Interpreting Normetanephrines-the Significance of Clinical Context

Introduction: Pheochromocytoma ranges in presentation, but the diagnostic hallmarks are increased catecholamine secretion in patients with an adrenal mass. However, interpretation requires consideration of the clinical state. Case: A 60-year-old man presented with 6 months of episodic flushing, night sweats, fatigue, back pain, and 20-pound weight loss. Vitals were notable for hypotension and mild tachycardia. He was thin with evidence of hyperpigmentation. Contrasted CT showed 15 cm heterogeneous masses of both adrenals and a rib lesion. Plasma normetanephrines were elevated on two separate measures (526 and 1,398 pg/mL, nl <=148). Plasma metanephrines were normal. Urine normetanephrines were increased 4-fold (2,165mcg/g Cr, n 108–524). Labs noted low DHEA-S (2 mcg/dL, n 38–313), high ACTH (204 pg/mL, n 6–50), random cortisol (5.2 mcg/dL, n 3.5–18.3), undetectable aldosterone, and high plasma renin activity (83 ng/mL/h, n 2.9–10.8). Cortisol peaked at 6.7 mcg/dL 1 hour after 250mcg of cosyntropin. MRI revealed over 15cm infiltrating masses arising from adrenals with modest flare on T2 imaging. Dotatate PET/CT showed mild uptake of bilateral adrenals and metastases to liver and bone. He was started on steroid replacement and doxazosin for presumed pheochromocytoma. He was transferred to our facility where he remained hypotensive despite adequate glucocorticoid and mineralocorticoid replacement. Once stabilized, repeat plasma normetanephrines were insignificant (218 pg/mL, n 0–145) and chromogranin was normal (68 ng/mL, n<93). Biopsy of the rib lesion confirmed diffuse large B-cell lymphoma. Discussion: Pheochromocytoma classically presents in the outpatient setting with palpitations, diaphoresis, pallor, and paroxysmal hypertension. Rarely, it results in hypertensive emergencies requiring hospitalization. In patients with catecholamine excess and an adrenal mass, pheochromocytoma is usually suspected. 3-fold or more increases of normetanephrines or metanephrines above upper cutoffs are rarely false-positives. However, this assumes clinical stability. Sympathoadrenal activation is a physiologic response to acute illness. Metanephrines in critically ill patients without pheochromocytoma approached those of pheochromocytoma in one study. Levels normalized upon recovery from illness, highlighting the importance of verifying biochemistries once the patient is stable. The degree of elevation in normetanephrines seen in this patient was a physiologic response to adrenal insufficiency and clinical instability. Pathology confirmed lymphoma rather than pheochromocytoma for which he was started on chemotherapy. Conclusion: Elevated normetanephrines is an appropriate physiological response in the acutely ill. Careful consideration of the clinical picture in conjunction with biochemical data is critical.

Physiologic Response to the COVID-19 Vaccine Measured Using Wearable Devices (Preprint)

BACKGROUND The Pfizer COVID-19 Vaccine employs a novel technology which utilizes messenger Ribonucleic Acid (mRNA) to deliver viral proteins to the host and elicit a protective immune response, but the short-term physiologic response to the vaccine has yet to be studied using wearable devices. OBJECTIVE Using wearable devices, we aim to characterize physiologic changes in response to COVID-19 vaccination in a small cohort of subjects. METHODS In this prospective observational study, physiologic data from 19 internal medicine residents at a single institution who received both doses of the Pfizer COVID-19 vaccine were collected using the WHOOP strap 3.0 to determine participant baseline resting heart rate (RHR), heart rate variability (HRV), respiratory rate (RR), and sleep duration. Primary outcomes included change from baseline in HRV, RHR, RR, and sleep duration. Percent change and standard deviation from baseline (defined as the 30 days of wear prior to vaccination) were calculated for six days after the first and second dose of the Pfizer COVID-19 for all participants who met inclusion and exclusion criteria. Symptom type, severity, and duration were reported as secondary outcomes. RESULTS In 19 individuals, mean age 28.8 (+/- 2.2), 53% female, percent change in HRV was decreased on day 1 (-13.44% +/- 13.62%) following administration of the first vaccine dose, and this response was blunted following dose 2 (-9.25% +/- 22.6%). RHR had a slight initial increase (+2.73% +/- 5.50%, +4.20% +/- 9.42%) after each dose and normalized after one day and RR showed no change compared to baseline after either vaccine dose. Sleep duration was increased up to 6 days post vaccine and peaked on day 3. Increased sleep duration prior to vaccine also demonstrated a more significant change in HRV compared to those who were sleep deprived (as determined by Pearson correlations). A more robust response in terms of symptom severity and duration was seen following dose 2. Arm soreness was the most reported symptom for both doses. CONCLUSIONS This represents the first observational study of the physiologic response in humans to any of the novel COVID-19 vaccines, as measured using wearable devices. We provide evidence that HRV decreases in response to both vaccine doses, with no consequent changes in RHR or RR. Sleep duration initially decreased following each dose and subsequently increased thereafter. Future studies with a larger cohort and comparison to other inflammatory and immune biomarkers, such as antibody response, will be needed to determine the true utility of this type of continuous wearable monitoring in regards to vaccine responses. Our data raises the possibility that increased sleep prior to vaccination may impact physiologic response, which could be used to track immune response to vaccination. CLINICALTRIAL NCT04304703: https://www.clinicaltrials.gov/ct2/show/NCT04304703

The Physiologic Response to Rescue Therapy with Vasopressin versus Epinephrine during Experimental Pediatric Cardiac Arrest

Background: While epinephrine is the mainstay of therapy during cardiopulmonary resuscitation, it is potentially detrimental to the cerebral vasculature and ineffective in certain populations. This study compares a rescue dose of vasopressin to a rescue dose of epinephrine after ineffective initial doses of epinephrine in diverse models of pediatric in-hospital cardiac arrest. 67 one- to three-month old female swine (10-30kg) in six experimental cohorts from one laboratory received hemodynamic-directed CPR, a resuscitation method where high quality chest compressions are provided and vasopressor administration is titrated to coronary perfusion pressure (CoPP) ³20 mmHg. Vasopressors are given when CoPP is <20 mmHg, in sequences of two doses of 0.02 mg/kg epinephrine separated by minimum one-minute, then a rescue dose of 0.4 U/kg vasopressin followed by minimum two-minutes. Invasive measurements were used to evaluate and compare the hemodynamic and neurologic effects of each vasopressor dose. Results: Increases in CoPP and cerebral blood flow (CBF) were greater with vasopressin rescue than epinephrine rescue (CoPP: +8.16 [4.35, 12.06] mmHg vs. +5.43 [1.56, 9.82] mmHg, p=0.022; CBF: +14.58 [-0.05, 38.12] vs. +0.00 [-0.77, 18.24] perfusion units (PFU), p=0.005). Twenty animals (30%) failed to achieve CoPP ³20 mmHg after two doses of epinephrine; 9/20 (45%) non-responders achieved CoPP ³20 mmHg after vasopressin. Among all animals, the increase in CBF was greater with vasopressin (+14.58 [-0.58, 38.12] vs. 0.00 [-0.77, 18.24] PFU, p=0.005).Conclusions: CoPP and CBF rose significantly more after rescue vasopressin than after rescue epinephrine. Importantly, CBF increased after vasopressin rescue, but not after epinephrine rescue. In the 30% that failed to meet CoPP of 20mmHg after two doses of epinephrine, 45% achieved target CoPP with a single rescue vasopressin dose.

6-Minute Push Test in Youth Who Have Spina Bifida and Who Self-Propel a Wheelchair: Reliability and Physiologic Response

Objective Despite the common occurrence of lower levels of physical activity and physical fitness in youth with spina bifida (SB) who use a wheelchair, there are very few tests available to measure and assess these levels. The purpose of this study was to determine reliability and the physiologic response of the 6-minute push test (6MPT) in youth with SB who self-propel a wheelchair. Methods In this reliability and observational study, a sample of 53 youth with SB (5–19 years old; mean age = 13 years 7 months; 32 boys and 21 girls) who used a wheelchair performed 2 exercise tests: the 6MPT and shuttle ride test. Heart rate, minute ventilation, respiratory exchange ratio, and oxygen consumption were measured using a calibrated mobile gas analysis system and a heart rate monitor. For reliability, intraclass correlation coefficients (ICCs), SE of measurement, smallest detectable change for total covered distance, minute work, and heart rate were calculated. Physiologic response during the 6MPT was expressed as percentage of maximal values achieved during the shuttle ride test. Results The ICCs for total distance and minute work were excellent (0.95 and 0.97, respectively), and the ICC for heart rate was good (0.81). The physiologic response during the 6MPT was 85% to 89% of maximal values, except for minute ventilation (70.6%). Conclusions For most youth with SB who use a wheelchair for mobility or sports participation, the 6MPT is a reliable, functional performance test on a vigorous level of exercise. Impact This is the first study to investigate physiologic response during the 6MPT in youth (with SB) who are wheelchair using. Clinicians can use the 6MPT to evaluate functional performance and help design effective exercise programs for youth with SB who are wheelchair using.