Interleukins (IL)-1β and -1α and tumor necrosis factor (TNF-α) were measured by radioimmunoassay in plasma samples from 44 healthy individuals, 15 patients in septic shock, and 6 volunteers infused ...with endotoxin. Plasma IL-1α levels were low (40 pg/ml) or undetectable in all situations. In 67% ofthe healthy subjects, plasma IL-1β levels were <70 pg/ml. Septic patients had higher plasma IL-1β levels (120± 17pg/ml, P =.001);those of surviving patients were higher than those of patients who died (P = .05). Plasma TNF-α concentrations in septic individuals were elevated (119 ± 30 pg/ml) and correlated with severity of illness (r = .73, P = .003), but no correlation was observed between plasma IL-1β and TNF-α concentrations in individual samples. Infusion of endotoxin caused a twofold elevation of IL-1β, from a baseline of 35 ± 5 pg/ml to a maximum of 69 ± 27 pg/ml at 180min (P <.05). Peak TNF-a levels after endotoxin infusion were 15 times higher than IL-1β levels, were attained more rapidly (90 min), and as with the septic patients, did not correlate with IL-1β levels. These data support the concept that plasma IL-1β and TNF-α concentrations are regulated independently and are associated with different clinical outcomes.
OBJECTIVESTo study the effects of endotoxin on magnesium homeostasis; to determine if progressive magnesium deficiency alters outcome from endotoxin challenge; and to evaluate the efficacy of ...magnesium therapy in reducing endotoxin-induced mortality.
DESIGNProspective, placebo-controlled, randomized, multiexperiment studies.
SETTINGResearch laboratory of a university hospital.
SUBJECTSMale Sprague Dawley rats (n equals 299).
INTERVENTIONSExperiment 1 was designed to test if endotoxin alters magnesium homeostasis. Circulating total and ionized magnesium (estimated by ultrafilterable values) concentrations were determined in blood samples collected from animals after the randomized administration of placebo or 0.3, 3.0, or 30 mg/kg of endotoxin. A baseline blood sample was collected and then a second blood sample was obtained at 5, 15, 30, 60, 120, or 180 mins after endotoxin or placebo administration. In experiment 2, animals were randomized to receive magnesium-sufficient diets or magnesium-deficient diets for 6 wks. After 6 wks, the effects of the randomized administration of 3.0 mg/kg endotoxin or placebo were evaluated on mortality and analyte values (pH and blood gases, sodium, potassium, chloride, glucose, ionized calcium, hematocrit, total and ultrafilterable magnesium concentrations) in the three study groups (magnesium-sufficient, 3-wk magnesium-deficient, or 6-wk magnesium-deficient). In experiment 3, magnesium-deficient animals were randomized to receive 50 mmol/kg magnesium chloride or placebo, before or after the administration of 3.0 mg/kg of endotoxin. Baseline and 24-hr analyte determinations were performed and outcome was analyzed.
MEASUREMENTS AND MAIN RESULTSExperiment 1Significant increases (p less than .05) in circulating total magnesium concentrations were found in animals that received 30 mg/kg of endotoxin, at 120 mins (0.79 plus minus 0.10 vs. 0.60 plus minus 0.05 mmol/L), and 180 mins (0.74 plus minus 0.04 vs. 0.56 plus minus 0.04 mmol/L) compared with baseline values. Similarly, significant increases (p less than .05) in ionized magnesium concentrations were observed 120 and 180 mins after 3.0 and 30 mg/kg of endotoxin compared with baseline values. Experiment 2Magnesium deficiency was strongly (p less than .02) associated with increased mortality from endotoxin challenge. Endotoxin administration (3.0 mg/kg) was lethal in 10 (43%) of 23 magnesium-sufficient animals, 15 (65%) of 23 3-wk magnesium-deficient animals, and 20 (83%) of 24 6-wk magnesium-deficient animals. Experiment 3In magnesium-deficient animals, rats treated with magnesium replacement therapy had significantly increased survival from endotoxin administration (15 52% of 29 vs. five 17% of 29, p less than .01) compared with placebo-treated animals.
CONCLUSIONSa) Endotoxin challenge causes significant increases in circulating total and ionized magnesium concentrations. b) Progressive magnesium deficiency is strongly associated with increased lethality, and magnesium replacement therapy provides significant protection from endotoxin challenge. c) These experimental results support the concept that cellular injury is probably associated with increases in circulating magnesium concentrations. Furthermore, these experimental findings suggest that magnesium deficiency predisposes to worse outcome from endotoxin challenge, and that replacement therapy in the setting of magnesium deficiency may be warranted, especially in critically ill subjects.(Crit Care Med 1995; 23:108-118)
In order to study the clinical consequences of postoperative hypomagnesemia, the serum magnesium (Mg) concentration was measured in samples of blood collected from 193 patients admitted to two ...postoperative ICUs. On admission to the ICU, 117 patients (61 percent) had hypomagnesemia (serum Mg <1.5 mEq/dl), 66 patients (34 percent) had normomagnesemia (1.5 to 2.0 mEq/dl), and ten patients (5 percent) had hypermagnesemia (>2.0 mEq/dl). There were no correlations between the severity of illness score (r = 0.145) or the degree of hypoproteinemia (r = 0.01) and the postoperative serum Mg level. Patients with sever hypomagnesemia (serum Mg ≤1.0 mEq/dl) experienced hypokalemia more often (p <0.02) than the others in the study. Furthermore, those with severe hypomagnesemia had a higher mortality rate (7/17 or 41 percent) than the remainder of the population studied (22/176 or 13 percent) (p<0.02). Those with severe hypomagnesemia had received aminoglycosides more often (p<0.001) than those with normal serum Mg concentrations. The serum Mg level was not a sensitive (68 percent) or specific (37 percent) predictor of survival. Our conclusions were as follows: (1) hypomagnesemia is common in postoperative ICU patients; and (2) patients in the postoperative ICU who have severe hypomagnesemia have a higher mortality and more hypokalemia than similarly ill patients with normomagnesemia. Because of the association between aminoglycoside therapy and severe hypomagnesemia, we recommend measurement of this variable in those patients receiving aminoglycosides. Furthermore, Mg replacement therapy is recommended for those patients with serum Mg values of 1 mEq/dl or less.
(Chest 1989; 95:391-97)
To determine the validity and clinical importance of a newly developed amperometric, enzymatic, substrate-specific electrode for the rapid measurement of circulating lactate concentrations.
A ...prospective multiexperiment study.
The critical care medicine research laboratory, intensive care unit (ICU), emergency department (ED), and general wards of a university-affiliated hospital.
A total of 1218 patients and control subjects were studied on one or more occasions.
Blood lactate concentrations, descriptive data, physiological parameters, and outcome results were determined in various patient populations.
Experiment 1: Lactate determinations performed with the new substrate-specific electrode were compared with two laboratory reference methods. Blood samples from 80 ICU patients and 165 ED patients formed the basis of this first experiment. There was excellent agreement between the test instrument and the two reference methods as reflected by bias (with reference method 1, 0.19 mmol/L; reference method 2, 0.09 mmol/L), precision (with reference method 1, +/- 0.47 mmol/L; reference method 2, +/- 0.34 mmol/L), and correlation data (with reference method 1, r = .92; reference method 2, r = .98). Experiment 2: The new test microchemistry instrument was used to analyze blood samples from 927 patients. The mean (SE) blood lactate concentrations in the various patient populations were 1.26 (0.04) mmol/L for control subjects (n = 85), 1.52 (0.03) mmol/L for general ward patients (n = 489; P < .001 vs normal subjects), 2.34 (0.15) mmol/L for ICU patients (n = 180; P < .001 vs normal subjects and general ward patients), and 2.44 (0.15) mmol/L for ED patients (n = 173; P < .001 vs normal subjects and general ward patients). None of the normal subjects and only one (0.2%) of 489 nonhypotensive general ward patients had a blood lactate value greater than 4 mmol/L. Circulating lactate concentrations greater than 4 mmol/L were 98.2% specific in predicting the need for hospital admission in patients presenting to the ED. Furthermore, lactate concentrations greater than 4 mmol/L were 96% specific in predicting mortality in hospitalized nonhypotensive patients. Experiment 3: Blood samples from 46 hypotensive ICU and ED patients and from 353 nonhypotensive ICU and ED patients (the latter samples were derived from experiment 2) were analyzed. A statistically significant difference was noted between the mean (SE) lactate concentration in hypotensive patients in the ICU and ED (4.75 0.75 mmol/L) when compared with nonhypotensive ICU and ED patients (2.28 0.10 mmol/L; P < .001). Furthermore, blood lactate values greater than 4 mmol/L were 87.5% specific in predicting mortality in hypotensive patients.
Lactate determinations performed using the new test instrument are precise and accurate. Blood lactate concentrations greater than 4 mmol/L are unusual in normal and noncritically ill hospitalized patients and warrant concern. In hospitalized (non-ICU) nonhypotensive subjects, as well as in critically ill patients, a blood lactate concentration greater than 4 mmol/L may portend a poor prognosis.
