Pediatric Patient With Altered Mental Status and Hypoxemia: Case Report

ILLUSTRATIVE CASE Pediatric Patient With Altered Mental Status and Hypoxemia Case Report Jeremy M. Root, MD,*† Marcela Vargas, MD,†‡ Luigi R. Garibaldi, MD,*‡ and Richard A. Saladino, MD*§ Abstract: Childhood cases of myxedema coma are extremely rare. We report a case of a 5-year-old girl transferred to a tertiary care pediatric emergency department with hypoxemia and altered mental status and diagnosed with severe hypothyroidism and myxedema coma in the setting of acute influenza infection. Although it is rare, myxedema coma must remain in the differential diagnosis for altered mental status and organ dysfunction in the pediatric population. Key Words: hypothyroidism, myxedema, altered mental status (Pediatr Emer Care 2016;00: 00–00) CASE A 5-year-old girl with no significant medical history was evaluated in our tertiary care pediatric emergency department during the winter season with complaints of cough, fever, gait unsteadiness, and changes in her behavior described as confusion and decreased alertness. Her parents also reported that she had a nonproductive cough for 10 days and progressive fatigue for several months before the emergency department visit. On the day of presentation, her parents noted that she was much less interactive than usual and was having difficulty responding appropriately to their questions. Otherwise, the review of systems was negative. Upon arrival to the pediatric emergency department, her physical examination revealed a temperature of 37.4°C (99.3°F), pulse rate of 88 beats per minute, respiratory rate of 16 breathsper minute, and blood pressure of 86/58 mm Hg. Her oxyhemoglobin saturation by pulse oximeter was 85% in room air. She was lethargic and was noninteractive with her parents and health care personnel. Her skin was dry and she was noted to be pale. Her conjunctivae were clear and periorbital edema was noted bilaterally; no peripheral edema was appreciated. Her neck was supple and without nuchal rigidity on flexion and there was no goiter on palpation. Her breathing was slightly shallow but she was in no respiratory distress. Her lung examination was clear to auscultation. Her cardiac examination was normal, including normal heart tones, no murmurs or rubs, and normal peripheral pulses and perfusion. She was not cyanotic. Her abdomen was soft, nontender, and mildly distended with normal bowel sounds and no hepatosplenomegaly. Her sexual maturity rating was Tanner stage 1. Her neurological examination revealed that she did not respond to visual, auditory, or tactile stimuli, nor did she follow commands. Her muscular tone was normal. She did withdraw from painful stimuli. Her deep tendon reflex responses had delayed relaxation at the ankles. Motor strength From the *Department of Pediatrics, University of Pittsburgh School of Medicine; †Department of Pediatrics, Children's Hospital of Pittsburgh; ‡Division of Pediatric Endocrinology, Department of Pediatrics, University of Pittsburgh School of Medicine; and §Division of Pediatric Emergency Medicine, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA. Disclosure: The authors declare no conflict of interest. Reprints: Jeremy M. Root, MD, Children's National Medical Center, Division of Emergency Medicine, 111 Michigan Ave NW, Washington DC, 20010 (e‐mail: jroot@childrensnational.org). Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0749-5161 Pediatric Emergency Care • Volume 00, Number 00, Month 2016 and cranial nerve examination were limited, because she did not follow commands. In the emergency department, the initial evaluation and management was focused on the patient's hypoxemia and depressed mental status. Initial blood glucose was 100 mg/dL (reference range, 70–126). A complete blood count was notable for a hemoglobin level of 10.3 g/dL (reference range, 11.5–13.5), hematocrit of 31.1% (reference range, 34%–40%), mean corpuscular volume of 85.4 fL (reference range, 75–87), and white blood cell count of 5.9  109 (reference range, 5.0–17.0  109) with 67% neutrophils, 2% bands, 27% lymphocytes, and 3% monocytes. A venous blood gas revealed a pH of 7.30, PCO2 of 57 mm Hg, and bicarbonate level of 25 mEq/L, consistent with respiratory acidosis. A 2-view chest radiograph showed low lung volumes without definite abnormality; a very small pleural effusion at the right costophrenic angle was noted (Fig. 1). An electrocardiogram (EKG) was performed, which showed normal sinus rhythm with RSR or QR pattern in V1 suggestive of right ventricular conduction delay (Fig. 2). Further work-up for altered mental status such as head computed tomography, lumbar puncture, and urine toxicology screen were not performed. Supplemental oxygen via nasal cannula normalized her oxygen saturation; however, the patient remained partially obtunded. Given the patient's altered mental status and unexplained hypoxemia, she was admitted to an inpatient medical team. During the patient's hospitalization, blood for additional evaluation of her thyroid function and pituitary axis was obtained, as were nasal secretions for a respiratory pathogen panel. Her thyroid function testing revealed a thyroid-stimulating hormone of 578 mIU/L (reference range, 0.5–5.7), thyroxine (T4) level of 2.7 μg/dL (reference range, 6.4–13.3), free T4 level of less than 0.07 ng/dL (reference range, 0.8–1.8), and triiodothyronine (total T3) level of 20 ng/dL (reference range, 126–216). An adrenocorticotropic hormone stimulation test was performed and showed a normal 60-minute cortisol response of 25 μg/dL, which excluded primary adrenal insufficiency. Further thyroid studies were notable for thyroglobulin antibodies of 513 IU/L (reference, <280) and thyroid peroxidase antibodies of 1273 IU/L (reference, <60). Her lipid panel revealed an elevated total cholesterol level of 442 mg/dL (reference, <200) and low density lipoprotein level of 339 mg/dL (reference, <129). An echocardiogram was notable for a mild pericardial effusion. Finally, nasal secretions were positive for antigen detection for influenza A. Because of worsening respiratory acidosis and increasing oxygen requirement, the patient was transferred to the pediatric intensive care unit (PICU), because there were concerns for impending respiratory failure. While in the PICU, she required further respiratory support including positive pressure ventilation (bilevel positive airway pressure), which resolved her hypoxia, hypercapnia, and respiratory acidosis. Despite improvement in her respiratory status, the patient's mental status failed to improve. She remained unresponsive to visual, auditory, or tactile stimuli and did not follow commands or recognize her parents, suggesting that her progressive obtundation was secondary to neither hypoxia nor hypercapnia. Based on her clinical condition in the context of her abnormal thyroid function tests, her clinical presentation was felt to be www.pec-online.com Copyright © 2016 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. 1 Pediatric Emergency Care • Volume 00, Number 00, Month 2016 Root et al tendon reflexes at her ankles normalized and she resumed ambulation without difficulty. Approximately 7 days after the thyroid hormone replacement was initiated, her mental status returned to her baseline. Because her respiratory and mental status improved, she was transferred to the general pediatric floor. Her thyroid replacement medications were transitioned to oral formulations and the doses were adjusted on the basis thyroid hormone levels and clinical response. The patient received liothyronine for a total of 4 days and completed a 5-day course of oseltamivir for her influenza A infection. She was discharged home on levothyroxine at a dose of 62.5 μg/d (100 μg/m2 per day). At a follow-up visit to the endocrinology clinic 1 month after hospital discharge, her thyroid function tests were normal, including a thyroid-stimulating hormone of 3.96 mIU/L (reference range, 0.7–5.7) and a free T4 of 1.53 ng/dL (reference range, 0.8–1.8). She was asymptomatic, specifically denying fatigue, constipation, and hair loss, and her physical examination was normal except for residual dry skin. A retrospective review of her growth records from her pediatrician indicated that from ages 4 to 5 years, her height had dropped from the 38th to the 14th percentile, whereas her weight percentile remained at the 25th percentile. FIGURE 1. Two-view chest x-ray obtained on initial presentation to the ED. secondary to severe hypothyroidism. Within 12 hours of presentation to the emergency department, intravenous levothyroxine 60 μg/d (80 μg/m2 per day) was initiated, followed by liothyronine, 2 μg every 12 hours (0.1 μg/kg per dose). Intravenous hydrocortisone, 2 mg/kg per day (0.5 mg/kg per dose), was also initiated by the attending physician in the PICU. After discussion with the consultant endocrinologist and review of the adrenocorticotropic hormone stimulation test, which excluded primary adrenal insufficiency, it was discontinued. Two days after the treatment with thyroid hormone replacement, her mental status improved significantly. She became increasingly more responsive to stimuli and began interacting with her family members and the clinical staff. The delayed deep DISCUSSION Myxedema was originally described in 1877 as a “peculiar” swelling of subcutaneous tissue characteristic of adult hypothyroidism.1,2 In 1879, myxedema coma with altered mental status was reported by the St. Thomas Hospital in London.3 A second case of myxedema coma was not published until 74 years later in 1953,4 indicative of the low incidence in the adult population.5 In childhood, cases of myxedema coma are even more rare.4 We found a single pediatric case report of a developmentally and growth-delayed 8-year-old patient diagnosed with myxedema coma secondary to pituitary insufficiency,5 but no cases in otherwise previously healthy children. It is generally felt that myxedema coma is rare and unrecognized, particularly in patients younger than 50 years.4,6 The presentation is often similar to other life-threatening conditions and includes hypothermia, heart failure, renal failure, and altered mental status. Common FIGURE 2. EKG obtained in the ED showing normal sinus rhythm with RSR' or QR pattern in V1 suggestive of right ventricular conduction delay. 2 www.pec-online.com © 2016 Wolters Kluwer Health, Inc. All rights reserved. Copyright © 2016 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Pediatric Emergency Care • Volume 00, Number 00, Month 2016 Patient With Altered Mental Status and Hypoxemia TABLE 1. Differential Diagnosis of Altered Mental Status Drugs and Toxins Drugs of abuse Medications Poisons Drug withdrawal Infections Metabolic Disturbances Sepsis Electrolyte disturbances Fever-related delirium Endocrine abnormalities Hypercapnea Hypoxemia Inborn errors of metabolism CNS Disorders Systemic Organ Failure CNS infections Seizures Head trauma Psychosis Cardiac failure Liver failure Renal failure Pulmonary disease Hematologic (polycythemia) Physical Disorders Burns Hyperthermia Hypothermia Trauma Adapted from Francis and Young (2014)12. precipitating factors include cold exposure, infection, trauma, and anesthesia.3 The clinical criteria that define myxedema coma are not precise, nor are they consistently described in the literature. Nonetheless, myxedema coma is generally described as a combination of severe hypothyroidism, changes in mentation (ranging from lethargy to unconsciousness), hypoxemia, respiratory acidosis, hemodynamic instability, and hypothermia.3,7 Paradoxically, coma is unusual.7 The pathophysiology of myxedema coma includes low intracellular levels of triiodothyronine (T3) often leading to hypothermia and organ dysfunction, including suppression of cardiac activity and brain function.6,8 It has also been proposed that the mechanism for decreased brain function in a hypothyroid state is decreased cerebral blood flow8–10 and impaired cerebral glucose metabolism.11 Furthermore, decreased central nervous system response to hypoxia may lead to respiratory failure.6 Our patient presented with depressed mentation and responsiveness, hypoxemia in the absence of respiratory distress, and respiratory acidosis. The differential diagnosis for altered mental status includes the following: toxins and medications, infections and sepsis, metabolic disturbances, hormone imbalances, hypoxemia, nutritional deficiencies, central nervous system (CNS) injuries or infections, systemic organ failure, and temperature instability (Table 1).12 The evaluation for pediatric patients with altered mental status includes an immediate bedside glucose determination. If there is a concern for infection, blood, urine, and cerebrospinal fluid counts and cultures should be obtained so intravenous antibiotics can be administered promptly if necessary. A head computerized tomography of the brain should be obtained if a specific etiology is not identified. If there are concerns for an inborn error of metabolism, clinicians should consider measuring serum ammonia and obtaining urine for organic acids. An electroencephalogram is recommended if there are concerns for nonclinical status epilepticus and an EKG is a standard part of the clinical work-up for the infant with transient altered mental status.13 The EKG findings of interventricular conduction delay, as seen in our patient, can be found in patients with severe hypothyroidism.14 Initially in the emergency department, our patient's altered mental status was presumed to be secondary to her hypoxemia. Importantly, the provision of supplemental oxygen in the emergency department as well as positive pressure ventilation in the PICU resolved her hypoxia and hypercapnia without improvement of her mental status. This then required the consideration of different etiologies for altered mental status. Our patient's constellation of symptoms in tandem with her physical examination and laboratory findings was consistent with severe hypothyroidism as the mostly likely cause of her progressive obtundation. Identification and treatment of her hypothyroidism within hours of presentation to the emergency department provided a reversal of her symptoms and an ultimate positive outcome. © 2016 Wolters Kluwer Health, Inc. All rights reserved. CONCLUSIONS Myxedema coma is known to be precipitated by a trigger event, most commonly an infection. Our patient had concurrent influenza A infection and presented with clinical characteristics of myxedema coma, suggesting that this uncommon diagnosis may occur in otherwise healthy children. Despite of its rarity, myxedema coma should remain in the differential for pediatric patients with altered mental status and unexplained hypoxemia. Prompt recognition of this diagnosis in the emergency department setting and timely therapy is essential to reduce associated morbidities. REFERENCES 1. Ord W. On Myxedema, a term proposed to be applied to an essential condition in the ‘cretinoid’ affection occassionally observed in middle-aged women. Med Chir Trans. 1878;61:57–78. 2. Aikawa J. The nature of myxedema: alterations in the serum electrolyte concentrations and radiosodium space and in the exchangeable sodium and potassium contents. Ann Intern Med. 1956;44:30–39. 3. Kwaku MP, Burman KD. Myxedema coma. J Intensive Care Med. 2007; 22:224–231. 4. Senior RM, Birge SJ, Wessler S, et al. The recognition and management of myxedema coma. JAMA. 1971;217:61–65. 5. Schutt-Aine JC. Hypothyroid myxedema and hyponatremia in an eight-year-old child: a case report. J National Med Assoc. 1980;72:705–708. 6. Mathew V, Misgar RA, Ghosh S, et al. Myxedema coma: a new look into an old crisis. J Thyroid Res. 2011;2011:ID 493462. 7. Nicoloff JT. Thyroid storm and myxedema coma. Med Clin North Am. 1985;69:1005–1017. 8. Sensenbach W, Madison L, Eisenberg S, et al. The cerebral circulation and metabolism in hyperthyroidism and myxedema. J Clin Invest. 1954;33: 1434–1140. 9. Scheinberg P, Stead EA Jr, Brannon ES, et al. Correlative observations on cerebral metabolism and cardiac output in myxedema. J Clin Invest. 1950;29:1139–1146. 10. O'Brien MD, Harris PW. Cerebral-cortex perfusion-rates in myxoedema. Lancet. 1968;291:1170–1172. 11. Constant EL, de Volder AG, Ivanoiu A, et al. Cerebral blood flow and glucose metabolism in hypothyroidism: a positron emission tomography study. J Clin Endocrinol Metab. 2001;86:3864–3870. 12. Francis J, Young B. Diagnosis of delirium and confusion states. UpToDate Web site. Available at: http://www.uptodate.com/contents/ diagnosis-of-delirium-and-confusional-states. Accessed August 13, 2014. 13. MacNeill EC, Vashist S. Approach to syncope and altered mental status. Pediatr Clin North Am. 2013;60:1083–1106. 14. Gavrilescu S, Luca C, Streian C, et al. Monophasic action potentials of right atrium and electrophysiological properties of AV conducting system in patients with hypothyroidism. Br Heart J. 1976;38:1350–1354. www.pec-online.com Copyright © 2016 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. 3