follow-up;
moreover, hypertension was cured in 33%, markedly improved in 53%, and mildly improved in 13% by the criteria
defined previously.14 Three patients refused adrenalectomy
despite having initially consented to it; they were not used to
analyze the diagnostic accuracy of t0 and t30 AVS data.
3
NS
100
10
High
Intermediate Very Low
ACTH Dose
Figure 1. Effects of the 3 ACTH protocols on the SIRIGHT (A) and
SILEFT (B) sides. An increase of the SI was evident bilaterally
after both the HD and the ID as a result of the marked stimulation of cortisol secretion from both sides. No changes were
found after the VLD. The value under baseline conditions for
each ACTH dose was set to 100%, and therefore the black bars
show the percent change from baseline.
Overall, after ACTH, the proportion of correctly lateralized
AVS studies was 60.6% and 50.0% with the HD or the ID,
respectively (Table 2). These rates correspond with a fall of
22.4% and 33.0% of correctly lateralized AVS studies as
compared with baseline AVS results. After the HD, aldosterone excess was lateralized to the wrong side in 3.0% and not
lateralized in 36.4% of the APA, which would have led to
misdiagnosing APA as idiopathic hyperaldosteronism in
more cases (⫹19.4%), as compared with t0 AVS results.
Because some centers use a cutoff for the LI of 5,8 we
investigated whether this cutoff would alter the results obtained with a cutoff of 2. We found that, with an LI cutoff of
5, the proportion of AVS studies correctly identified at t0 was
markedly lower (53.2%) than with a cutoff of 2 (83.0%; Table
3). Moreover, after the HD, this rate fell by 14.3% (to 39.4%);
therefore, the missed lateralization rate increased by the same
percentage to 60.6%.
Hypertension
A
PCC IVC (ng/mL)
200
May 2009
t0 (baseline)
t30 (30min after ACTH stimulation)
NS
P < 0.001
P < 0.001
150
NS
0
P < 0.02
NS
High dose
Intermediate dose
100
10
1
High
Intermediate Very Low
ACTH Dose
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NS
300
250
PAC IVC (ng/L)
NS
100
50
B
1000
LI
4
P < 0.001
P < 0.001
NS
200
150
100
50
0
High
Intermediate Very Low
ACTH Dose
Figure 2. A, Effects of the 3 different ACTH protocols on
PCCIVC. The HD and the ID similarly increased (P value not significant, for comparison) PCCIVC significantly vs t0 values. The
VLD induced no significant change. B, Effects of the 3 ACTH
doses on PACIVC. The HD and ID, but not the VLD, induced a
significant increase of PACIVC.
Discussion
Although AVS represents the gold standard for identifying
the surgically curable subtypes of PA,2,15 uncertainties on the
optimal protocol for maximizing its diagnostic performance
remain. We prospectively investigated the usefulness of 3
popular protocols of ACTH administration using bilaterally
simultaneous AVS to avoid the potential bias associated with
the different timing of blood sampling between sides.
ACTH dose
Figure 3. Effects of the high and intermediate ACTH protocols
on identification of the lateralized aldosterone secretion. On
average, neither protocol increased the LI but rather lowered it,
although the decrease was significant only with HD.
The ID, a 10-fold lower dose, has also been extensively
used at some centers,8,16,17 but its advantages have never been
shown thus far. In our hands, this dose, given as a bolus
followed by a continuous infusion, elicited results quite
similar to those of the HD: it increased PCC in the adrenal
vein and, to a lesser extent, in the IVC blood, where the
changes of adrenal hormone concentration reflect the contribution of both adrenal glands (Figure 2); hence, it enhanced
the SI. These results confirm findings of a smaller study with
the HD9,10 and extend to the ID the conclusion that ACTH
stimulation facilitates the ascertainment of selective adrenal
vein catheterization during AVS. The ID, given as a priming
dose followed by a continuous infusion, increased the SI on
both sides to a significantly greater extent than the HD,
indicating that it induces a more sustained cortisol response,
at least within the 30-minute time span of this study.
Much lower doses of ACTH have also been contended to
enhance the diagnostic accuracy of AVS,5,7 because APA
would be exquisitely sensitive to ACTH.18,19 An overstimulation of the “healthy” gland might, therefore, blunt the
aldosterone gradient between the APA and the contralateral
side. The effect of the lowest ACTH proposed thus far,5,7 ⬇1
Table 2. Proportion of Correctly and Misclassified
Lateralization Rates and Changes From Baseline (t0) After
ACTH Stimulation (t30) of AVS Protocols in Patients With
Unilateral APA
LI Cutoff⫽2
Effect of ACTH Stimulation Protocols on Cortisol
Secretion and SI
The HD (250 ␮g as IV bolus) was initially used based on the
hypothesis that it could maximally stimulate hormone secretion, minimize the confounding effects of stress and pulsatile
hormone secretion, thus enhancing the identification of surgically curable PA subtypes. We found that this ACTH dose
markedly stimulates cortisol secretion and, therefore, facilitates the ascertainment of selectivity of adrenal vein catheterization, thus supporting previous results9,10
LI Cutoff⫽5
HD ACTH,
%
ID ACTH,
%
HD ACTH,
%
ID ACTH,
%
Lateralization to the
correct side
61 (⫺22)
50 (⫺33)
39 (⫺14)
50 (⫺3)
Lateralization to the
wrong side
3 (⫹3)
12 (⫹12)
…
…
Missed lateralization
36 (⫹19)
37 (⫺20)
61 (⫹14)
50 (⫹3)
Lateralization
Values in parentheses are percentage changes for t30 from t0. . . . indicates
no data.
Seccia et al
Table 3. Percentage of Correctly Lateralized AVS Studies at
t0 and t30 After HD and ID ACTH Stimulation at Different
Cutoffs of the LI in 47 Patients Who Have Bilaterally
Selective AVS Studies
LI Cutoff Value
AVS Studies
2.0, %
5.0, %
Baseline (n⫽47)
83
53
HD ACTH (n⫽33)
61
39
ID ACTH (n⫽8)
50
50
Overall ACTH (n⫽41)
58
41
Overall ACTH includes AVS studies with both HD and ID.
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million-fold lower than the HD, on cortisol and aldosterone
secretion, was, therefore, investigated to test this hypothesis.
We found that the VLD had no appreciable effect on PCC in
the IVC and adrenal vein blood. Hence, under the moderately
stressful conditions occurring during AVS, this dose of
ACTH stimulation does not improve the selectivity of AVS.
ACTH Stimulation Protocols and
Aldosterone Secretion
The VLD induced no changes in PAC in the infrarenal IVC
blood, thus supporting the conclusion that this dose is too low
to induce any measurable change of the adrenocortical
hormone secretion during AVS. The changes of PACIVC with
the HD or the ID protocol paralleled those of PCCIVC and did
not differ significantly between doses. Thus, unlike the VLD,
these doses equipotently stimulate adrenocortical hormone
secretion.
ACTH Doses for the Identification of Lateralized
Aldosterone Secretion
The adoption of strict predefined diagnostic criteria based on
surgery, pathology, and follow-up data permitted us to
conclusively diagnose unilateral forms of excess aldosterone
secretion,11 which entailed APA in 82% and multiple unilateral adrenocortical micronodules in 1 of our patients. The
hyperaldosteronism was cured postadrenalectomy in all;
moreover, all exhibited a clear-cut fall of blood pressure
and/or medications postadrenalectomy. Hence, the adrenalectomy side could be used as a referent to determine whether
the HD and ID protocols improved the identification of
surgically curable PA. On average, both the HD and the ID
protocols induced a decrease, rather than the anticipated
increase of the LI (Figure 3), thus confirming results of
previous smaller studies,9,10 as well as the heterogeneous
nature of the APA responsiveness to ACTH in vivo.9
The LI value depends by definition on the secretion of
aldosterone from the APA side and from the contralateral
adrenal cortex. Moreover, contralateral suppression was contended to be a distinctive feature of APA,5 this notwithstanding the fact that in situ hybridization studies evidenced
persistent aldosterone synthesis even in the adrenal cortex
surrounding the APA.20 Therefore, it was worth examining
the aldosterone secretion response to ACTH of the contralateral gland as well. After we found a paradoxical blunting of
lateralization with the HD,9 we hypothesized that this HD
ACTH Stimulation During Adrenal Vein Sampling
5
could trigger a response not only of the gland harboring the
presumably “more ACTH-sensitive” APA but also of the
“less sensitive” contralateral gland. An ACTH dose within
the “physiological range” could be devoid of such undesirable action and might, therefore, be useful for revealing an
APA in the patients without lateralization at a baseline. Our
results with either the VLD or the ID do not lend any support
to this contention. Instead, they suggest that ACTH stimulation can lead to erroneous results in terms of ascertaining
lateralization of aldosterone excess in a substantial rate of
cases (Table 2), regardless of the choice of the cutoff value
for the SI. The molecular heterogeneity of APA in terms of
steroidogenic enzymes and regulatory factor gene expression
revealed by whole transcriptome studies,21 rather than the
ACTH dose or protocol used to stimulate the adrenal secretion,
could account for the variable effects of ACTH on the LI.
Clinical Implications of These Results
From the practical standpoint, the administration of ACTH
during AVS with the HD or the ID protocol facilitates the
ascertainment of selectivity but translates into the failure to
identify correctly the APA side in 3.0% and 12.5%, respectively. Furthermore, misclassification of the APA as idiopathic hyperaldosteronism occurred in more than one third of
the cases with both doses (Table 2). Thus, ACTH stimulation
can be more confusing than useful for identifying the surgically curable subtype of PA.
Using the popular cutoff value of 5 for the LI, lateralization
to the APA side was seen in less AVS studies than with a
cutoff of 2; moreover, a greater proportion was misdiagnosed
as having idiopathic hyperaldosteronism with the HD and
with the ID (Table 2). Thus, the diagnostic accuracy of the
AVS studies markedly fell with either dose, leading to the
preclusion of curative adrenalectomy in a fairly large rate of
PA patients.
Limitations of the Study
The use of simultaneous bilateral AVS was necessary in this
study to avoid a time-related bias in the evaluation of the
ACTH effect. Because most centers do not use simultaneous
bilateral sampling procedures, it might be argued that the
present results do not apply to studies using a single-catheter
approach. However, this seems unlikely, because at experienced centers, the time difference between the right and left
adrenal vein catheterization is usually only few minutes, eg,
well within the 30-minute time span of the ACTH effect on
hormone secretion that we documented in this study.
Conclusions
A high and an intermediate ACTH dose stimulated cortisol
secretion from the adrenal with APA and from the contralateral one, thus improving the ascertainment of the selectivity
of adrenal vein catheterization during AVS. By contrast, the
lowest previously proposed dose5,7 had no appreciable effect
on cortisol secretion and, therefore, was not helpful for
confirming the selectivity of AVS. The improvement in the
ascertainment of selectivity occurring with both the high and
the intermediate ACTH doses was overridden by the confounding effect on identification of lateralized aldosterone
6
Hypertension
May 2009
excess. Therefore, we do not recommend using systematic
ACTH stimulation.
10.
Perspectives
Further investigation should be devoted to determine whether
the HD given as a bolus plus a continuous infusion would
produce identical results to the ID. Moreover, whether other
stimulatory tests22 can provide better results remains a goal
for future research.
Sources of Funding
11.
12.
This work was supported by grants from FORICA and the Società
Italiana dell’Ipertensione Arteriosa (to A.C.P. and G.P.R.) and from
the University of Padova (to T.M.S.).
13.
Disclosures
None.
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