SHORT COMMUNICATION
Effect of Fludrocortisone Acetate on Chronic Unexplained Nausea and Abdominal Pain in Children With Orthostatic Intolerance John E. Fortunato, §Ashley L. Wagoner, yRachel L. Harbinson, Ralph B. D’Agostino Jr, zHossam A. Shaltout, and zDebra I. Diz
jj
ABSTRACT Background: We hypothesized that orthostatic intolerance (OI) is associated with gastric dysrhythmias, nausea, and abdominal pain, which improves using fludrocortisone to treat OI. Methods: Patients (n ¼ 16, girls) with OI completed questionnaires before and after fludrocortisone treatment (age 14.8 2.8 years). Ten patients underwent electrogastrograms (EGGs) before fludrocortisone. Results: All EGGs showed gastric dysrhythmias. Fludrocortisone reduced mean scores as follows: nausea, 3.1 0.8 to 2.1 1.1 (P ¼ 0.016); dizziness, 3.0 1.0 to 2.2 1.1 (P ¼ 0.0371); abdominal pain, 2.8 1.3 to 1.9 1.4 (P ¼ 0.0063); flushing, 2.3 1.2 to 1.5 1.4 (P ¼ 0.0476); and missing school, 2.2 1.5 to 1.2 1.5 (P ¼ 0.0078). Conclusions: Chronic nausea and abdominal pain accompany OI and improve with OI treatment. Key Words: chronic unexplained nausea, dysautonomia, electrogastrogram, fludrocortisone, neurally mediated hypotension, postural orthostatic tachycardia syndrome, tilt table testing
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hronic nausea and abdominal pain are common symptoms in both children and adults. Although extremely debilitating, they are often difficult to define objectively. When routine Received April 16, 2013; accepted January 6, 2014. From the Department of Pediatrics, Division of Pediatric Gastroenterology and Nutrition, University of Colorado, Aurora, the yDepartment of Pediatrics, Division of Pediatric Gastroenterology and Nutrition, the zHypertension and Vascular Research Center, the §Neuroscience Graduate Program, Wake Forest Graduate School of Arts & Sciences, and the jjDepartment of Biostatistics, Wake Forest School of Medicine, Winston-Salem, NC Address correspondence and reprint requests to John E. Fortunato, MD, Department of Pediatrics, Children’s Hospital Colorado, 13123 E 16th Ave, Aurora, CO 80045 (e-mail: John.Fortunato@childrenscolorado. org) This article has been developed as a Journal CME Activity by NASPGHAN. Visit http://www.naspghan.org/wmspage.cfm?parm1=742 to view instructions, documentation, and the complete necessary steps to receive CME credit for reading this article. This work was supported by a grant from the American Heart Association, National Center Clinical Research Program, AHA12CRP9420029 (Dr Fortunato, PI). www.clinicaltrials.gov registration number: WFUBAHA01. The authors report no conflicts of interest. Copyright # 2014 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000305
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gastrointestinal (GI) diagnostic testing fails to identify a cause for the nausea or pain, patients are generally treated with empiric therapy in an attempt to alleviate their symptoms. The origin of these symptoms is likely multifactorial with precipitating triggers and mechanisms not well described. We have identified a group of children between the ages 10 and 18 years whose diagnostic workup for unexplained nausea has revealed underlying cardiovascular (CV) instability manifesting as orthostatic intolerance (OI) (1). During a 2-year period, 79% (72/91) of our patients with chronic nausea, unexplained by routine GI diagnostic testing, demonstrated symptoms suggestive of OI—predominantly postural orthostatic tachycardia syndrome (POTS). POTS is usually characterized by symptoms such as dizziness or light-headedness. It often presents with vague abdominal symptoms that can be mistakenly diagnosed as a functional GI disorder if symptoms of OI are not elicited during evaluation. We believe that the OI represents a cause of the nausea in a majority of these individuals, as treatment of the POTS with fludrocortisone reduced the symptoms of nausea as recently published (1). It was the objective of this study to more fully assess symptoms associated with the chronic unexplained nausea and abdominal pain. Therefore, a newly recruited group of patients were asked to complete a symptom questionnaire before and following treatment with fludrocortisone to determine whether treatment of OI improves both OI and GI symptoms. We further aimed to determine the prevalence of gastric dysrhythmia in the population of subjects with OI by measuring electrogastrograms (EGGs).
METHODS Patients with unexplained nausea and OI diagnosed by tilt table test (n ¼ 16; all girls) rated severity of nausea, vomiting, dizziness, syncope, abdominal pain, constipation, anorexia, flushing, and missing school from 0 (none) to 4 (severe) before and after a minimum of 4 weeks of fludrocortisone (0.1–0.2 mg/day). No additional new medications other than fludrocortisone were given at the time questionnaires were administered. All of the patients included had upper endoscopy before tilt testing, which did not explain their symptoms. Of the 16 subjects, 10 underwent electrogastrograms (EGG) before treatment.
Tilt Table Test All tilt table tests were performed before fludrocortisone was started. Head upright tilt was performed from 0 to 70 degrees for 45 minutes. Continuous measures of heart rate (HR) and heart rhythm were obtained, and mean arterial pressure was recorded every 2 minutes after upright tilt. POTS was defined as an HR 120 bpm or a 40 bpm increase from baseline sustained for 2 minutes
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BPM
Heart rate
140.00
100.00
80.00 0.00
4.00
8.00
12.00
Minutes
B
200.00
BPM
Heart rate
150.00
100.00
12.00
24.00
36.00
Minutes
120.00
C
BPM
Heart rate
105.00
90.00
75.00
60.00 0.00
8.00
16.00
24.00
Minutes
FIGURE 1. Representative HR tracings demonstrating sustained tachycardia in POTS subjects diagnosed after 10 minutes of upright tilt (A), and after 45 minutes of upright tilt (B). Marked decline in HR in a subject with OH shortly after a decrease in blood pressure (C). BPM ¼ blood pressure monitor; HR ¼ heart rate; OH ¼ orthostatic hypotension; POTS ¼ postural orthostatic tachycardia syndrome.
during the first 10 minutes of tilt (Fig. 1). Orthostatic hypotension (OH) was defined as a 25 mmHg decrease in systolic blood pressure (BP) from baseline sustained for a minimum of 2 minutes (2–4). Neurocardiogenic syncope was defined based on each patient’s clinical symptoms during the tilt. The diagnosis of clinical syncope was made by the cardiologist responsible for interpretation of the tilt table test.
EGG The EGG was performed and analyzed as described by Koch et al (5), including 15-minute baseline tracing after which subjects ingested noncarbonate water for 5 minutes or until full. EGG continued for 30 minutes after water ingestion. Frequencies were defined as bradygastria (1.0–2.5 cpm), normal (2.5–3.75 cpm), and tachygastria (3.75–10 cpm). Mixed dysrhythmias were defined as a combination of tachygastria and bradygastria. Water ingestion was considered abnormal if subjects were unable to tolerate a minimum of 600 mL of room-temperature water.
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Descriptive statistics for age, GI diagnosis, GI symptoms, and OI symptoms were calculated for all of the participants. For continuous variables means and standard deviations (values shown in tables and text are mean standard deviation) were calculated, and for categorical variables counts and percents were calculated. To compare the pre- versus postfludrocortisone treatment variables, a series of paired t tests were performed comparing the changes in each of the 10 individual items on the questionnaire (eg, nausea, fatigue, dizziness) as well as a calculated summary score for the 10 items (sum of the 10 prescore values and sum of the 10 postscore values). We also examined whether there were differences between the 2 major diagnosis groups—POTS alone and syncope (with and without POTS) using 2-sample t tests. Finally, we compared the diagnosis groups for EGG and water ingestion variables on the subset of patients with those measures available using the Fisher exact test. Results with P < 0.05 were considered statistically significant.
RESULTS
50.00
0.00
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Statistical Analysis
160.00
A
120.00
The mean age standard deviation was 14.8 2.8 years. The response to tilt was defined in 2 groups: response within the first 10 minutes of tilt and the response throughout the entire 45 minutes of tilt. Within the first 10 minutes of tilt, the 16 subjects were categorized as follows: POTS (n ¼ 10), OH (n ¼ 1), syncope (n ¼ 1), and normal (n ¼ 4) (Table 1). During this first 10 minutes of tilt, 11 of 16 had orthostatic symptoms and 7 of 16 experienced nausea. By the end of the 45-minute tilt, 11 of 16 patients experienced syncope, including 5 of the subjects initially diagnosed with POTS. During the course of the entire 45-minute tilt table test, all of the subjects demonstrated OI: POTS alone (n ¼ 5), syncope alone (n ¼ 1), POTS followed by syncope (n ¼ 9), and OH followed by syncope (n ¼ 1). Fourteen of 16 reported experiencing orthostatic symptoms, and 11 of 16 reported nausea during the full 45-minute tilt. Representative HR tracings for subjects with POTS defined during the first 10 minutes (Fig. 1A) or during the 45 minutes (Fig. 1B) of upright tilt, as well as an example of OH (Fig. 1C), are shown in Figure 1. Of the 10 EGGs performed before fludrocortisone treatment, all were abnormal. The dysrhythmias were defined as tachygastria (n ¼ 6) and mixed dysrhythmia (n ¼ 4). Water ingestion was abnormally low for 5 of 10 subjects. Fludrocortisone treatment reduced mean symptom scores as described in Table 2. Nausea, dizziness, abdominal pain, flushing, and missing school improved after OI treatment with fludrocortisone. In contrast, vomiting, syncope, constipation, and anorexia did not significantly improve. Overall, fludrocortisone improved symptoms as shown by the summation of differences across symptoms, 6.2 7.4 (P ¼ 0.0046). There was no statistical difference in symptom scores when patients with POTS and syncope or OH were compared with those with POTS alone.
DISCUSSION We described a group of pediatric patients presenting to our clinic with chronic nausea and OI, most of whom also demonstrated gastric dysrhythmias before treatment (1). OI was associated with nausea in 15 of 17 patients, which subjectively improved after treatment with the aldosterone agonist fludrocortisone (1). The goal of our present study was to confirm the general findings in the original cohort of subjects by extending our assessments in a different group of patients. In addition, we wished to more objectively define the degree of symptomatic improvement using a questionnaire to assess nausea and other common symptoms www.jpgn.org
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The mean HR and BP per patient (pretilt) are followed by maximum HR, change in HR from supine mean HR, minimum BP, and cardiovascular diagnosis per patient defined after 10 and 45 minutes of head upright tilt, respectively, and EGG diagnosis. BP ¼ blood pressure; EGG ¼ electrogastrogram; HR ¼ heart rate; OH ¼ orthostatic hypotension; POTS ¼ postural orthostatic tachycardia syndrome.
Tachy Mixed Tachy
Mixed Tachy Mixed Tachy Tachy syncope syncope syncope syncope
Mixed
69 64 99 101 87 66 72 91 77 78 76 90 86 100 83 75
113/63 101/60 109/71 116/81 102/61 110/57 118/70 112/60 124/68 144/77 107/62 81/57 131/70 134/88 136/80 101/62
91 122 111 120 121 94 105 126 141 115 109 125 138 124 161 117
22 58 12 19 34 28 33 35 64 37 33 35 52 24 78 42
56/33 109/82 94/72 107/68 95/68 106/66 72/50 104/63 124/68 136/82 96/64 84/65 121/80 135/93 111/77 92/62
Syncope POTS Normal POTS POTS Normal OH POTS POTS Normal Normal POTS POTS POTS POTS POTS
133 126 148 141 111 105 148 141 128 129 141 146 139 180 121
69 27 47 54 45 33 57 64 50 53 51 60 39 97 46
84/59 33/23 71/48 69/45 106/66 59/39 86/74 73/53 72/43 59/45 82/64 121/80 126/80 81/37 86/63
POTS with POTS with POTS with POTS with POTS with Syncope POTS with POTS with POTS with POTS with POTS POTS POTS POTS POTS
syncope syncope syncope syncope syncope
Effect of Fludrocortisone Acetate on Nausea and Abdominal Pain
19 15 13 14 13 16 16 14 16 16 16 6 16 17 16 14
Diagnosis Min BP Mean BP
Max HR
DHR
Min BP
Diagnosis
Max HR
DHR
Up to 45 min 10 min Supine
Mean HR Age, y Patient No.
TABLE 1. HR and BP per patient are shown during 15-minute supine period (pretilt, after 10 min of head-upright tilt, and after 45 min of head-upright tilt)
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EGG diagnosis
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observed in association with functional GI disorders in these new subjects. Our findings are consistent with those reported by Safder et al (6) in which subjects with functional abdominal pain (triggered by tilt testing) and POTS demonstrate greater benefit from fludrocortisone than those whose GI symptoms were not reproducible during tilt. Although Safder et al (6) assessed an overall ‘‘response to treatment’’ score for patients retrospectively, our study examined the change in severity of specific symptoms. In Safder’s study, patient diagnosis was based on CV responses to tilt during the first 10 minutes, even though GI symptoms were reported and used for grouping based on the full duration of the tilt test (40 minutes). The study also diagnosed patients based on what the investigators believed to be the underlying disorder. Of the 32 POTS patients with recurring GI symptoms upon tilt, 56% also experienced syncope similar to our study. Our study reports the CV response to tilt and GI symptoms at both 10- and 45-minute time intervals. Providing data for both time points demonstrate a progression of CV symptoms from the 10-minute cutoff to that at 45 minutes, for example, POTS to syncope, initial normal tilt response to syncope. More important, for multiple patients the accompanying GI symptoms would have been missed if only the 10-minute tilt diagnosis had been considered. Although the relevance of the CV data from the latter part of the tilt study requires further investigation, these findings and those of Safder et al raise the notion that the longer tilt identifies subjects experiencing orthostatic induction of GI symptoms. Fludrocortisone treatment of OI in patients with chronic unexplained nausea resulted in decreased nausea, but also improved symptoms of abdominal pain, dizziness, and flushing, even though it did not improve or prevent syncope. It was also associated with improved school attendance. These data, taken in concordance with the CV and GI responses to tilt, suggest that the combination of CV and GI symptoms experienced throughout the full duration of the tilt may be a stronger predictor of effective therapeutics for children with chronic nausea. These findings also suggest that these GI symptoms may be secondary to OI, although a potentially more generalized dysautonomia associated with GI motility perturbation cannot be ruled out at the present time since there were not uniform improvements in all GI symptoms with the fludrocortisone treatment. OI is common among Americans with approximately 15% of all of the children experiencing syncope before the end of adolescence (7,8). Despite the link between the autonomic nervous system and GI motility function, determining the presence of orthostatic symptoms is not part of routine GI clinical assessment. Diverse pathophysiological mechanisms may contribute to both the GI and CV symptoms; however, a better understanding of the specific autonomic disturbances in patients with chronic nausea and abdominal pain may allow more timely and better clinical management of these patients, including selection of drugs such as b blockers, which have been empirically used to treat both OI and functional GI disorders (9). Further studies including measurement of neurohumoral factors such as catecholamines and vasopressin are needed to better define the mechanisms of OI and nausea in children to allow more focused and rational treatment, because these hormones are associated with nausea and gastric dysrhythmias (10–13,14). To better define a potential relation between nausea, OI, and motility abnormalities, we performed baseline EGG recordings before starting treatment. All of the subjects tested demonstrated a gastric dysrhythmia, most notably tachygastria. These data are consistent with previous literature reporting presentations of abnormal and highly variable gastric myoelectrical activity in POTS patients (1,15). This is not the first time an association between OI
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TABLE 2. Mean symptom score (SD) per symptom before and after fludrocortisone treatment
Symptom Nausea Vomiting Dizziness Syncope Abdominal pain Constipation Anorexia Flushing Missing school
Mean symptom score before fludrocortisone
Mean symptom score after fludrocortisone
Improvement, %
P
3.1 0.8 0.7 0.8 3.0 1.0 0.8 1.2 2.8 1.3 1.6 1.5 2.1 1.4 2.3 1.2 2.2 1.5
2.1 1.1 0.5 1.1 2.2 1.1 0.4 0.7 1.9 1.4 1.3 1.6 1.7 1.3 1.5 1.4 1.2 1.5
32 28 28 49 32 23 22 33 44
0.0016 NS 0.0371 NS 0.0063 NS NS 0.0476 0.0078
P < 0.05 was considered significant; NS ¼ not significant; SD ¼ standard deviation.
and GI symptoms has been described. Posturally mediated HR changes resulting in abnormal gastric electrical activity in patients with functional abdominal pain have recently been reported in children (16,17). Several studies have also demonstrated that abnormal gastric myoelectrical activity in pediatric patients plays a role in the pathophysiology of functional dyspepsia, nausea, and feeding problems (18–24). Our study has limitations. The sample size was small and all of subjects were girls; however, female predominance of the cohort reflects the fact that 75% to 80% of patients diagnosed as having POTS are girls (25). The questionnaire used in the study has not yet been validated. Although validated questionnaires exist for dysautonomia and chronic nausea, there is no symptom questionnaire that addresses the combination of symptoms particularly in the pediatric population. Future studies are necessary to evaluate and validate an appropriate instrument to clinically assess the degree of both autonomic and GI symptoms in these patients. The inclusion of a pediatric psychologist would also strengthen a subsequent study to account for confounding variables such as anxiety or depression, thereby supporting the notion of the recommended multidisciplinary approach to functional GI disorders of childhood (26). In addition, EGGs were performed only before starting fludrocortisone treatment. Whether the rhythm disturbances are corrected by the fludrocortisone treatment would provide revealing information on the relation between the GI and CV symptoms. Finally, the mechanism for the nausea in these subjects remains unclear, and the effect of upright tilt on EGG has not yet been described. Thus, healthy asymptomatic children would be optimal controls for future studies. In conclusion, the origin of chronic nausea as well as symptoms included within the spectrum of functional GI disorders is likely multifactorial, with precipitating triggers and mechanisms not well described. Thus, treatment strategies are empiric at best. There is a paucity of data examining the relation between OI and chronic nausea and even less associated with pediatric patients; however, the findings from our previous and the present study, achieved using noninvasive tilt table tests and EGGs, suggest that this association is common. For the pediatric gastroenterologist, expanding the scope of questions asked to include symptoms of dizziness, syncope, tachycardia, or flushing may be warranted when assessing children with nausea and abdominal pain of a functional nature particularly for refractory GI symptoms. Moreover, tilt evaluation during a 45-minute period may aid in diagnosis. Although the association between dysautonomia and motility problems has not been fully established, these early data suggest that a relation between dysautonomia with nausea and gastric dysrhythmias may exist.
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REFERENCES 1. Fortunato JE, Shaltout HA, Larkin MM, et al. Fludrocortisone improves nausea in children with orthostatic intolerance (OI). Clin Auton Res 2011;21:419–23. 2. Rowe PC, Calkins H, DeBusk K, et al. Fludrocortisone acetate to treat neurally mediated hypotension in chronic fatigue syndrome. JAMA 2001;285:52–9. 3. Freeman R, Weiling W, Axelrod FB, et al. Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Clin Auton Res 2011;21:69–72. 4. Sullivan SD, Hanauer J, Rowe PC, et al. Gastrointestinal symptoms associated with orthostatic intolerance. J Pediatr Gastroenterol Nutr 2005;40:425–8. 5. Koch KL, Hong SP, Xu L. Reproducibility of gastric myoelectrical activity and the water load test in patients with dysmotility-like dyspepsia symptoms and in control subjects. J Clin Gastroenterol 2000;31:125–9. 6. Safder S, Chelimsky TC, O’Riordan MA, et al. Autonomic testing in functional gastrointestinal disorders: implications of reproducible gastrointestinal complaints during tilt table testing. Gastroenterol Res Pract 2009;2009:868496. 7. Drossman DA, Corazziari E, Delvaux M (Eds): et al. ROME III: Functional Gastrointestinal Disorders. Lawrence, KS: Allen Press; 2006. 8. Hyams JS, Burke G, Davis PM, et al. Abdominal pain and irritable bowel syndrome in adolescents: a community-based study. J Pediatr 1996;129:220–6. 9. Grubb BP, Kanjwal Y, Kosinski DJ. The postural tachycardia syndrome: a concise guide to diagnosis and management. J Cardiovasc Electrophysiol 2006;17:108–12. 10. Koch KL, Summy-Long J, Bingaman S, et al. Vasopressin and oxytocin responses to illusory self-motion and nausea in man. J Clin Endocrinol Metab 1990;71:1269–75. 11. Koch KL. A noxious trio: nausea, gastric dysrhythmias and vasopressin. Neurogastroenterol Motil 1997;9:141–2. 12. Kim MS, Chey WD, Owyang C, et al. Role of plasma vasopressin as a mediator of nausea and gastric slow wave dysrhythmias in motion sickness. Am J Physiol 1997;272 (4 pt 1):G853–62. 13. Kim CH, Zinsmeister AR, Malagelada JR. Mechanisms of canine gastric dysrhythmia. Gastroenterology 1987;92:993–9. 14. Wagoner AL, Shaltout HA, D’Agostino RB, et al. Relationship of arginine vasopressin and blood pressure in patient with orthostatic intolerance. Hypertension 2013;62:A261. 15. Seligman WH, Low DA, Asahina M, et al. Clin Auton Res 2012;23:73– 80. 16. Safder S, Chelimsky TC, O’Riordan MA, et al. Gastric electrical activity becomes abnormal in the upright position in patients with postural tachycardia syndrome. J Pediatr Gastroenterol Nutr 2010;51:314–8. 17. Friesen CA, Lin Z, Schurman JV, et al. Autonomic nervous system response to a solid meal and water loading in healthy children: its relation to gastric myoelectrical activity. Neurogastroenterol Motil 2007;19:376–82.
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Effect of Fludrocortisone Acetate on Nausea and Abdominal Pain
18. Friesen CA, Lin Z, Hyman PE, et al. Electrogastrography in pediatric functional dyspepsia: relationship to gastric emptying and symptom severity. J Pediatr Gastroenterol Nutr 2006;42:265–9. 19. Diamanti A, Bracci F, Gambarara M, et al. Gastric electric activity assessed by electrogastrography and gastric emptying scintigraphy in adolescents with eating disorders. J Pediatr Gastroenterol Nutr 2003; 37:35–41. 20. Riezzo G, Chiloiro M, Guerra V, et al. Comparison of gastric electrical activity and gastric emptying in healthy and dyspeptic children. Dig Dis Sci 2000;45:517–24. 21. Koch ILL. Physiological Basis of Electrogastrography. New York: Oxford University Press; 2003. 22. Koch KL, Tran TN, Stern RM, et al. Gastric myoelectrical activity in premature and term infants. Neurogastroenterol Motil 1993;5:41–7.
23. Levy J, Harris J, Chen J, et al. Electrogastrographic norms in children: toward the development of standard methods, reproducible results, and reliable normative data. J Pediatr Gastroenterol Nutr 2001;33:455–61. 24. Cucchiara S, Minella R, Riezzo G, et al. Reversal of gastric electrical dysrhythmias by cisapride in children with functional dyspepsia. Report of three cases. Dig Dis Sci 1992;37:1136–40. 25. Stewart JM. Chronic orthostatic intolerance and the postural tachycardia syndrome (POTS). J Pediatr 2004;145:725–30. 26. Fortunato JE, Wagoner AL, Diz DI, et al. Association between anxiety and chronic unexplained nausea in youth with orthostatic intolerance. Paper presented at: Biology and Control of Nausea and Vomiting 2013; Pittsburgh, PA; October 3–4, 2013.
Ascaris Fishing Ascaris lumbricoides is an old-world parasite that is believed to infect one-sixth of the world’s population. Birch-juice, raw carrots, mercury clusters, and tobacco-smoke enemas were common recommendations.
Tobacco-smoke enema kit. Note bellows at the top of the assembled parts. Smoldering tobacco was placed in the central chamber. (Courtesy Wikimedia Commons.)
When tobacco-smoke enemas failed, other curious vermifuges were suggested. Perhaps most intriguing was the whimsical method Nils Rosen von Rosenstein preferred (in Underra¨ttelser om Barn Sjukdomar [1764]): ‘‘. . .[after] tying a string to a piece of fresh pork, [I] introduce it into the intestinum rectum, and pulling it out again after a little time; for a number of these worms will then always follow. This must be done repeatedly, changing the pork at each time, in order to evacuate them all.’’
An Uppsala University professor in Sweden, Nils Rosen von Rosenstein (1706–1773) introduced clinical instruction in pediatrics to the curriculum. A series of his lectures during a period of 10 years were considered so outstanding, the Swedish Royal Academy of Sciences reprinted them as a pediatrics text called Underra¨ttelser om Barn Sjukdomar. Rosen’s book was translated into 5 languages, reaching most of Europe’s evolving disciples of pediatric medicine. The English edition by Andrew Sparrman (1748–1820) was printed in 1776.
—Contributed by Angel R. Colo´n, MD
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Effect of Fludrocortisone Acetate on Chronic Unexplained Nausea and Abdominal Pain in Children With Orthostatic Intolerance John E. Fortunato, §Ashley L. Wagoner, yRachel L. Harbinson, Ralph B. D’Agostino Jr, zHossam A. Shaltout, and zDebra I. Diz
jj
ABSTRACT Background: We hypothesized that orthostatic intolerance (OI) is associated with gastric dysrhythmias, nausea, and abdominal pain, which improves using fludrocortisone to treat OI. Methods: Patients (n ¼ 16, girls) with OI completed questionnaires before and after fludrocortisone treatment (age 14.8 2.8 years). Ten patients underwent electrogastrograms (EGGs) before fludrocortisone. Results: All EGGs showed gastric dysrhythmias. Fludrocortisone reduced mean scores as follows: nausea, 3.1 0.8 to 2.1 1.1 (P ¼ 0.016); dizziness, 3.0 1.0 to 2.2 1.1 (P ¼ 0.0371); abdominal pain, 2.8 1.3 to 1.9 1.4 (P ¼ 0.0063); flushing, 2.3 1.2 to 1.5 1.4 (P ¼ 0.0476); and missing school, 2.2 1.5 to 1.2 1.5 (P ¼ 0.0078). Conclusions: Chronic nausea and abdominal pain accompany OI and improve with OI treatment. Key Words: chronic unexplained nausea, dysautonomia, electrogastrogram, fludrocortisone, neurally mediated hypotension, postural orthostatic tachycardia syndrome, tilt table testing
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hronic nausea and abdominal pain are common symptoms in both children and adults. Although extremely debilitating, they are often difficult to define objectively. When routine Received April 16, 2013; accepted January 6, 2014. From the Department of Pediatrics, Division of Pediatric Gastroenterology and Nutrition, University of Colorado, Aurora, the yDepartment of Pediatrics, Division of Pediatric Gastroenterology and Nutrition, the zHypertension and Vascular Research Center, the §Neuroscience Graduate Program, Wake Forest Graduate School of Arts & Sciences, and the jjDepartment of Biostatistics, Wake Forest School of Medicine, Winston-Salem, NC Address correspondence and reprint requests to John E. Fortunato, MD, Department of Pediatrics, Children’s Hospital Colorado, 13123 E 16th Ave, Aurora, CO 80045 (e-mail: John.Fortunato@childrenscolorado. org) This article has been developed as a Journal CME Activity by NASPGHAN. Visit http://www.naspghan.org/wmspage.cfm?parm1=742 to view instructions, documentation, and the complete necessary steps to receive CME credit for reading this article. This work was supported by a grant from the American Heart Association, National Center Clinical Research Program, AHA12CRP9420029 (Dr Fortunato, PI). www.clinicaltrials.gov registration number: WFUBAHA01. The authors report no conflicts of interest. Copyright # 2014 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000305
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gastrointestinal (GI) diagnostic testing fails to identify a cause for the nausea or pain, patients are generally treated with empiric therapy in an attempt to alleviate their symptoms. The origin of these symptoms is likely multifactorial with precipitating triggers and mechanisms not well described. We have identified a group of children between the ages 10 and 18 years whose diagnostic workup for unexplained nausea has revealed underlying cardiovascular (CV) instability manifesting as orthostatic intolerance (OI) (1). During a 2-year period, 79% (72/91) of our patients with chronic nausea, unexplained by routine GI diagnostic testing, demonstrated symptoms suggestive of OI—predominantly postural orthostatic tachycardia syndrome (POTS). POTS is usually characterized by symptoms such as dizziness or light-headedness. It often presents with vague abdominal symptoms that can be mistakenly diagnosed as a functional GI disorder if symptoms of OI are not elicited during evaluation. We believe that the OI represents a cause of the nausea in a majority of these individuals, as treatment of the POTS with fludrocortisone reduced the symptoms of nausea as recently published (1). It was the objective of this study to more fully assess symptoms associated with the chronic unexplained nausea and abdominal pain. Therefore, a newly recruited group of patients were asked to complete a symptom questionnaire before and following treatment with fludrocortisone to determine whether treatment of OI improves both OI and GI symptoms. We further aimed to determine the prevalence of gastric dysrhythmia in the population of subjects with OI by measuring electrogastrograms (EGGs).
METHODS Patients with unexplained nausea and OI diagnosed by tilt table test (n ¼ 16; all girls) rated severity of nausea, vomiting, dizziness, syncope, abdominal pain, constipation, anorexia, flushing, and missing school from 0 (none) to 4 (severe) before and after a minimum of 4 weeks of fludrocortisone (0.1–0.2 mg/day). No additional new medications other than fludrocortisone were given at the time questionnaires were administered. All of the patients included had upper endoscopy before tilt testing, which did not explain their symptoms. Of the 16 subjects, 10 underwent electrogastrograms (EGG) before treatment.
Tilt Table Test All tilt table tests were performed before fludrocortisone was started. Head upright tilt was performed from 0 to 70 degrees for 45 minutes. Continuous measures of heart rate (HR) and heart rhythm were obtained, and mean arterial pressure was recorded every 2 minutes after upright tilt. POTS was defined as an HR 120 bpm or a 40 bpm increase from baseline sustained for 2 minutes
39
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Fortunato et al
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BPM
Heart rate
140.00
100.00
80.00 0.00
4.00
8.00
12.00
Minutes
B
200.00
BPM
Heart rate
150.00
100.00
12.00
24.00
36.00
Minutes
120.00
C
BPM
Heart rate
105.00
90.00
75.00
60.00 0.00
8.00
16.00
24.00
Minutes
FIGURE 1. Representative HR tracings demonstrating sustained tachycardia in POTS subjects diagnosed after 10 minutes of upright tilt (A), and after 45 minutes of upright tilt (B). Marked decline in HR in a subject with OH shortly after a decrease in blood pressure (C). BPM ¼ blood pressure monitor; HR ¼ heart rate; OH ¼ orthostatic hypotension; POTS ¼ postural orthostatic tachycardia syndrome.
during the first 10 minutes of tilt (Fig. 1). Orthostatic hypotension (OH) was defined as a 25 mmHg decrease in systolic blood pressure (BP) from baseline sustained for a minimum of 2 minutes (2–4). Neurocardiogenic syncope was defined based on each patient’s clinical symptoms during the tilt. The diagnosis of clinical syncope was made by the cardiologist responsible for interpretation of the tilt table test.
EGG The EGG was performed and analyzed as described by Koch et al (5), including 15-minute baseline tracing after which subjects ingested noncarbonate water for 5 minutes or until full. EGG continued for 30 minutes after water ingestion. Frequencies were defined as bradygastria (1.0–2.5 cpm), normal (2.5–3.75 cpm), and tachygastria (3.75–10 cpm). Mixed dysrhythmias were defined as a combination of tachygastria and bradygastria. Water ingestion was considered abnormal if subjects were unable to tolerate a minimum of 600 mL of room-temperature water.
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Descriptive statistics for age, GI diagnosis, GI symptoms, and OI symptoms were calculated for all of the participants. For continuous variables means and standard deviations (values shown in tables and text are mean standard deviation) were calculated, and for categorical variables counts and percents were calculated. To compare the pre- versus postfludrocortisone treatment variables, a series of paired t tests were performed comparing the changes in each of the 10 individual items on the questionnaire (eg, nausea, fatigue, dizziness) as well as a calculated summary score for the 10 items (sum of the 10 prescore values and sum of the 10 postscore values). We also examined whether there were differences between the 2 major diagnosis groups—POTS alone and syncope (with and without POTS) using 2-sample t tests. Finally, we compared the diagnosis groups for EGG and water ingestion variables on the subset of patients with those measures available using the Fisher exact test. Results with P < 0.05 were considered statistically significant.
RESULTS
50.00
0.00
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Statistical Analysis
160.00
A
120.00
The mean age standard deviation was 14.8 2.8 years. The response to tilt was defined in 2 groups: response within the first 10 minutes of tilt and the response throughout the entire 45 minutes of tilt. Within the first 10 minutes of tilt, the 16 subjects were categorized as follows: POTS (n ¼ 10), OH (n ¼ 1), syncope (n ¼ 1), and normal (n ¼ 4) (Table 1). During this first 10 minutes of tilt, 11 of 16 had orthostatic symptoms and 7 of 16 experienced nausea. By the end of the 45-minute tilt, 11 of 16 patients experienced syncope, including 5 of the subjects initially diagnosed with POTS. During the course of the entire 45-minute tilt table test, all of the subjects demonstrated OI: POTS alone (n ¼ 5), syncope alone (n ¼ 1), POTS followed by syncope (n ¼ 9), and OH followed by syncope (n ¼ 1). Fourteen of 16 reported experiencing orthostatic symptoms, and 11 of 16 reported nausea during the full 45-minute tilt. Representative HR tracings for subjects with POTS defined during the first 10 minutes (Fig. 1A) or during the 45 minutes (Fig. 1B) of upright tilt, as well as an example of OH (Fig. 1C), are shown in Figure 1. Of the 10 EGGs performed before fludrocortisone treatment, all were abnormal. The dysrhythmias were defined as tachygastria (n ¼ 6) and mixed dysrhythmia (n ¼ 4). Water ingestion was abnormally low for 5 of 10 subjects. Fludrocortisone treatment reduced mean symptom scores as described in Table 2. Nausea, dizziness, abdominal pain, flushing, and missing school improved after OI treatment with fludrocortisone. In contrast, vomiting, syncope, constipation, and anorexia did not significantly improve. Overall, fludrocortisone improved symptoms as shown by the summation of differences across symptoms, 6.2 7.4 (P ¼ 0.0046). There was no statistical difference in symptom scores when patients with POTS and syncope or OH were compared with those with POTS alone.
DISCUSSION We described a group of pediatric patients presenting to our clinic with chronic nausea and OI, most of whom also demonstrated gastric dysrhythmias before treatment (1). OI was associated with nausea in 15 of 17 patients, which subjectively improved after treatment with the aldosterone agonist fludrocortisone (1). The goal of our present study was to confirm the general findings in the original cohort of subjects by extending our assessments in a different group of patients. In addition, we wished to more objectively define the degree of symptomatic improvement using a questionnaire to assess nausea and other common symptoms www.jpgn.org
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The mean HR and BP per patient (pretilt) are followed by maximum HR, change in HR from supine mean HR, minimum BP, and cardiovascular diagnosis per patient defined after 10 and 45 minutes of head upright tilt, respectively, and EGG diagnosis. BP ¼ blood pressure; EGG ¼ electrogastrogram; HR ¼ heart rate; OH ¼ orthostatic hypotension; POTS ¼ postural orthostatic tachycardia syndrome.
Tachy Mixed Tachy
Mixed Tachy Mixed Tachy Tachy syncope syncope syncope syncope
Mixed
69 64 99 101 87 66 72 91 77 78 76 90 86 100 83 75
113/63 101/60 109/71 116/81 102/61 110/57 118/70 112/60 124/68 144/77 107/62 81/57 131/70 134/88 136/80 101/62
91 122 111 120 121 94 105 126 141 115 109 125 138 124 161 117
22 58 12 19 34 28 33 35 64 37 33 35 52 24 78 42
56/33 109/82 94/72 107/68 95/68 106/66 72/50 104/63 124/68 136/82 96/64 84/65 121/80 135/93 111/77 92/62
Syncope POTS Normal POTS POTS Normal OH POTS POTS Normal Normal POTS POTS POTS POTS POTS
133 126 148 141 111 105 148 141 128 129 141 146 139 180 121
69 27 47 54 45 33 57 64 50 53 51 60 39 97 46
84/59 33/23 71/48 69/45 106/66 59/39 86/74 73/53 72/43 59/45 82/64 121/80 126/80 81/37 86/63
POTS with POTS with POTS with POTS with POTS with Syncope POTS with POTS with POTS with POTS with POTS POTS POTS POTS POTS
syncope syncope syncope syncope syncope
Effect of Fludrocortisone Acetate on Nausea and Abdominal Pain
19 15 13 14 13 16 16 14 16 16 16 6 16 17 16 14
Diagnosis Min BP Mean BP
Max HR
DHR
Min BP
Diagnosis
Max HR
DHR
Up to 45 min 10 min Supine
Mean HR Age, y Patient No.
TABLE 1. HR and BP per patient are shown during 15-minute supine period (pretilt, after 10 min of head-upright tilt, and after 45 min of head-upright tilt)
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EGG diagnosis
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observed in association with functional GI disorders in these new subjects. Our findings are consistent with those reported by Safder et al (6) in which subjects with functional abdominal pain (triggered by tilt testing) and POTS demonstrate greater benefit from fludrocortisone than those whose GI symptoms were not reproducible during tilt. Although Safder et al (6) assessed an overall ‘‘response to treatment’’ score for patients retrospectively, our study examined the change in severity of specific symptoms. In Safder’s study, patient diagnosis was based on CV responses to tilt during the first 10 minutes, even though GI symptoms were reported and used for grouping based on the full duration of the tilt test (40 minutes). The study also diagnosed patients based on what the investigators believed to be the underlying disorder. Of the 32 POTS patients with recurring GI symptoms upon tilt, 56% also experienced syncope similar to our study. Our study reports the CV response to tilt and GI symptoms at both 10- and 45-minute time intervals. Providing data for both time points demonstrate a progression of CV symptoms from the 10-minute cutoff to that at 45 minutes, for example, POTS to syncope, initial normal tilt response to syncope. More important, for multiple patients the accompanying GI symptoms would have been missed if only the 10-minute tilt diagnosis had been considered. Although the relevance of the CV data from the latter part of the tilt study requires further investigation, these findings and those of Safder et al raise the notion that the longer tilt identifies subjects experiencing orthostatic induction of GI symptoms. Fludrocortisone treatment of OI in patients with chronic unexplained nausea resulted in decreased nausea, but also improved symptoms of abdominal pain, dizziness, and flushing, even though it did not improve or prevent syncope. It was also associated with improved school attendance. These data, taken in concordance with the CV and GI responses to tilt, suggest that the combination of CV and GI symptoms experienced throughout the full duration of the tilt may be a stronger predictor of effective therapeutics for children with chronic nausea. These findings also suggest that these GI symptoms may be secondary to OI, although a potentially more generalized dysautonomia associated with GI motility perturbation cannot be ruled out at the present time since there were not uniform improvements in all GI symptoms with the fludrocortisone treatment. OI is common among Americans with approximately 15% of all of the children experiencing syncope before the end of adolescence (7,8). Despite the link between the autonomic nervous system and GI motility function, determining the presence of orthostatic symptoms is not part of routine GI clinical assessment. Diverse pathophysiological mechanisms may contribute to both the GI and CV symptoms; however, a better understanding of the specific autonomic disturbances in patients with chronic nausea and abdominal pain may allow more timely and better clinical management of these patients, including selection of drugs such as b blockers, which have been empirically used to treat both OI and functional GI disorders (9). Further studies including measurement of neurohumoral factors such as catecholamines and vasopressin are needed to better define the mechanisms of OI and nausea in children to allow more focused and rational treatment, because these hormones are associated with nausea and gastric dysrhythmias (10–13,14). To better define a potential relation between nausea, OI, and motility abnormalities, we performed baseline EGG recordings before starting treatment. All of the subjects tested demonstrated a gastric dysrhythmia, most notably tachygastria. These data are consistent with previous literature reporting presentations of abnormal and highly variable gastric myoelectrical activity in POTS patients (1,15). This is not the first time an association between OI
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Fortunato et al
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TABLE 2. Mean symptom score (SD) per symptom before and after fludrocortisone treatment
Symptom Nausea Vomiting Dizziness Syncope Abdominal pain Constipation Anorexia Flushing Missing school
Mean symptom score before fludrocortisone
Mean symptom score after fludrocortisone
Improvement, %
P
3.1 0.8 0.7 0.8 3.0 1.0 0.8 1.2 2.8 1.3 1.6 1.5 2.1 1.4 2.3 1.2 2.2 1.5
2.1 1.1 0.5 1.1 2.2 1.1 0.4 0.7 1.9 1.4 1.3 1.6 1.7 1.3 1.5 1.4 1.2 1.5
32 28 28 49 32 23 22 33 44
0.0016 NS 0.0371 NS 0.0063 NS NS 0.0476 0.0078
P < 0.05 was considered significant; NS ¼ not significant; SD ¼ standard deviation.
and GI symptoms has been described. Posturally mediated HR changes resulting in abnormal gastric electrical activity in patients with functional abdominal pain have recently been reported in children (16,17). Several studies have also demonstrated that abnormal gastric myoelectrical activity in pediatric patients plays a role in the pathophysiology of functional dyspepsia, nausea, and feeding problems (18–24). Our study has limitations. The sample size was small and all of subjects were girls; however, female predominance of the cohort reflects the fact that 75% to 80% of patients diagnosed as having POTS are girls (25). The questionnaire used in the study has not yet been validated. Although validated questionnaires exist for dysautonomia and chronic nausea, there is no symptom questionnaire that addresses the combination of symptoms particularly in the pediatric population. Future studies are necessary to evaluate and validate an appropriate instrument to clinically assess the degree of both autonomic and GI symptoms in these patients. The inclusion of a pediatric psychologist would also strengthen a subsequent study to account for confounding variables such as anxiety or depression, thereby supporting the notion of the recommended multidisciplinary approach to functional GI disorders of childhood (26). In addition, EGGs were performed only before starting fludrocortisone treatment. Whether the rhythm disturbances are corrected by the fludrocortisone treatment would provide revealing information on the relation between the GI and CV symptoms. Finally, the mechanism for the nausea in these subjects remains unclear, and the effect of upright tilt on EGG has not yet been described. Thus, healthy asymptomatic children would be optimal controls for future studies. In conclusion, the origin of chronic nausea as well as symptoms included within the spectrum of functional GI disorders is likely multifactorial, with precipitating triggers and mechanisms not well described. Thus, treatment strategies are empiric at best. There is a paucity of data examining the relation between OI and chronic nausea and even less associated with pediatric patients; however, the findings from our previous and the present study, achieved using noninvasive tilt table tests and EGGs, suggest that this association is common. For the pediatric gastroenterologist, expanding the scope of questions asked to include symptoms of dizziness, syncope, tachycardia, or flushing may be warranted when assessing children with nausea and abdominal pain of a functional nature particularly for refractory GI symptoms. Moreover, tilt evaluation during a 45-minute period may aid in diagnosis. Although the association between dysautonomia and motility problems has not been fully established, these early data suggest that a relation between dysautonomia with nausea and gastric dysrhythmias may exist.
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REFERENCES 1. Fortunato JE, Shaltout HA, Larkin MM, et al. Fludrocortisone improves nausea in children with orthostatic intolerance (OI). Clin Auton Res 2011;21:419–23. 2. Rowe PC, Calkins H, DeBusk K, et al. Fludrocortisone acetate to treat neurally mediated hypotension in chronic fatigue syndrome. JAMA 2001;285:52–9. 3. Freeman R, Weiling W, Axelrod FB, et al. Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Clin Auton Res 2011;21:69–72. 4. Sullivan SD, Hanauer J, Rowe PC, et al. Gastrointestinal symptoms associated with orthostatic intolerance. J Pediatr Gastroenterol Nutr 2005;40:425–8. 5. Koch KL, Hong SP, Xu L. Reproducibility of gastric myoelectrical activity and the water load test in patients with dysmotility-like dyspepsia symptoms and in control subjects. J Clin Gastroenterol 2000;31:125–9. 6. Safder S, Chelimsky TC, O’Riordan MA, et al. Autonomic testing in functional gastrointestinal disorders: implications of reproducible gastrointestinal complaints during tilt table testing. Gastroenterol Res Pract 2009;2009:868496. 7. Drossman DA, Corazziari E, Delvaux M (Eds): et al. ROME III: Functional Gastrointestinal Disorders. Lawrence, KS: Allen Press; 2006. 8. Hyams JS, Burke G, Davis PM, et al. Abdominal pain and irritable bowel syndrome in adolescents: a community-based study. J Pediatr 1996;129:220–6. 9. Grubb BP, Kanjwal Y, Kosinski DJ. The postural tachycardia syndrome: a concise guide to diagnosis and management. J Cardiovasc Electrophysiol 2006;17:108–12. 10. Koch KL, Summy-Long J, Bingaman S, et al. Vasopressin and oxytocin responses to illusory self-motion and nausea in man. J Clin Endocrinol Metab 1990;71:1269–75. 11. Koch KL. A noxious trio: nausea, gastric dysrhythmias and vasopressin. Neurogastroenterol Motil 1997;9:141–2. 12. Kim MS, Chey WD, Owyang C, et al. Role of plasma vasopressin as a mediator of nausea and gastric slow wave dysrhythmias in motion sickness. Am J Physiol 1997;272 (4 pt 1):G853–62. 13. Kim CH, Zinsmeister AR, Malagelada JR. Mechanisms of canine gastric dysrhythmia. Gastroenterology 1987;92:993–9. 14. Wagoner AL, Shaltout HA, D’Agostino RB, et al. Relationship of arginine vasopressin and blood pressure in patient with orthostatic intolerance. Hypertension 2013;62:A261. 15. Seligman WH, Low DA, Asahina M, et al. Clin Auton Res 2012;23:73– 80. 16. Safder S, Chelimsky TC, O’Riordan MA, et al. Gastric electrical activity becomes abnormal in the upright position in patients with postural tachycardia syndrome. J Pediatr Gastroenterol Nutr 2010;51:314–8. 17. Friesen CA, Lin Z, Schurman JV, et al. Autonomic nervous system response to a solid meal and water loading in healthy children: its relation to gastric myoelectrical activity. Neurogastroenterol Motil 2007;19:376–82.
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18. Friesen CA, Lin Z, Hyman PE, et al. Electrogastrography in pediatric functional dyspepsia: relationship to gastric emptying and symptom severity. J Pediatr Gastroenterol Nutr 2006;42:265–9. 19. Diamanti A, Bracci F, Gambarara M, et al. Gastric electric activity assessed by electrogastrography and gastric emptying scintigraphy in adolescents with eating disorders. J Pediatr Gastroenterol Nutr 2003; 37:35–41. 20. Riezzo G, Chiloiro M, Guerra V, et al. Comparison of gastric electrical activity and gastric emptying in healthy and dyspeptic children. Dig Dis Sci 2000;45:517–24. 21. Koch ILL. Physiological Basis of Electrogastrography. New York: Oxford University Press; 2003. 22. Koch KL, Tran TN, Stern RM, et al. Gastric myoelectrical activity in premature and term infants. Neurogastroenterol Motil 1993;5:41–7.
23. Levy J, Harris J, Chen J, et al. Electrogastrographic norms in children: toward the development of standard methods, reproducible results, and reliable normative data. J Pediatr Gastroenterol Nutr 2001;33:455–61. 24. Cucchiara S, Minella R, Riezzo G, et al. Reversal of gastric electrical dysrhythmias by cisapride in children with functional dyspepsia. Report of three cases. Dig Dis Sci 1992;37:1136–40. 25. Stewart JM. Chronic orthostatic intolerance and the postural tachycardia syndrome (POTS). J Pediatr 2004;145:725–30. 26. Fortunato JE, Wagoner AL, Diz DI, et al. Association between anxiety and chronic unexplained nausea in youth with orthostatic intolerance. Paper presented at: Biology and Control of Nausea and Vomiting 2013; Pittsburgh, PA; October 3–4, 2013.
Ascaris Fishing Ascaris lumbricoides is an old-world parasite that is believed to infect one-sixth of the world’s population. Birch-juice, raw carrots, mercury clusters, and tobacco-smoke enemas were common recommendations.
Tobacco-smoke enema kit. Note bellows at the top of the assembled parts. Smoldering tobacco was placed in the central chamber. (Courtesy Wikimedia Commons.)
When tobacco-smoke enemas failed, other curious vermifuges were suggested. Perhaps most intriguing was the whimsical method Nils Rosen von Rosenstein preferred (in Underra¨ttelser om Barn Sjukdomar [1764]): ‘‘. . .[after] tying a string to a piece of fresh pork, [I] introduce it into the intestinum rectum, and pulling it out again after a little time; for a number of these worms will then always follow. This must be done repeatedly, changing the pork at each time, in order to evacuate them all.’’
An Uppsala University professor in Sweden, Nils Rosen von Rosenstein (1706–1773) introduced clinical instruction in pediatrics to the curriculum. A series of his lectures during a period of 10 years were considered so outstanding, the Swedish Royal Academy of Sciences reprinted them as a pediatrics text called Underra¨ttelser om Barn Sjukdomar. Rosen’s book was translated into 5 languages, reaching most of Europe’s evolving disciples of pediatric medicine. The English edition by Andrew Sparrman (1748–1820) was printed in 1776.
—Contributed by Angel R. Colo´n, MD
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