Does Low-Dose Intravenous Methylprednisolone Pulse Therapy Produce Unacceptable Adverse Effects in Children?

doi:10.4236/ojneph.2013.34033

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Open Journal of Nephrology, 2013, 3, 189-193

Published Online December 2013 (http://www.scirp.org/journal/ojneph)

http://dx.doi.org/10.4236/ojneph.2013.34033

Open Access OJNeph

Does Low-Dose Intravenous Methylprednisolone

Pulse Therapy Pr oduce Unacceptable Adverse

Effects in Children?*

Daishi Hirano1,2, Shuichiro Fujinaga1, Amane Endo1, Tsuneki Watanabe1, Hi ro y u ki Ida2

1Division of Nephrology, Saitama Children’s Medical Center, Saitama, Japan

2Department of Pediatrics, Jikei University School of Medicine, Tokyo, Japan

Email: [email protected]

Received September 22, 2013; revised October 20, 2013; accepted November 15, 2013

which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ABSTRACT

Background: Intravenous methylprednisolone pulse therapy has been used since the late 1960s for acute transplant

rejection or severe renal involvement in systemic lupus erythematosus and primary glomerulonephritis. However, re-

ports of serious adverse effects such as life-threatening cardiac arrhythmias and sudden death raise questions about its

safety. Objective: To investigate the incidence of significant adverse effects associated with low-dose methylpredniso-

lone pulse therapy (LDMPT) in pediatric patients. Methods: We retrospectively analyzed adverse effects during and

after LDMPT in 68 patients (median age: 11.4 years; 43% male) with various glomerular diseases who were admitted to

Saitama Children’s Medical Center between April 2007 and December 2010. LDMPT consisted of pulse methylpred-

nisolone (15 - 20 mg/kg; maximum 600 mg/d) for 3 consecutive days weekly for 2 - 3 weeks. Results: Although ad-

verse effects occurred in 54 of 68 patients (79%), most were mild and transient. Transient glycosuria was noted in 46

patients (68%), hypertension in 6 (9%), elevated intraocular pressure in 6 (9%), hypokalemia in 5 (7%), and liver dam-

age in 2 (3%). No late-onset adverse effects such as osteoporotic fractures, steroid diabetes mellitus, or short stature

were observed. Conclusion: LDMPT appears to be relatively safe and well tolerated in children with various glomeru-

lar diseases.

Keywords: Methylprednisolone Pulse Therapy; Adverse Effects; Side Effects; Steroid; Children

1. Introduction

Conventional high-dose intravenous methylprednisolone

pulse therapy (HDMPT) first came into clinical use over

40 years ago to treat acute renal graft rejection. Although

MPT has since become an essential tool for clinicians

treating various kidney diseases, little is known about its

mechanism of effect and magnitude of associated adverse

effects [1-5]. The most serious problems associated with

HDMPT in adults are cardiovascular reactions, including

death [6,7], but in children, the adverse effects are re-

ported by some researchers to be quite different [8]. The

most common adverse effects in children are psychiatric

reactions (e.g., mood alteration, hyperactivity, psychosis,

disorientation, and sleep disturbances), which are seen in

about 10% of children receiving HDMPT [8]. According

to recent reports, these adverse effects are associated

with higher doses of methylprednisolone (mPSL) and

higher rates of intravenous administration [5,9]. In fact,

Klein-Gitelman et al. reported that remarkable improve-

ment was observed in some children with a decreased

dose or an increased time interval between administra-

tions [8]. However, adverse effects of decreased doses of

mPSL have not been clearly delineated. Based on these

reports, we now treat a variety of kidney diseases using

“low-dose” MPT (LDMPT), which extends the infusion

time (>2 h) and reduces the dosage, in order to reduce

adverse effects. The objective of this study was to deter-

mine the frequency and severity of adverse effects asso-

ciated with LDMPT in pediatric patients.

2. Patients and Materials

2.1. Patients

In this retrospective case series study, we collected and

*The authors have no conflicts of interest to declare.

D. HIRANO ET AL.

190

analyzed data on 196 courses of LDMPT given to 68

children (29 boys, 39 girls) at the Saitama Children’s

Medical Center in Saitama, Japan from April 2007

through December 2010. Informed consent was obtained

from the patients’ parents. Prior to LDMPT, all patients

were given a complete physical examination in order to

screen and exclude those with known infections, uncon-

trolled hypertension, congestive heart failure, or uncon-

trolled diabetes mellitus. The physical examination in-

cluded measurement and evaluation of systolic blood

pressure, diastolic blood pressure, and baseline chemistry

parameters. Only data from patients with normal values

for these parameters were included in the analysis.

2.2. Low-Dose Methylprednisolone Pulse

Therapy

LDMPT was defined as mPSL administered at a dose of

15 - 20 mg/kg/d (maximum: 600 mg/d) in 50 - 100 ml of

5% dextrose solution given intravenously over 2 h for 3

consecutive days weekly for 2 - 3 weeks. In comparison,

the “high dose” for HDMPT is 30 mg/kg/d (maximum 1

g/d). All LDMPT administrations took place in a hospital

setting under physician supervision, with monitoring of

vital signs every 30 min or more frequently if an abnor-

mality was found or the patient experienced any symp-

toms.

2.3. Adverse Effects

Adverse effects were defined as any new symptom or

sign (e.g., skin rash, headache, dizziness, dysgeusia,

chest pain, palpitations, dyspnea, nausea, osteonecrosis

of the femoral head, psychiatric reaction, steroid diabetes

mellitus, and short stature) that appeared during or after

each LDMPT course Adverse effects were categorized as

either early or late onset. Early-onset adverse effects

were defined as those appearing during LDMPT or with-

in 4 weeks after initiation of LDMPT, and late-onset ad-

verse effects were defined as those appearing ≥4 weeks

after initiation of LDMPT. For late-onset adverse effects

such as osteonecrosis of the femoral head or short stature,

we analyzed data from 34 children with IgA nephropathy

(IgAN) who had been followed for ≥1 year. We identi-

fied other adverse sequelae from diagnostic procedures

such as laboratory tests or from records of vital signs

(blood pressure and heart rate changes) outside the nor-

mal range. We retrieved data from medical records rele-

vant to the number, frequency, and total dosage of

LDMPT administrations. We also collected information

pertaining to diagnosis, age, sex, laboratory data at the

time of reaction, other medications received, and history

of other adverse drug events.

2.4. Statistical Analysis

Continuous variables were expressed as median and

range; categorical variables were expressed as number

and percentage values. Statistical analysis was performed

using SAS software, version 9.3 (SAS Institute, Cary,

NC). Statistical significance was defined as p < 0.05.

3. Results

3.1. Patient Characteristics

Table 1 summarizes the characteristics of patients trea-

ted with LDMPT. The patients were 29 boys (43%) and

39 girls (57%), with a median age was 11.4 years (range:

1.4 - 18.1 years), who together had received 196 LDMPT

treatments. Underlying disease was IgAN in 35 patients

(51%), Henoch-Schönlein purpura nephritis in 20 (29%),

membranoproliferative glomerulonephritis in 6 (9%),

nephrotic syndrome in 5 (7%), and other in 2 (4%). Six-

ty-six children received <3 LDMPT treatments and 2

received ≥4 LDMPT treatments. Median mPSL dose was

15.0 mg/kg/d (range: 7.9 - 24.1 mg/kg/d); since the ma-

ximum mPSL dosage that could be given was 600 mg/d,

the dose could be <15 mg/kg, but could be slightly >20

mg/kg because standard size ampules (100 mg or 250 mg)

were used.

3.2. Early-Onset Adverse Effects

Early-onset adverse effects occurred in 54 of 68 children

(79%), but most were mild, transient, and required no

medical treatment (Table 2). Transient glycosuria, the

most common symptom, was seen in 46 children (68%).

It occurred within the first 3 doses of LDMPT, but usu-

ally disappeared soon after LDMPT course ended. Mild

hypertension was noted in 6 children (9%), but all re-

quired antihypertensive medication to control blood

pressure. These children continued LDMPT with the

antihypertensive agents without further significant ad-

Table 1. Baseline characteristics of patients receiving low-

dose methylprednisolone pulse ther apy (LDMP T).

Total number of patients 68

Sex (male/female) 29/39

Median age, years (range) 11.4 (1.4 - 18.1)

Number of LDMPT courses

Total number of LDMPT courses 196

1 - 3 times/patient 181/66

>3 times/patient 15/2

Disease, n (%)

IgA nephropathy 35 (51)

Henoch-Schönlein purpura nephritis 20 (29)

Membranoproliferative glomerulonephritis 6 (9)

Nephrotic syndrome 5 (7)

Other 2 (4)

Open Access OJNeph

D. HIRANO ET AL. 191

Table 2. Adverse effects during and after low-dose methyl-

prednisolone pulse therapy.

Adverse effect n (%)

Transient glycosuria 46 (68)

Hypertension 6 (9)

Elevated intraocular pressure 6 (9)

Hypokalemia 5 (7)

Elevated liver transaminase levels 2 (3)

Severe adverse effect

Bacterial infection 0 (0)

Cardiac arrhythmia 0 (0)

Bradycardia 0 (0)

Thrombosis 0 (0)

Peptic ulcer 0 (0)

Acute pancreatitis 0 (0)

Neuropsychiatric disorder 0 (0)

verse effects. Other adverse effects associated with

LDMPT included elevated intraocular pressure, hypo-

kalemia, and liver damage, which were detected in 6

(9%), 5 (7%), and 2 (3%) patients, respectively. None of

the children needed treatment for severe adverse effects

such as cardiac arrhythmia, bradycardia, bacterial infec-

tion, thrombosis, peptic ulcer, acute pancreatitis, or neu-

ropsychiatric disorder.

3.3. Late-Onset Adverse Effects

To assess late-onset adverse effects, we analyzed data

from the 34 children with IgAN who had been given

bone density tests while being followed for ≥1 year. Me-

dian height of these patients at last observation was

−0.09 standard deviation score (SDS) for normal-for-age

height (range: −1.57 to +2.28 SDS), and none of these

patients had abnormally short stature (−2.0 SDS). There

were no statistical differences between the median SDS

before LDMPT and that for the last observation. We

found no documented case of osteonecrosis.

4. Discussion

This study investigated the frequency and severity of

adverse effects associated with LDMPT in pediatric pa-

tients. Although MPT has become an important thera-

peutic modality for clinicians treating autoimmune dis-

eases, there is as yet insufficient evidence for its mecha-

nism of action and magnitude of benefits and adverse ef-

fects [10]. Moreover, its adverse effects are reported to

differ between adults and children.

In a previous prospective study of the frequency and

severity of adverse reactions associated with HDMPT in

children with rheumatic disease, Klein-Gitelman et al.

found that 46% (22/213) had adverse reactions, although

none required hospitalization [8]. Baethge et al. also re-

ported that HDMPT had an acceptably low incidence of

significant adverse effects in adults [11]. In contrast,

Garrett et al. found adverse effects in 56% of a group of

adult patients with rheumatic disease who received

HDMPT, of whom 24% needed medical intervention

[12]. Undoubtedly MPT can lead to severe life-threat-

ening complications such as cardiac arrhythmias, sudden

death, circulatory collapse, and cardiac arrest [6,7]. How-

ever, most of the reported cases have involved adults

with underlying cardiac disease, usually following rapid

administration of large doses of mPSL (>500 mg admin-

istered over <10 min) [6]. In human studies, pulse dosing

of intravenous mPSL alters the stimulation threshold of

myocardial cells. It also alters serum potassium and uri-

nary excretion of both potassium and sodium. These

changes might conceivably alter electrolyte shifts across

the myocardial cell membrane [13,14]. In our study, pa-

tients were free of underlying cardiac disease prior to the

onset of renal disease or intractable hypertension. Also,

our patients were given mPSL over 2 h, with frequent

monitoring of vital signs, and no episodes of serious car-

diovascular adverse effects occurred. However, some did

experience hypertension that responded rapidly to appro-

priate intervention.

The most common adverse effect among our pediatric

patients was renal glycosuria. Glucocorticoids impair glu-

cose metabolism mainly by inducing insulin resistance

and increasing hepatic gluconeogenesis. Insulin resis-

tance appears to occur at both receptor and post-receptor

sites, and variations between glucocorticoids with regard

to insulin binding do exist. Glucocorticoids can also in-

duce hyperglycemia through the stimulation of α-cells,

leading to hyperglucagonemia and increased glycogenoly-

sis [15,16]. These hyperglycemic effects are responsible

for the so-called steroid diabetes observed in 25% (6) of

subjects treated with long-term oral corticosteroid thera-

py [17,18]. Unlike oral treatment, however, there is insuf-

ficient quantitative data on the hyperglycemic effects of

intravenous MPT. What we do know is that in a study by

Baethge et al. 19% (16/84) of adults with rheumatic dis-

ease had hyperglycemic effects associated with HDMPT,

with only 1 insulin-dependent patient requiring hypogly-

cemic therapeutic adjustment [11]. Feldman-Billard et

al.’s analysis of serial fasting blood glucose measure-

ments in 198 nondiabetic and 28 diabetic patients with

eye disease treated by MPT revealed that the diabetic

patients tended to show a cumulative hyperglycemic ef-

fect of iterative MPT, whereas nondiabetic patients were

able to spontaneously regulate MPT-induced hypergly-

cemia [19]. These findings indicate that close glycemic

monitoring is not needed during MPT with nondiabetic

patients.

Open Access OJNeph

D. HIRANO ET AL.

192

In a cohort of 539 patients with systemic lupus ery-

thematosus, Zonana-Nacach et al. found no association

between intravenous steroid therapy and osteoporotic

fractures, but did find an association with high dose oral

steroids, reporting a strong association between cumula-

tive prednisolone dose and adverse effects [20]. In our

study, we fortunately did not experience late-onset ad-

verse effects such as osteoporotic fractures, steroid dia-

betes mellitus, and short stature. This might be because

we administered a lower dose of oral mPSL (1 mg/kg/d,

maximum 30 mg/d) on alternate days after LDMPT.

The minimum effective dose of mPSL is unclear.

While one study has suggested that doses as low as 320

mg administered intravenously or intramuscularly are as

effective as 1 g of intravenous mPSL [21], another study

has shown that reducing the intravenous mPSL dose

from 1 g to 500 mg results in a substantial loss of effi-

cacy [22]. Our findings suggest that LDMPT could be a

potentially effective and safe alternative for pediatric pa-

tients with various glomerular diseases. However, more

studies are needed to further characterize the optimal

dosages and mechanisms of action of MPT.

5. Limitations

The present study was a retrospective analysis of treat-

ment performed at a single center, so there may be some

selection bias in the cohort. The single center cohort de-

sign also limits the external validity of our findings. In

addition, we could not determine the true frequency of

minor adverse effects such as metallic taste and facial

flushing because of the manner in which this retrospec-

tive study was performed. However, we are confident

that we did not miss any serious treatment complications.

6. Conclusion

This case series indicated that LDMPT might have an

acceptably low risk of significant adverse effects and

therefore can be an effective treatment modality for pe-

diatric patients with various glomerular diseases.

7. Tables

Table 1 summarizes the characteristics of patients treated

with LDMPT.

Adverse effects were categorized as either early or late

onset. And Table 2 summarizes the adverse effects dur-

ing and after low-dose methylprednisolone pulse therapy.

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