The clinical utility of plasma and urine metanephrines in hypertensive emergency.

INTRODUCTION: Metanephrines (MTNs) are metabolites of catecholamines and are constantly produced in high amounts by pheochromocytomas and paragangliomas (PPGLs). Marked MTN elevations (> 3 times the upper limit of normal [ULN]) are highly suggestive of PPGL. The frequency of marked MTN elevations in non-PPGL hypertensive emergencies (HTNEs) is unknown. METHODS: We retrospectively analyzed plasma free metanephrine (PMTN) and 24-h urinary fractionated metanephrine (UMTN) levels in 48 consecutive patients (59.7 ± 15.6 years; 48% female; BMI: 31 ± 9.7 kg/m2) hospitalized for HTNE, defined as systolic blood pressure (SBP) > 180 mmHg or diastolic blood pressure (DBP) > 120 mmHg with end-organ damage. PMTNs were measured in 47 patients, UMTNs were measured in 16 patients, and both PMTNs and UMTNs were measured in 15 patients. RESULTS: PMTN/UMTN levels were not associated with SBP/DBP, comorbidities, end-organ damage, or interfering medications, the exception being that plasma normetanephrines (PNMNs) were significantly associated with comorbidities (Adj. R2 = 0.16; p = 0.04) and interfering medications (Adj. R2 = 0.15; p = 0.03), although with weak correlation. Marked MTN (specifically PNMN) elevations (647, 521, and 453 pg/mL; normal ≤ 148 pg/mL) were noted in only three patients (6%). DISCUSSION: Marked MTN elevations in HTNE are uncommon. Therefore, we recommend against measuring MTN in the setting of an apparent precipitating cause of HTNE to avoid unnecessary testing and imaging. Testing for MTN in HTNE should be pursued only when there is no clear precipitating cause and in cases where there is strong underlying clinical suspicion for PPGL. However, should testing be performed, marked MTN elevations should not be disregarded as being a commonly occurring result of HTNE.

Plasma Epinephrine Contributes to the Development of Experimental Hypoglycemia-Associated Autonomic Failure.

BACKGROUND: Recurrent hypoglycemia blunts counter-regulatory responses to subsequent hypoglycemic episodes, a syndrome known as hypoglycemia-associated autonomic failure (HAAF). Since adrenergic receptor blockade has been reported to prevent HAAF, we investigated whether the hypoglycemia-associated rise in plasma epinephrine contributes to pathophysiology and reported interindividual differences in susceptibility to HAAF. METHODS: To assess the role of hypoglycemia-associated epinephrine responses in the susceptibility to HAAF, 24 adult nondiabetic subjects underwent two 2-hour hyperinsulinemic hypoglycemic clamp studies (nadir 54 mg/dL; 0-2 hours and 4-6 hours) on Day 1, followed by a third identical clamp on Day 2. We challenged an additional 7 subjects with two 2-hour infusions of epinephrine (0.03 µg/kg/min; 0-2 hours and 4-6 hours) vs saline on Day 1 followed by a 200-minute stepped hypoglycemic clamp (90, 80, 70, and 60 mg/dL) on Day 2. RESULTS: Thirteen out of 24 subjects developed HAAF, defined by ≥20% reduction in average epinephrine levels during the final 30 minutes of the third compared with the first hypoglycemic episode (P < 0.001). Average epinephrine levels during the final 30 minutes of the first hypoglycemic episode were 2.3 times higher in subjects who developed HAAF compared with those who did not (P = 0.006).Compared to saline, epinephrine infusion on Day 1 reduced the epinephrine responses by 27% at the 70 and 60 mg/dL glucose steps combined (P = 0.04), with a parallel reduction in hypoglycemic symptoms (P = 0.03) on Day 2. CONCLUSIONS: Increases in plasma epinephrine reproduce key features of HAAF in nondiabetic subjects. Marked interindividual variability in epinephrine responses to hypoglycemia may explain an individual's susceptibility to developing HAAF.

Hypertensive emergency masquerading as phaeochromocytoma: a report of two cases.

We report two cases of patients who were hospitalised for hypertensive emergency. In both cases, laboratory testing during admission revealed elevated normetanephrines in the range of 4-5 times the upper limit of normal using liquid chromatography with mass spectrometry. Imaging studies did not localise any phaeochromocytoma or paraganglioma (PPGL). Repeat biochemical testing after discharge was within normal limits in both cases. These observations suggest that hypertensive emergency should be recognised as a potential cause of 'false-positive' laboratory findings in the diagnostic assessment for PPGL.

Opioid Receptor Activation Impairs Hypoglycemic Counterregulation in Humans.

Although intensive glycemic control improves outcomes in type 1 diabetes mellitus (T1DM), iatrogenic hypoglycemia limits its attainment. Recurrent and/or antecedent hypoglycemia causes blunting of protective counterregulatory responses, known as hypoglycemia-associated autonomic failure (HAAF). To determine whether and how opioid receptor activation induces HAAF in humans, 12 healthy subjects without diabetes (7 men, age 32.3 ± 2.2 years, BMI 25.1 ± 1.0 kg/m2) participated in two study protocols in random order over two consecutive days. On day 1, subjects received two 120-min infusions of either saline or morphine (0.1 µg/kg/min), separated by a 120-min break (all euglycemic). On day 2, subjects underwent stepped hypoglycemic clamps (nadir 60 mg/dL) with evaluation of counterregulatory hormonal responses, endogenous glucose production (EGP, using 6,6-D2-glucose), and hypoglycemic symptoms. Morphine induced an ∼30% reduction in plasma epinephrine response together with reduced EGP and hypoglycemia-associated symptoms on day 2. Therefore, we report the first studies in humans demonstrating that pharmacologic opioid receptor activation induces some of the clinical and biochemical features of HAAF, thus elucidating the individual roles of various receptors involved in HAAF's development and suggesting novel pharmacologic approaches for safer intensive glycemic control in T1DM.

Understanding hypoglycemia in hospitalized patients.

Controlling blood glucose in hospitalized patients is important as both hyperglycemia and hypoglycemia are associated with increased cost, length of stay, morbidity and mortality. A limiting factor in stringent control is the concern of iatrogenic hypoglycemia. The association of hypoglycemia with mortality has led to clinical guideline changes recommending more conservative glycemic control than had previously been suggested, with the use of patient specific approaches when appropriate. Healthier, stable patients may be managed with stricter control while the elderly and severely ill may be managed less aggressively. While the avoidance of hypoglycemia is essential in clinical practice, recent studies suggest that a higher mortality rate occurs in spontaneous rather than iatrogenic hypoglycemia. Therefore, inpatient hypoglycemia may be viewed more as a biomarker of disease rather than a true cause of fatality.