On the safety and tolerability of high-dose iv steroid pulses in Multiple sclerosis patients

On the safety and tolerability of high-dose iv steroid pulses in Multiple sclerosis patients

Evdokia Efthymiou1*, Céline Gächter1, Michael Linnebank1, 2

1Department of Neurology, University Hospital Zurich, Switzerland
2 Helios Clinic Hagen-Ambrock, Germany

  1. *Corresponding author: Dr. Evdokia Efthymiou, University Hospital Zurich, Department of Neurology, Frauenklinikstrasse 26, 8091 Zurich, Switzerland. Phone: 0041 44 255 1111; Fax: 0041 44 255 4429. Email: Evdokia.efthymiou@usz.ch

Abstract

Background:

High-dose steroid pulses, e.g. for the treatment of autoimmune disease, have possible life – threatening side effects.

Objective

To evaluate the safety of high-dose intravenous steroid treatment in patients with clinically isolated syndrome or Multiple Sclerosis in an outpatient setting.

Methods

Steroid pulses performed in our day hospital during 2009-2012 were analyzed.

Results

: In the analysis 175 patients were evaluated. Moderate hypokalaemia was detected in 3.6% at baseline (lowest level 3.1 mmol/l), 11.8% on day three (lowest level 3.0 mmol/l) and in 19.3% on day five (lowest level 2.9 mmol/l). The greatest decline (1.8 mmol/l) was observed in a patient with an initial hyperkalemia (5.4 mmol/l). No severe hypokalaemia occurred. At baseline, random blood glucose levels were normal in all patients. During treatment, seven patients showed hyperglycemia on day two, two on day three, one on day four and none on day five. No serious side effects occurred. The most frequent adverse events were sleep disturbances (24%), gastrointestinal side effects (12%) and facial flush/sweating (9.5%).

Conclusion

Steroid pulse treatment seems to be generally safe in an outpatient setting. Potassium and glucose levels should be monitored during treatment; as abnormal levels may occur in patients with initially normal levels as well

Keywords

side effects; steroid; multiple sclerosis; tolerability

Introduction

MS is an autoimmune disease affecting the central nervous system (CNS). Initially, most patients show a relapsing – remitting course of the disease, in which acute inflammatory lesions cause demyelination and axonal damage as histological correlates of clinical relapses. Usually, clinical symptoms of relapses due to lesions in the brain or the spinal cord develop within hours or a few days and show a complete or incomplete remission. Relapses may affect visual, motor, sensibility or autonomous function, depending on the lesions’ locations. Other than inflammation, MS is characterized by neurodegeneration which is not dependent to the relapses. Both, relapses and neurodegeneration contribute to the disability progression of multiple sclerosis patients. [1] Acute MS relapses are treated with intravenous or, less commonly, oral high dose steroid pulses. [2-5] Steroids close the blood – brain barrier, which is disturbed in acute MS lesions, and their anti-inflammatory effects contribute to an acceleration of the decay of the inflammatory activity and speed the clinical remission. [6] A steroid pulse, (e.g. 1000 mg/d methylprednisolone) is administered daily, usually intravenously for three to five days. Such therapies are usually well tolerated. Side effects and risks of short-term, high dose administration of steroids include fluid retention, hypokalemia, hyperglycemia, insomnia, psychiatric disorders, steroid ulcers, thrombosis, increased risk of infections, flushing, acne, metallic taste in the mouth, increased appetite and anaphylactic reactions. In three placebo – controlled trials, steroid – treatment of MS relapses was not associated with serious adverse events [7-9]. Milligan et al. reports as the most frequent side effects the reddening of the face, ankle swelling and a metallic taste in the mouth. In a study by Durelli et al. sleeping disturbances and mood changes were common side effects [8]. Sellebjerg et al. reported frequent gastrointestinal side effects [9]. In 150 patients treated with 250 mg intravenous methylprednisolone every six hours for three days due to optic neuritis, one patient developed psychotic depression and one acute pancreatitis, respectively, which were not observed in oral and the placebo treatment group [10], Glucose and potassium levels were measured in this trial, but were not reported in the results. A retrospective analysis by Lyons et al. reports 11 patients (4.6%) with glycosuria and elevated blood glucose levels, but no interventions were required [11].

Concerning the potential severe side effects including psychotic reactions, hyperglycemia, hypokalemia or anaphylactic reactions, there is still an uncertainty whether steroid pulses should be given in an inpatient or in an outpatient setting. Prior starting the therapy, patients should be screened for current infections, as steroids depress the cellular and humoral immune response [6], and since infections can exacerbate neurological symptoms in MS patients mimicking relapses. Steroids can lead to hyperglycemia by inducing gluconeogenesis via glucocorticoid effects and to hypokalemia via mineralocorticoid effects. Therefore, the potassium and glucose levels are monitored during a high dose steroid therapy.

In this retrospective single-center cohort study, we report the safety and tolerability of high dose steroid pulses in the treatment of MS relapses in an outpatient setting.

Methods

In our department, MS relapses are regularly treated with high – dose intravenous steroid pulses in an outpatient setting, unless patients require hospitalization due to the severity of relapses or other circumstances, which is rare. Retrospectively, we analyzed all steroid – treatments of MS relapses with high – dose steroids in our day hospital during three years, 2009 – 2012. Patients with clinically isolated syndrome as potential first manifestation of MS and patients with MS according to the McDonald 2005 or 2010 criteria were included [12,13]. The duration of treatment was three days, or, if symptoms were not clearly remitting by day three, five days. In the clinical routine, patients were asked daily about occurrence of the most relevant treatment side effects. All patients received a proton pump inhibitor (esomeprazole, 40 mg) per os during the treatment and low – molecular – weight heparin subcutaneously (adapted to body – weight) as thrombosis prophylaxis.

Potassium levels were measured at day one before starting high – dose steroid therapy, on day three and, if applicable, on day five. The reference range of our laboratory is 3.3 – 4.5 mmol/l. Random blood glucose (RBG) levels were measured before each steroid application (normal < 11.1 mmol/l).

This was a retrospective analysis of anonymized patient data that finished in 2014 and that also served for quality control. According to Swiss law this study did not require patient consent or an ethics vote.

Results

In the study 175 patients were included. The baseline characteristics are depicted in Table 1.

 

Table 1. Baseline characteristics

 

  N (percent)
Sex (Women) 122 (69.7%)
CIS 53  (30.3%)
MS 122 (69.7%)
Diabetes mellitus type 2 2    (1.1%)

 

CIS: clinically isolated syndrome; MS: multiple sclerosis; N: number of patients

 

Two patients had diabetes mellitus type 2 as concomitant disease. The number of analyzed patients decreased during the treatment period, as some continued the treatment in medical centers closer to their residences. No patient discontinued steroid therapy due to safety or tolerability issues.

 

In general, steroid therapy was well tolerated. No serious adverse events occurred. One patient was hospitalized for treatment continuation as experienced facial flush and shortness of breath for some minutes after the first steroid pulse. He tolerated the second pulse well, but mild symptoms reoccurred after the third application without changes in vital signs (blood pressure, heart rate or oxygen saturation). Symptoms disappeared after one hour without intervention.

 

Sleep disturbance was the most common side effect followed by gastrointestinal side effects, facial flush/sweating, headache and mood alterations/restlessness. Adverse effects based on questioning and self-reporting are listed in Table 2.

 

Table 2: Adverse events reported during steroid treatment.

 

Side effects N (percent)
Sleep disturbance 42 (24%)
Gastrointestinal side effects 21 (12%)
Facial flush/ sweating 18 (10%)
Headache 15 (8.5%)
Mood alterations/ restlessness 15 (8.5%)
Dizziness 7   (4%)
Taste alterations 6  (3.5%)
Shortness of breath 5  (3%)
Palpitations 3  (2%)
Edema 3  (2%)
Paresthesia 2  (1%)
Acne 2  (1%)
Pruritus 1  (0.5%)
Tinnitus 1  (0.5%)

N: Number of patients

 

Baseline potassium levels, shown in Table 3, ranged between 3.1 – 5.4 mmol/l (mean 3.8 mmol/l), while the lowest individual level during therapy was 2.9 – 4.8 mmol/l (mean 3.5 mmol/l). Hypokalemia was detected in six patients before and in 34 patients during treatment. Five patients with a low baseline potassium level had a value of 3.2 mmol/l, one patient had 3.1 mmol/l. Only in one case, the responsible physicians decided to initiate an oral substitution. Nevertheless, in four of the patients with low baseline hypokalemia, potassium levels increased during treatment without substitution, the sixth patient was treated elsewhere from day two on, follow up data was not available. 17 patients showed hypokalemia on the third day, with 3.0 mmol/l as the lowest individual level observed. In 12 of these patients a substitution was started (oral 1 – 2x 30mmol per day). Only one patient showed a further decrease, i.e. by 0.2 mmol/l. 17 further patients with normal potassium levels on day three had levels below the reference range on day five with 2.9 mmol/l as the lowest individual level. In two patients, an oral potassium substitution was initiated. However, five of the patients with baseline potassium values of 4.0 mmol/l or higher (N=54) developed hypokalemia during the steroid treatment. Three were substituted and showed an increase of potassium after substitution.

 

Table 3: Potassium level during steroid treatment.

 

  Patients with low potassium

(<3.3mmol/L)

Lowest potassium value

(mmol/L)

Baseline (N=167) 3.6 % (N=6) 3.1
Day 3     (N=144) 11.8 % (N=17) 3.0
Day 5    (N=114) 19.3 % (N=22) 2.9

 

N: number of patients

 

Altogether, 20 patients received oral potassium substitution. For 11 patients, follow -up potassium levels were available: in eight of them, potassium levels increased by 0.65 mmol/l in average (range: 0.2 – 1.1 mmol/l). Despite of oral substitution potassium levels continued decreasing slightly by 0.2 – 0.4 mmol/l in three patients. The largest individual decrease in potassium level during therapy ranged between 0 -1.8 mmol/l (mean 0.4 mmol/l). The largest decline was observed in a patient with hyperkalemia at baseline.

 

At baseline no patient presented with increased random blood glucose levels. During steroid pulse therapy nine patients developed an increased RBG (Table 4). Among the eight patients who showed an elevated RBG on the second and third day seven patients had no diagnosis of diabetes mellitus. One patient with diabetes exhibited an elevated RBG on the second and third day. The most increased RBG measurement was found in a patient without diabetes on the fourth day, RBG was normal in all patients on day five. Altogether, nine patients showed hyperglycemia at on any of the treatment days, including one of the two patients with known diabetes mellitus, who was non-compliant concerning his oral antidiabetic agents.

 

Table 4: RBG level during steroid treatment

 

  Increased RBG (N)

 

Highest RBG value

(mmol/L)

Baseline (N=160) 0 9.6
Day 2     (N=163) 7 (1) 13.2
Day 3     (N=162) 2 (1) 14.6
Day 4     (N=120) 1(0) 11.2
Day 5     (N=107) 0 9.8

 

RBG: Random blood glucose; DM: Diabetes mellitus type 2; N: number of patients

Discussion

This analysis aimed at investigating the safety of high dose steroid therapy of CIS/ MS relapses in an outpatient setting. Hypokalemia and hyperglycemia are potentially life-threatening side – effects of steroid pulses. Low potassium levels are induced by a mineralocorticoid effect of methylprednisolone, which leads to an increased potassium excretion in urine. A mild hypokalaemia as it was observed in this study is usually asymptomatic, but severe hypokalaemia (potassium level < 2.5 mmol/l) holds the risk of cardiac arrhythmias. In our analysis the lowest individual value was 2.9 mmol/l, and the largest decrease during treatment was 1.8 mmol/l, while many patients showed almost unchanged potassium levels during steroid treatment. Therefore, regarding the potassium level, it seems recommendable to measure at baseline and during steroid therapy, as the baseline value is not predictive for changes during treatment. Whereas, during steroid therapy, potassium levels spontaneously increased in some patients with mild hypokalemia at baseline, other patients showed decreasing potassium levels in spite of oral substitution. Thus, oral substitution of 1-2x 30mmol/day may not be recommended for cases with clinically relevant hypokalemia.

Steroids induce the gluconeogenesis and reduce the glucose uptake in the periphery, which may result in hyperglycemia. The elevated blood glucose level leads to fluid – and electrolyte loss because of osmotic diuresis. The consequence of the intracellular dehydration could be an alteration in consciousness (i.e. diabetic coma) as an acute complication. In this study only little changes were detected in the RBG level even in patients with diabetes mellitus as concomitant disease.

One patient developed an infusion reaction on the first day of treatment and was hospitalized to continue treatment as an inpatient. The infusion reaction itself did not require hospitalization, thus, we do not rate this as serious adverse event. In the other patients, only mild and well – known adverse events were reported. Sleep disturbances were most common (24%), which may be reduced by respective medication. Gastrointestinal side effects were also quite often reported by patients (12%). Dyspeptic symptoms such as upper abdominal pain, impaired digestion, nausea or vomiting were reported in spite of the preventive oral administration of proton pump inhibitors in all patients. However, also the proton pump inhibitors might have contributed to some of the gastrointestinal side effects. 10% experienced facial flush or sweating, and one patient reported pruritus, but no severe anaphylactic reaction occurred. Mood alterations or restlessness were reported by 8.5% of patients. Severe psychopathological alterations like psychotic symptoms did not occur. Other side effects such as headache, metallic taste, dizziness, palpitations, paresthesia, edema, shortness of breath, acne or tinnitus emerged rarely and were mild.

Conclusion

High dose steroid therapy was well tolerated in the majority of our CIS/ MS patients and, thus may be a good option in an outpatient setting for most patients with relapses.

Funding Acknowledgement

This work received no specific grant from any funding agency in the public, commercial, or not – for – profit sectors.

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