Abstract
Introduction
Orthostatic intolerance (OI) is a common disorder for children and adolescents in outpatient clinics that is characterized by orthostatic symptoms, palpitations, light-headedness, and fatigue.1-3 Approximately 8.5% of children and adolescents at outpatient clinics have OI in Japan. 4 Meanwhile, at least 500 000 OI patients have been reported in the United States, which may be higher due to lack of clinical awareness of OI. 5 Symptoms vary among patients with OI.6-10 Orthostatic tests, such as active standing tests or head-up tilt tests, identify the subtypes of OI, including orthostatic hypotension and postural orthostatic tachycardia (POTS). 3 Although most patients’ quality of life and symptoms improve without medical treatment, some patients have severe symptoms and impaired quality of life, resulting in school absenteeism and social withdrawal.6-10
Patients with OI are prescribed drugs to expand plasma volume, to increase peripheral vasoconstriction, or to compensate for the high catecholamine levels. 2 Midodrine, an alpha-1 adrenergic agonist, has been the current standard of medication for orthostatic hypotension. 11 Recent studies outside of Japan have shown that midodrine is also effective for other types of OI, including POTS.12,13 The Japanese guidelines recommend midodrine treatment as the first-line pharmacological treatment for OI. 4
Although midodrine is widely used for patients with OI, the effectiveness of midodrine is limited. Previous studies showed that more than 20% to 30% of patients with OI did not improve their symptoms.12-14 However, the information regarding prognostic factors in children and adolescents with OI is still limited. 14 Understanding clinical prognostic factors is important to improve choices for appropriate treatments in patients with OI.
We investigated clinical prognostic factors for children and adolescents with OI who were treated with midodrine.
Materials and Methods
Data Source and Patients
The design of this study was a retrospective cohort study. The authors reviewed electronic medical records for outpatients who were treated with midodrine between April 2011 and March 2014 in the Department of General Pediatrics and Interdisciplinary Medicine at the National Center for Child Health and Development. We excluded patients with secondary OI.15,16 OI was clinically diagnosed based on clinical symptoms and the active standing test.2,4,17 In the active standing test, blood pressure was measured and an electrocardiogram taken in the supine position before the active standing test, immediately after standing, after 5 minutes, and after 10 minutes. When patients stated that they felt uncomfortable during the active standing test, the active standing test was suspended. Midodrine was prescribed after patients were diagnosed based on the symptoms of OI and results from the active standing test.
Outcomes and Predictors
Outcomes were assessed by improvement of symptoms at the first month after midodrine was initiated for patients. Outcomes were categorized as either improved (including completely resolved) after midodrine (Improvement group) or not improved after midodrine (No-improvement group). Outcomes were recorded in the medical chart by pediatricians after obtaining information from patients and parents.
To identify predictors, we collected information on patients’ characteristics (age, sex, body mass index, school absenteeism), symptoms using an orthostatic checklist, and the results of the active standing test. Percentiles of body mass index were categorized into 3 groups: underweight (<5%), normal (5%-84.9%), and overweight/obese (≥85%) based on the literature.18-20 Because there were few children with obesity, overweight/obese were combined into 1 group. School absenteeism was defined as missing 30 school days or more during the academic year based on the Ministry of Education, Culture, Sports, Science and Technology’s definition. 21
Symptoms were assessed using orthostatic checklists from the Japanese pediatric OI guidelines. 4 The following parameters from the active standing test were assessed: heart rate and systolic and diastolic blood pressure before, immediately after, 5 minutes after, and 10 minutes after the active standing test. Differences in heart rate and systolic and diastolic blood pressure after the standing test compared to being in the supine position were calculated. To consider age-dependent variations in the differences in heart rate and blood pressure after compared to before the active standing test, percentage differences were also calculated.22-24
Statistical Analyses
Statistical significance for unadjusted comparisons was determined using the Chi-square test for categorical variables. We present summary data of baseline characteristics in patients with OI as frequency (percentage) for categorical variables and mean (standard deviation) or median (interquartile range) for continuous variables. Differences in the results of the active standing test were assessed between the Improvement and No-improvement groups by using the Mann-Whitney
Ethical Approval and Informed Consent
This study was approved by the ethics committee at the National Center for Child Health and Development (#1069). Because this was a retrospective observational study reporting anonymized data, informed consent was not required.
Results
We identified 166 patients with OI who underwent the active standing test and received treatment with midodrine. There were no patients with secondary OI in the present study. Of 166 patients who were treated with midodrine after completing the standing test, 7 patients were excluded from the analysis because their symptoms were not described at 1 month of midodrine treatment. A total of 159 patients were included for this study. The mean age of these patients was 13.8 years (range 7-18), 88/159 (55%) patients were girls, and 109/159 (69%) patients had school absenteeism (Table 1). The most common symptoms were pallor (27/159 [17%]), followed by palpitations or dyspnea (24/259 [15%]), and loss of appetite (21/259 [13%]).
Characteristics of Patients with Orthostatic Intolerance.
Percentiles of body mass index were categorized into underweight (<5%), normal (5%-84.9%), and overweight/obese (≥85%).
Abbreviation: OI, orthostatic intolerance.
Symptoms were derived from the checklists for OI from the Japanese pediatric OI guidelines.
Table 1 also compares demographics and symptoms of OI patients before midodrine administration. Of 159 patients, the symptoms were improved in 134/159 (84%) patients; the symptoms were not improved in 25/159 (16%) patients. Patients in the Improvement group were significantly less likely to be underweight than those in the No-improvement group (9/134 [7%] vs 7/25 [28%],
Table 2 shows results of the active standing test in patients with OI. Systolic and diastolic blood pressures at 10 minutes were significantly lower in the Improvement group than those in the No-improvement group (systolic blood pressure: 104 mmHg vs 109 mmHg,
Results of Orthostatic Intolerance Test Compared in Patients With No-improvement and Improvement After Midodrine Treatment.
Abbreviations:HR, heart rate; DBP, diastolic blood pressure; SBP, systolic blood pressure.
Changes of HR from supine position to standing = HR after standing − HR before standing.
Changes of SBP from supine position to standing = SBP after standing − SBP before standing.
Changes of DBP from supine position to standing = DBP after standing − DBP before standing.
Percent change in HR from supine position to standing = (HR after standing − HR before standing)/HR before standing × 100.
Percent change in SBP from supine position to standing = (SBP after standing − SBP before standing)/SBP before standing × 100.
Percent change in DBP from supine position to standing = (DBP after standing − DBP before standing)/DBP before standing × 100.
Table 3 shows univariate logistic regression analysis on prognostic factors for the improvement of symptoms in OI patients after midodrine treatment. Patients in the Improvement group were significantly less likely to be underweight (odds ratio [OR], 0.16; 95% confidence interval [95%CI], 0.05-0.51) compared to the No-improvement group. Patients in the Improvement group were significantly more likely to say initially that they “feel uncomfortable during standing” (OR, 3.48; 95%CI, 1.36-8.89) and showed significantly lower changes in diastolic blood pressure from the supine position to 10 minutes after the standing position test than those in the No-improvement group (OR, 0.93; 95%CI, 0.87-0.98).
Odds ratios for improvement of symptoms in patients with orthostatic intolerance, using logistic regression.
Abbreviations:CI, confidence interval; HR, heart rate; SBP, systolic blood pressure, DBP; diastolic blood pressure.
Odds ratios were calculated using univariate logistic regression. Age, HR, DBP, and SBP were treated as continuous variables. Those other than these variables were treated as categorical variables.
Symptoms were assessed using the checklists for OI from the Japanese pediatric OI guidelines.
Changes of HR from supine position to standing = HR after standing − HR before standing
Changes of SBP from supine position to standing = SBP after standing − SBP before standing
Changes of DBP from supine position to standing = DBP after standing − DBP before standing
Percent change in HR from supine position to standing = (HR after standing − HR before standing)/HR before standing × 100
Percent change in SBP from supine position to standing = (SBP after standing − SBP before standing)/SBP before standing × 100
Percent change in DBP from supine position to standing = (DBP after standing − DBP before standing)/DBP before standing × 100
Discussion
We found that approximately 80% of patients had improved symptoms after midodrine use. Our findings indicate that the predictors of improvement of symptoms after midodrine treatment were low diastolic blood pressure after standing and orthostatic symptoms. Patients with underweight had significantly less improvement than patients without underweight. To our knowledge, this may be the first study to investigate clinical predictors in pediatric patients with OI.
Studies from outside of Japan have shown that midodrine is recommended for OI types other than orthostatic hypotension, including POTS.12,13 Midodrine was the first-line pharmacological treatment administered to patients diagnosed based on symptoms of OI and the results of the active standing test in the present study. Patients with OI had various types of symptoms, including orthostatic symptoms, palpitations, light-headedness, and fatigue.1-3 Due to the variability in symptoms, identifying those that show recovery following treatment with midodrine will be useful for improving medication choice. We found that the clinical symptom that may be useful for predicting improvements in OI patients after midodrine treatment was “patients feel uncomfortable during standing position, sometimes, fainting”. Other orthostatic symptoms, such as dizziness did not affect prognosis. Midodrine may therefore be a better choice for patients who feel uncomfortable in the standing position who sometimes faint.
Results from the active standing test showed that a larger drop in blood pressure measured 10 minutes after the active standing test was a predictor of improved outcomes in OI patients. A study in China showed that lower blood pressure in the orthostatic test was linked to a poor prognosis in patients with POTS, which is consistent with our results. 14 We think that midodrine treatment may be more likely to improve patients with delayed orthostatic hypotension than those with other types of OI. These findings may be explained by the pharmacological effects of midodrine. Midodrine treatment improves orthostatic blood pressure through vasoconstriction of arterioles and venous capacitance vessels. 24 Our results suggest that midodrine is the most suitable medication for delayed orthostatic hypotension.
Another finding indicates that underweight was associated with no improvement of symptoms after midodrine use. Earlier studies have shown that autonomic dysfunction of the cardiovascular system was reported in anorexia nervosa because of low body weight.25,26 Studies reported that body mass index was associated with postural hypotension in adults.27,28 Although underweight was associated with orthostatic intolerance, midodrine may not be effective for orthostatic intolerance under these conditions.
In cases where midodrine is not effective, the Japanese guidelines recommend administering amezinium metilsulfate for OI.4,29 To expand plasma volume, fludrocortisone is also an option for initial orthostatic hypotension and hyperadrenergic POTS, subtypes of OI.2,3 For POTS, a beta blocker is recommended.2-4,30 International consensus guidelines for treatment of pediatric OI are lacking. Further clinical studies are required to establish international guidelines for pediatric OI.
Several limitations of the present study should be acknowledged. First, improvements of symptoms in patients with OI were assessed by pediatricians during clinical visits. We did not assess through standardized questionnaires. Second, improvement of symptoms was assessed at the first month after midodrine treatment, and some patients who improved did not visit the clinic. Long-term outcomes remain unknown, although orthostatic symptoms could be chronic and recurrent. Third, we investigated the predictors of effectiveness of midodrine; however, the results of effectiveness of midodrine should be interpreted with caution because of the lack of a control group. Predictors of improvements among patients who were not administered midodrine remain unknown. Fourth, some items in the OI assessment tool comprise 2 symptoms, such as palpitations and dyspnea. 4 Although the 2 symptoms may be derived from related organs, each symptom should be assessed separately. Fifth, the cut-off point of BMI percentile for underweight has not been well established. In the present study, the fifth percentile of BMI was defined as severely underweight that can affect prognosis of OI. 20 However, milder underweight may also affect prognosis of OI.
In summary, we investigated predictors of OI in children and adolescents who received midodrine, a widely used drug for OI. Our results suggest that midodrine is more effective for delayed orthostatic hypotension than other types of OI. These findings should be helpful to further studies for the choice of treatment in patients with OI.
Footnotes
Author Contributions
Declaration of Conflicting Interests
Funding
ORCID iDs
