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Background: Opioid overdose is a leading cause of death among injection drug users. Over half of injection drug users report at least one nonfatal overdose during their lifetime. Death from opioid overdose rarely occurs instantaneously, but rather over the course of one to three hours, allowing ample time for providing life-saving measures. In response to the prevalence of overdoses in the U.S., there are a growing number of overdose prevention and naloxone distribution programs targeting the injection drug using community.

A prospective study measured ionized calcium and parathormone sequentially at 48- to 72-hour intervals in 25 surgical intensive care unit patients. Twelve patients (48%) died at mean day 40 and median day 26. Levels of ionized calcium, parathormone, blood urea nitrogen, creatinine, albumin, magnesium, and phosphate for patients who lived were compared with levels for patients who died. The incidence of hypotension, renal failure (creatinine greater than or equal to 3.0), and bacteremia, as well as the amount of red cell, crystalloid, and colloid administration for the two groups was compared. Hypotension, bacteremia, red cells, crystalloid, and colloid were no different. On days 1 and 2 ionized calcium levels were significantly lower and parathormone levels significantly higher in nonsurviving patients; this difference persisted through days 3 and 4. Blood urea nitrogen and creatinine levels increased early in nonsurviving patients but renal failure, which occurred in nine nonsurviving patients, did not develop until mean day 14, median day 18. The phosphate level was slightly higher but still within normal range in nonsurviving patients. By days 5 and 6 ionized calcium and parathormone levels were no different in nonsurviving patients, despite there being no improvement in renal function. Magnesium and albumin levels were no different between groups. Ionized calcium levels are lower and parathormone levels higher early in nonsurviving patients. This difference is not readily explained by associated clinical conditions, including renal dysfunction. Although etiology remains unclear, low ionized calcium and elevated parathormone are early predictors of mortality in critically ill surgical patients.

Ouabain has been identified in the plasma and adrenal glands of several mammals, including humans. To investigate possible adrenal secretion of ouabain in vivo, at rest, and in response to acute blood volume changes, we prepared trained adult dogs (n = 10) with splenectomy and unilateral adrenal venous (AV) cannulation. Two days later, after an overnight fast, dogs had either 1) 20% hemorrhage (hem) or 2) 20% blood volume expansion (exp; 6% Dextran 70, 0.9% NaCl) in random order. In AV and arterial plasma (ART), ouabain was measured by a ouabain-specific immunoassay, and cortisol and aldosterone were measured by radioimmunoassay. ART and AV ouabain concentration did not change after hem or exp [P = not significant (NS)]. In 94 of 97 paired samples, the concentration of ouabain in AV was greater than that in ART (Wilcoxon, P < 0.001), and the mean ouabain concentration was greater in AV (756.4 +/- 85.7 pmol/l) than ART (235.4 +/- 18.5 pmol/l; P < 0.001). The mean AV-to-ART ouabain concentration ratio was 5.7 +/- 1.29. Adrenal secretion of ouabain was not influenced by hem or exp (analysis of variance, P = NS). Adrenal secretion of cortisol and aldosterone increased after hem (P < 0.05) and was unaltered by exp (P = NS). This study demonstrates that ouabain is secreted by the adrenal gland in the awake dog. However, adrenal ouabain secretion and arterial blood ouabain are not altered by acute hem or exp.

To test whether or not splanchnic neural input to the adrenal gland affects secretion of steroids from the adrenal cortex, the thoracic splanchnic nerve was electrically stimulated in pentobarbital-anesthetized dogs after hypophysectomy and replacement with physiological concentrations of ACTH. An adrenal vein cannula was placed to permit measurement of cortisol, corticosterone, 11 -deoxycortisol, epinephrine and norepinephrine secretion rates and adrenal blood flow. Plasma ACTH was measured and the presentation rate of ACTH was calculated as the product of plasma ACTH concentration and adrenal plasma flow. Dogs were infused initially with ACTH for 60 min at 2 ng/min followed by infusion for 60 min at 10 ng/min. Within each infusion period, the distal end of the nerve was stimulated (20 V; 0.5-ms pulse duration) at 4 and at 20 Hz for 10 min each. Nerve stimulation resulted in a frequency-dependent increase in mean arterial pressure, in epinephrine and norepinephrine secretion and in adrenal blood flow. Arterial ACTH remained constant during nerve stimulation; however, increased adrenal blood flow resulted in increased presentation rate of ACTH to the adrenal. Cortisol secretion increased in response to nerve stimulation at 4 and 20 Hz during infusion of 2 and 10 ng/min ACTH and occurred prior to changes in presentation rate of ACTH. Corticosterone secretion also increased after stimulation at both frequencies, but the response was observed only during infusion of 10 ng/min ACTH. In contrast, 11-deoxycortisol decreased after nerve stimulation at 4 Hz but showed no response after stimulation at 20 Hz during infusion of 2 and 10 ng/min ACTH. Steroid ratios were calculated to assess the possible involvement of specific steroidogenic enzymes in the observed responses. The cortisol to 11-deoxycortisol ratio was increased, whereas the cortisol to corticosterone ratio was not affected by nerve stimulation, suggesting a change in 11-β-hydroxylase activity. These data show that splanchnic nerve stimulation can increase cortisol secretion independently of changes in arterial ACTH. The effect of splanchnic nerve activity on cortisol secretion may result from increasing vascular delivery of ACTH to the adrenal, from release of a non pituitary humoral factor with steroidogenic activity or from direct stimulation of steroidogenesis by an adrenal neurotransmitter substance.

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