Effect of combined cortisol-endotoxin administration on peripheral blood leukocyte counts and phenotype in normal humans.

We studied the role of lipopolysaccharide and the associated hypercortisolemic response as mediators of leukocyte changes associated with endotoxemia. Normal human subjects were given continuous, 12-hour, intravenous infusions of cortisol. After 6 hours of cortisol infusion, lipopolysaccharide (20 U/kg) was administered in an intravenous bolus. Plasma cortisol and blood leukocyte counts and lymphocyte subset proportions were evaluated every hour throughout the 12-hour study period. After 6 hours of cortisol infusion, lymphocyte counts and proportions of CD4+ helper/inducer T cells had declined significantly. The fact that these cells did not decline further in response to lipopolysaccharide and continued cortisol infusion suggests that lipopolysaccharide-induced lymphocyte changes are cortisol dependent. In contrast, the granulocytosis normally observed after lipopolysaccharide administration was unaffected by cortisol infusion. Finally, the monocyte counts and proportions of B cells (HLA-DR+ or CD20+ cells) responded to cortisol infusion and LPS in a pattern distinct from that of lipopolysaccharide alone. These results indicate that lipopolysaccharide-induced hypercortisolemia plays a role in immune modulation during endotoxemia.     

Total parenteral nutrition and bowel rest modify the metabolic response to endotoxin in humans.

Intestinal mucosal atrophy, as induced by total parenteral nutrition (TPN) and/or prolonged bowel rest, is hypothesized to enhance bowel endotoxin (LPS) translocation and may alter host responses to infection. To examine the effect of TPN-induced bowel atrophy on the response to LPS, 12 healthy volunteers were randomized to receive either enteral feedings (ENT, n = 6) or seven days of TPN without oral intake (TPN, n = 6). Enteral or TPN feedings were terminated 12 hours before the study period when a constant dextrose infusion (50 mg/kg/hour) was initiated and continued throughout the subsequent study period. After placement of arterial, hepatic vein, and femoral vein catheters, metabolic parameters were determined before and for six hours after an intravenous E. coli LPS challenge (20 U/kg). Subsequent peak levels of arterial glucagon (ENT, 189 +/- 39 pg/mL; TPN, 428 +/- 48; p less than 0.01), arterial epinephrine (ENT, 236 +/- 52 pg/mL; TPN, 379 +/- 49; p less than 0.05) and hepatic venous cachectin/tumor necrosis factor (cachectin/TNF) (ENT, 250 +/- 56 pg/mL; TPN, 479 +/- 136; p less than 0.05) were significantly higher in the TPN group than in the ENT group. The extremity efflux of lactate (ENT, -16 +/- 4 micrograms/min-100cc tissue; TPN, -52 +/- 13; t = 2 hours; p less than 0.05) and of amino acids (ENT, -334 +/- 77 nmol/min-100cc tissue; TPN, -884 +/- 58; t = 4 hours; p less than 0.05) were higher in the TPN subjects after the endotoxin challenge. Circulating C-reactive Protein (CRP) levels measured 24 hours postendotoxin were also significantly higher in the TPN subjects (ENT, 1.7 +/- 0.2 mg/dL; TPN, 3.2 +/- 0.3; p less than 0.01). Hence the counter-regulatory hormone and splanchnic cytokine responses to LPS were enhanced after TPN and bowel rest. This is associated with a magnified acute-phase response, peripheral amino acid mobilization, and peripheral lactate production. Thus antecedent TPN may influence the metabolic alterations seen in infection and sepsis via both an exaggerated counter-regulatory hormone response as well as an enhanced systemic and splanchnic production of cytokines.     

Pulmonary hypertension and polymorphonuclear leukocyte elastase after esophageal cancer operations

To evaluate the role of polymorphonuclear leukocyte (PMN) elastase in pulmonary impairment occurring after operation for esophageal cancer, 10 patients were randomized preoperatively into two equal groups. One group received a placebo infusion and the other, an infusion of the PMN elastase inhibitor ulinastatin. In the placebo group, the mean plasma PMN elastase level increased from 154 +/- 23 micrograms/L preoperatively to 449 +/- 56 micrograms/L at 6 hours postoperatively (p less than 0.01), whereas the mean plasma fibronectin concentration decreased from 490 +/- 70 micrograms/mL preoperatively to 265 +/- 81 micrograms/L on postoperative day 2 (p less than 0.01). The mean pulmonary vascular resistance increased markedly from 151 +/- 24 dynes.s.cm-5.m-2 preoperatively to 284 +/- 76 dynes.s.cm-5.m-2 at 6 hours postoperatively (p less than 0.01). In the group given ulinastatin, 150,000 units every 12 hours from the start of the operation, the mean PMN elastase value at 6 hours postoperatively was lower (275 +/- 66 micrograms/L; p less than 0.01) and the fibronectin level on postoperative days 1 and 2, higher (p less than 0.05). A lower pulmonary vascular resistance was noted into day 2 (p less than 0.05). Our results suggest that PMN elastase may participate in the development of postoperative pulmonary impairment.     

Increased neutrophil mobilization and decreased chemotaxis during cortisol and epinephrine infusions

Although hormones are putative mediators of neutrophil changes after injury, the effects of trauma-induced levels of plasma cortisol and epinephrine on circulating neutrophils have not been reported in humans. The dynamics of PMN mobilization and chemotaxis were evaluated during 19 infusions of epinephrine or cortisol or a combined infusion of both hormones in ten normal volunteers. Basal levels of epinephrine and cortisol increased during infusions to levels consistent with those reported following severe injury. Circulating neutrophil counts increased in parallel with plasma cortisol levels. Epinephrine mobilized the entire marginated pool of neutrophils, and the neutrophil half-life was extended from a normal of 6.6 hours to 10.4 hours by cortisol. Chemotaxis after six hours of epinephrine infusion was reduced compared with baseline chemotaxis. In four volunteers who had a second infusion of cortisol, chemotaxis was significantly depressed ten days after the infusion compared with baseline. From these data we conclude that stress levels of epinephrine mobilize the marginated pool of granulocytes into the circulating pool in a linear fashion, and cortisol raises the half-life of circulating neutrophils. Reduced neutrophil chemotaxis seen as a consequence of these infusions could account for some of the increased susceptibility to infection that occurs after major trauma.     

Endocrine reaction pattern in abdominal surgical patients as affected by isoflurane anesthesia

The effects of isoflurane anaesthesia on the per- and postoperative change in blood concentrations of aldosterone, cortisol, dehydroepiandrosterone, insulin, prolactin, thyroxine, t3-uptake, epinephrine, norepinephrine, dopamine, glucose, FFS, lactate, and pyruvate were investigated in connection with major abdominal surgery. Contrary to prolactin levels (8.42 +/- 1.71 ng/ml----46.25 +/- 6.78 ng/ml; p less than 0.001) the plasma concentrations of the adrenal steroids aldosterone, cortisol, and dehydroepiandrosterone sank initially after induction of anaesthesia with thiopentone. However, after skin incision the levels of aldosterone (49.9 +/- 11.6 pg/ml----202.1 +/- 57.6 pg/ml; p less than 0.01), cortisol (16.7 +/- 2.57 ng/dl----25.2 +/- 3.72 ng/dl; p less than 0.01) and DHEA (2.70 +/- 0.99 ng/ml----5.02 +/- 1.03 ng/ml; p less than 0.05) rose significantly. Generally, plasma insulin was not markedly influenced by isoflurane anaesthesia and surgery. No significant alterations in plasma catecholamine concentrations were observed.     

Important role of adrenergic mechanisms in acute glucose counterregulation following insulin-induced hypoglycemia in type I diabetes. Evidence for an effect mediated by beta-adrenoreceptors

During hypoglycemia induced by an i.v. insulin infusion for 60 min, rates of plasma glucose (PG) decrease and recovery, PG nadir, and plasma counter-regulatory hormone and free fatty acid responses were studied in eight type I uncomplicated diabetic subjects and eight nondiabetic subjects. Each subject was tested three times at two different rates of insulin infusion (25 and 32 mU/m2/min): (1) during infusion of saline, (2) during infusion of phentolamine + propranolol (combined alpha, beta-blockade), and (3) during infusion of propranolol alone (isolated beta-blockade) for 150 min. At the time of the studies, the diabetic subjects had been made euglycemic by an overnight i.v. insulin infusion. During infusion of insulin (25 mU/m2/min) and saline, the rates of PG decrease and recovery were slower (P less than 0.01) and PG nadir was delayed in the diabetic subjects. Moreover, their plasma glucagon response was blunted while plasma epinephrine, norepinephrine, growth hormone, and cortisol responses were similar in both groups. Infusion of insulin at 32 mU/m2/min caused larger decreases in PG than had been observed when insulin was infused at 25 mU/m2/min. Plasma glucagon responses increased in the nondiabetic subjects (P less than 0.05) but not in the diabetic subjects. However, in the diabetic subjects, plasma epinephrine increased more than in the nondiabetic subjects (P less than 0.05). There was an inverse correlation between the individual plasma epinephrine responses and the plasma glucagon responses in the diabetic subjects (r = -0.72) but not in the nondiabetic subjects. Alpha, beta-adrenergic blockade decreased the plasma glucose nadir and impaired the rate at which normoglycemia was restored in the diabetic subjects (P less than 0.005 vs. saline) but not in the nondiabetic subjects. Plasma catecholamine and growth hormone responses were increased and plasma FFA recovery was suppressed in both groups (P less than 0.05 vs. saline), while the cortisol responses were unaltered. During isolated beta-adrenergic blockade, changes in plasma glucose, counterregulatory hormones and FFA were essentially identical to those observed during combined alpha, beta-adrenergic blockade in both groups except that the augmented plasma norepinephrine responses were no longer apparent. Conclusions: although epinephrine is not essential for prompt restoration of normoglycemia in normal man following insulin-induced hypoglycemia, it plays a major role in glucose counterregulation in diabetics who have an impaired glucagon secretion in response to hypoglycemia. These counterregulatory effects of epinephrine are mediated by beta-adrenoreceptors.     

Effect of cardiopulmonary bypass on circulating lymphocyte function.

Extracorporeal cardiopulmonary bypass (CPB) has been associated with a wide variety of immunological derangements, including a transient postoperative impairment of lymphocyte function. We examined changes in phenotypic and nonspecific cytotoxicity of peripheral blood mononuclear cells after extracorporeal CPB. The peripheral blood samples obtained from 10 patients were subjected to natural killer and cytotoxic T lymphocyte activity assay before and at intervals after CPB. Phenotypic analysis of peripheral blood lymphocytes was performed in 5 patients before and immediately after CPB. We observed a significant increase in peripheral blood CD8+ cells (cytotoxic/suppressor T lymphocytes) (16.1% +/- 2.5% versus 22.5% +/- 2.1%; p less than .005) and a decrease in CD4+ cells (helper/inducer T lymphocytes) (46.1% +/- 3.5% versus 36.1% +/- 3.5%; p less than 0.02) immediately after extracorporeal circulation. The CD8/CD4 ratio in peripheral blood was significantly increased immediately after bypass (0.53 versus 0.80; p less than 0.001). No significant changes in percentages of other leukocyte subsets in peripheral blood were noted. The activity of cytotoxic T lymphocytes and natural killer cells in peripheral blood was impaired on postoperative days 1 and 3 but was restored to preoperative values by removal of mononuclear phagocytes from these cells. The decrease in natural killer cell and cytotoxic T lymphocyte activity in peripheral blood may signify a temporary impairment of the effector arm of the cell-mediated immunity in the post-operative period. The observed changes in peripheral blood phenotype and function may be involved in early organ injury and infectious complications after CPB.     

Tumor necrosis factor and endotoxin induce similar metabolic responses in human beings

After injury, infection, or major operations a number of predictable metabolic responses occur. It has been proposed that the cytokine tumor necrosis factor (TNF)/cachectin is a primary mediator of these host responses. To test this hypothesis, we studied 16 tumor-bearing humans with normal renal and hepatic function, who received 24-hour continuous intravenous infusions of escalating doses of recombinant TNF (4 to 636/micrograms/m2/24 h). Serial measurements were made of vital signs and plasma concentrations of TNF, interleukin-1, adrenocorticotropic hormone, cortisol, iron, glucose, and C-reactive protein. Low doses of TNF had minimal metabolic effects, but infusions of greater than or equal to 545 micrograms/m2/24 hr (n = 8) resulted in fever, pituitary, and stress hormone release and acute phase changes. These alterations were compared with the changes that occurred in healthy humans (n = 13) receiving intravenous bolus injections of Escherichia coli endotoxin (4 ng/kg). TNF infusion in doses greater than or equal to 545 micrograms/m2/24 hr produced peak plasma TNF concentrations and metabolic responses that were similar to those after endotoxin injection. Interleukin-1 concentrations remained basal after TNF or endotoxin administration. TNF may represent the primary afferent signal that initiates many of the metabolic responses associated with sepsis and endotoxemia.     

The rapid induction by interleukin-2 of pulmonary microvascular permeability.

The clinical use of interleukin-2 (IL-2) is limited by severe cardiopulmonary dysfunction. This study examines the mechanism of respiratory failure related to IL-2, using sheep with chronic lung lymph fistulae. Awake animals were infused with an intravenous (I.V.) bolus of IL-2 10(5) U/kg (n = 5) or its excipient (EXC) control (n = 3), every 8 hours for 4 to 5 days. Cardiopulmonary function was monitored daily for at least one 8-hour period. Within 2 hours after each IL-2 administration, mean pulmonary arterial pressure (MPAP) rose. On Day 1, the mean rise was from 13 to 26 mmHg (p less than 0.05), and on Day 5, to 29 mmHg (p less than 0.05). MPAP returned to baseline levels after 2-3 hours. Pulmonary arterial wedge pressure was unchanged from 4 mmHg. There were transient falls in arterial oxygen tension, from 88 to 77 mmHg on Day 1 and to 73 mmHg (p less than 0.05) on Day 5. Lung lymph flow (QL) rose from 2.4 to 6.8 ml/30 minutes (p less than 0.05) on Day 1, and from 4.7 to 10.2 ml/30 minutes (p less than 0.05) on Day 5, whereas the lymph/plasma protein ratio increased on Day 1 from 0.69 to 0.83 (p less than 0.05) and from 0.63 to 0.71 (p less than 0.05) on Day 5. This documents an increase in pulmonary microvascular permeability. Thromboxane (Tx)B2 levels increased transiently after each IL-2 injection in plasma from 195 to 340 pg/ml (p less than 0.05) and in lung lymph from 222 to 772 pg/ml (p less than 0.05) on Day 1, and to similar levels on Day 5. There was a progressive rise in cardiac output from 5.7 to 8.6 1/minute (p less than 0.05) during the 5 days of infusion. Systemic blood pressure did not change. Temperature rose from 39.1 to 41.2 C (p less than 0.05), and shaking chills were common. There was a progressive fall in leukocyte count, from 8.4 to 3.2 X 10(3)/mm3 (p less than 0.05) by Day 5, reflecting a 77% fall in lymphocytes. Lung lymph lymphocyte counts rose, and lymphocyte clearance increased.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mechanism of prevention of postburn hypermetabolism and catabolism by early enteral feeding.

This study was performed to investigate the mechanism whereby immediate enteral feeding after burn injury reduces postburn hypermetabolism and hypercatabolism. Fifty-seven burned guinea pigs (30% TBSA) were divided into three groups: A (N = 19), given 175 kcal/kg/day beginning 2 hours after burn; B (N = 20), given 175 kcal/kg/day with an initial 72-hour adaptation period; and C (N = 18), given 200 kcal/kg/day with the same adaptation period as B. Resting metabolic expenditure (RME) on PBD 13 was lowest in group A (109% of preburn level), compared with group B (144%, p less than 0.001) and group C (137%, p less than 0.01). On PBD 1, group A had the greatest jejunal mucosal weight and thickness (p less than 0.001), and mucosal weight had negative correlations with plasma cortisol (r = 0.829, p less than 0.001) and glucagon (r = 0.888, p less than 0.001). Two weeks after burn, urinary vanillyl mandelic acid (VMA) excretion, plasma cortisol, and glucagon were lowest in group A (p less than 0.05 to p less than 0.01). These hormones also significantly correlated with RME (p less than 0.01 to p less than 0.001). These findings suggest that immediate postburn enteral feeding can prevent hypermetabolism via preservation of gut mucosal integrity and prevention of excessive secretion of catabolic hormones.     

Effect of stress hormones on splanchnic substrate and insulin disposal after glucose ingestion in healthy humans

To compare cortisol and epinephrine action on oral glucose tolerance, healthy humans were infused with either cortisol (0.1 mg X kg-1 X h-1), epinephrine (5.4 micrograms X kg-1 X h-1), or saline before and after a 75-g glucose load, thereby elevating the respective plasma hormone concentrations into the pathophysiologic range. In the basal state, epinephrine increased arterial concentrations of glucose, beta-hydroxybutyrate, and free fatty acids (FFA) as well as splanchnic output of glucose and beta-hydroxybutyrate and splanchnic FFA more than cortisol. Postprandially, C-peptide release and hyperinsulinemia were blunted by epinephrine initially and increased less thereafter than during cortisol infusion. The rise in arterial glucose after glucose ingestion as calculated by the area under the curve was more marked (P less than .01) after epinephrine [( 1.90 +/- 0.08 M) 150 min] and cortisol [( 1.41 +/- 0.05 M) 150 min] than in the control study [( 1.07 +/- 0.04 M) 150 min]. In parallel, the stress hormones induced an almost identical 24 and 31% rise in mean splanchnic glucose output versus control values (normal, 44.8 +/- 2.5; cortisol, 55.3 +/- 3.3; epinephrine, 58.9 +/- 6.9 g/150 min). The associated rise in arterial concentrations and splanchnic output of insulin above control values was considerably greater during cortisol but unchanged during epinephrine exposure. Epinephrine but not cortisol induced a rise versus the control study in splanchnic uptake of lactate and FFA, as well as in pyruvate output, whereas plasma beta-hydroxybutyrate and acetoacetate remained unchanged. The postprandial splanchnic glucose output-to-splanchnic C-peptide output ratio did not differ from normal during epinephrine but was reduced (P less than .01) during cortisol administration.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antihypertensive mechanism of ketanserin in postoperative hypertension after cardiopulmonary bypass

The effect of ketanserin (0.15 mg/kg followed by an infusion at 6 mg/hr) was studied in 13 patients who developed hypertension (blood pressure greater than 150/90 mm Hg) after cardiopulmonary bypass (CPB) for coronary artery bypass grafting. Eleven patients responded to ketanserin with a decrease of arterial pressure from 159 +/- 15/83 +/- 10 mm Hg to 131 +/- 9/70 +/- 12 mm Hg (P less than 0.01), which was sustained during the subsequent infusion of ketanserin. Mean plasma ketanserin concentrations were maintained at 187 micrograms/L (range 118-525). No significant changes in plasma levels of 5-hydroxyindoles or in platelet 5-hydroxytryptamine content were observed during or after CPB, or after administration of ketanserin. Plasma epinephrine (398 +/- 124 pg/ml) and norepinephrine (1161 +/- 673 pg/ml) concentrations were markedly increased during the hypertensive period after CPB. Plasma epinephrine concentrations decreased (P less than 0.01) during ketanserin infusion to 213 +/- 101 pg/ml, whereas plasma norepinephrine concentrations did not change. The pressor response to three graded doses of phenylephrine was decreased during CPB (P less than 0.01), and a further decrease (P less than 0.05) occurred during infusion of ketanserin. The hypotensive effect of ketanserin after CPB may be attributable to alpha 1-adrenoceptor blockade rather than to its antiserotoninergic effect. Serotonin does not appear to be involved in the short-term disturbances of arterial pressure during or after CPB.     

Effect of prostaglandin E in multiple experimental models. IV. Effect on resistance to endotoxin and tumor necrosis factor shock

Administration of a long-acting prostaglandin E, 16,16-dimethyl-PGE (dPGE), to rats improves their survival of bacterial peritonitis. We examined the mechanism of this protective effect with reference to its interaction with the release of cachectin (TNF). Sixty rats received saline, 20 micrograms/kg dPGE, or 80 micrograms/kg dPGE 12 hr prior to endotoxin and continuing for 48 hr. Survival rates for the saline, 20 micrograms/kg dPGE, and 80 micrograms/kg dPGE groups were 0, 40, and 85%, respectively. Forty rats received saline or 80 micrograms/kg dPGE, with the initial dose being 3 hr following endotoxin challenge and continuing for 48 hr. Survival rates for both groups were 0%. Sixty rats received saline or 80 micrograms/kg dPGE at 12 and 1 hr prior to endotoxin. Two hours after challenge, they were sacrificed and plasma TNF levels were assayed. The plasma TNF level in saline-treated rats was 22.72 +/- 0.83 ng/ml and in the dPGE-treated group, 16.03 +/- 1.13 ng/ml (P less than 0.001).     

The complex pattern of cytokines in sepsis. Association between prostaglandins, cachectin, and interleukins.

Although the cytokines tumor necrosis factor (TNF), interleukin-1 (IL-1), and interleukin-6 (IL-6) are important mediators of hemodynamic, metabolic, and immunologic alterations in the host during sepsis, it is not known whether there is any association between the release of these cytokines and prostanoids during sepsis. Sepsis induced by cecal ligation and puncture in rats led to a persistent elevation (p less than 0.05) of plasma TNF until 10 hours, steadily increasing (p less than 0.05) IL-1 plasma levels, and enhanced (p less than 0.05) IL-6 plasma levels at all time points compared to the sham group. Prostaglandin E2 plasma levels were elevated (p less than 0.05) at 5 hours (153 +/- 29 pg/mL; control: 47 +/- 11 pg/mL) and 10 hours (96 +/- 16 pg/mL; control: 21 +/- 5 pg/mL). Prostaglandin E2 production by splenic macrophages (sM phi) from septic animals was increased (p less than 0.05) at 5 hours (9.1 +/- 2.2 ng/mL) and 10 hours (5.6 +/- 1.5 ng/mL) compared to controls (3.3 +/- 0.3 ng/mL at 5 hours; 1.3 +/- 1.3 ng/mL at 10 hours). Incubation of sM phi from septic animals with ibuprofen enhanced (p less than 0.05) IL-1 and TNF synthesis, while IL-6 production was reduced (p less than 0.05). These results indicate that the alterations in prostanoid release and elevated plasma prostanoids may regulate the release and consequently the circulating levels of cytokines during sepsis.     

The metabolic and ventilatory response to the infusion of stress hormones.

Sepsis and trauma result in increases in epinephrine, glucagon, and cortisol secretion as well as alterations in respiratory pattern that is characterized by increased minute ventilation, decreased tidal volume, and increased frequency. Six male subjects were infused for 5.5 hours with cortisol, epinephrine, and glucagon in amounts designed to simulate plasma levels seen in patients following trauma. During the initial 20 minutes of the hormone infusion, minute ventilation (VE), oxygen consumption (VO2), and carbon dioxide production (VCO2) increased above preinfusion values. VCO2 increased more than VO2 resulting in an increase in respiratory quotient (RQ) from 0.93 to 1.14. The increase in VE was due to increased tidal volume and not frequency (f). After 4.5 hours, the VE, VO2, and VCO2 were still above preinfusion levels but the RQ had decreased to 0.98 because of a decrease in VCO2. Frequency had increased from 19 +/- 4.8 breaths/min preinfusion to 22 +/- 4.7 after 4.5 hours. After 4.5 hours, VT was still above preinfusion levels while pH and PaCO2 had decreased below them. The latter was associated with an increase in serum lactate. At no time was a decrease in tidal volume observed. Therefore, the infusion of these hormones does not simulate all the alterations observed during trauma and sepsis.     

Effect of epinephrine and somatostatin-induced insulin deficiency on ketone body kinetics and lipolysis in man

The effect of elevated plasma epinephrine concentrations (approximately equal to 800 pg/ml) on ketone body kinetics was determined in postabsorptive normal subjects using primed-continuous infusions of 3-14C-acetoacetate. Infusion of epinephrine (60 ng/kg/min) resulted in a transient increase in total ketone body production to a maximum of 2.5-fold the basal rate within 45 min (P less than 0.01 versus controls). Ketone body uptake increased with a delay, compared with production, causing a 2.8-fold increase in total ketone body concentrations (P less than 0.05 versus controls). Plasma free fatty acid (FFA) and blood glycerol concentrations increased transiently during epinephrine; their course was similar to that of ketone body production. Epinephrine administration resulted in hyperglycemia, hyperlactatemia, and a modest increase in plasma insulin and glucagon concentrations. To assess epinephrine's effect on ketone body kinetics during lack of insulin, and to avoid epinephrine-induced alterations in plasma insulin and glucagon concentrations, epinephrine was also infused combined with somatostatin (6.5 micrograms/kg/h). During somatostatin infusion, epinephrine administration resulted in an enhanced and sustained elevation of total ketone body production from 4.4 +/- 0.8 to 15.1 +/- 1.2 mumol/kg/min (P less than 0.01 versus somatostatin alone). Ketone body concentrations increased markedly from 310 +/- 63 to 1763 +/- 137 mumol/L (P less than 0.01 versus somatostatin alone); the ketonemic effect was enhanced due to a 40% decrease of the metabolic clearance rate associated with somatostatin infusion. The increase in plasma FFA and blood glycerol concentrations during somatostatin-induced insulin deficiency was transiently enhanced by epinephrine, such that they increased to 3.2- and 5.6-fold their basal values after 45 min, respectively (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

T4 and T8 lymphocytic populations after total hip replacement

Immunosuppression is involved in the occurrence of sepsis after surgical trauma. A postoperative lymphocytopenia is a recognised fact. In the opposite, studies on T-lymphocytes helpers (CD 4) and suppressors (CD 8) resulted in conflicting results. The aim of this study was to assess the variations in these two T-lymphocyte sub-populations using strongly standardized conditions in order to minimize the risk of non specific variations: same surgeon, same surgical technique, blood samples collected just before induction, immediately and 24 hours after surgery, automatized measures (Technicon H1). The results confirmed the lymphocytopenia, 24 hours after surgery, but no differences on CD 4 and CD 8 percentages were noted. It is concluded that during the first 24 postoperative hours surgery does not change the relative proportions of T-helpers and T-suppressors. Their measurement is not more useful than total lymphocyte count for assessment of postoperative immunosuppression.     

Stellate ganglion block modifies the distribution of lymphocyte subsets and natural-killer cell activity

BACKGROUND: Recent investigations suggest that the sympathetic nervous system affects the immune system. This study examined whether stellate ganglion block (SGB) affects the immune response, specifically the distribution of lymphocyte subsets and natural-killer (NK) cell activity. METHODS: Ten volunteers received three different treatments in random order at 7-day intervals: (1) SGB with 7 ml of 1% lidocaine; (2) an identical volume of normal saline injected at the same site as SGB; and (3) an identical volume of 1% lidocaine injected intramuscularly. Blood samples were drawn before and 30 min after treatment. The distribution of lymphocyte subsets was analyzed, and NK cell activity was measured. Plasma concentrations of epinephrine, norepinephrine, adrenocorticotropic hormone, and cortisol were measured. RESULTS: Any value in the normal saline and intramuscular treatments did not change significantly. After SGB, the plasma concentrations of epinephrine and norepinephrine decreased significantly (P < 0.01), but adrenocorticotropic hormone and cortisol values were unchanged. Increases were observed in the proportion of B cells (from 18.4 +/- 3.0% to 20.0 +/- 3.8%; P < 0.01) and T cells (from 64.2 +/- 4.1% to 67.1 +/- 4.2%; P < 0.01). A decrease in the proportion of NK cells was observed (from 13.4 +/- 2.7% to 9.8 +/- 2.2%; P < 0.01). The proportion of CD4+ cells increased (P < 0.01), and that of CD8+ cells decreased (P < 0.01), so that the CD4+ cell/CD8+ cell ratio increased (P < 0.01). The proportion of CD29+ (helper-inducer T) cells increased (P < 0.05), but that of CD45RA+ (suppressor-inducer T) cells did not change. NK cell activity decreased significantly (from 33.6 +/- 8.3% to 29.1 +/- 7.6%; P < 0.01). CONCLUSIONS: A small but significant alteration in lymphocyte subsets and in NK cell activity by SGB indicates that local sympathetic nerve block may modulate the immune response.     

The effects of continuous epidural anesthesia and analgesia on stress response and immune function in patients undergoing radical esophagectomy

We investigated whether perioperative extensive epidural block (C3-L) affects postoperative immune response in patients undergoing radical esophagectomy. Patients undergoing radical esophagectomy were randomly assigned to either general anesthesia with continuous epidural infusion via 2 epidural catheters that was continued for postoperative analgesia (group E, n = 15) or intraoperative general anesthesia and postoperative IV morphine analgesia (group G, n = 15). Plasma levels of stress hormones, cytokines, C-reactive protein (CRP), leukocyte counts, and distribution of lymphocyte subsets were assessed before and after surgery and on postoperative days (PODs) 1 and 3. In comparison with group E, significant increases in plasma epinephrine level at the end of surgery (P < 0.05) and norepinephrine level at the end of surgery (P < 0.01) and on POD1 (P < 0.01) and POD3 (P < 0.01) and significant decrease in cluster of differentiation (CD4/CD8 ratio) at the end of surgery (P < 0.05) were observed in group G. However, there were no significant differences in other variables between groups. In both groups, plasma cortisol, adrenocorticotropic hormone, interleukin (IL)-1beta, IL-6, IL-10, and CRP levels were increased after surgery (each group P < 0.01) and IL-1beta, IL-6, IL-10, and CRP were still increased on POD1 and POD3 (each change, each group P < 0.01). Leukocyte counts were increased on POD1 (each group P < 0.05) and POD3 (each group P < 0.01). The proportion of lymphocytes decreased from the end of surgery to POD3 (each group P < 0.01). The proportion of B cells was increased on POD1 (each group P < 0.01); that of natural killer cells was decreased at POD1 and POD3 (each group P < 0.01). We conclude that tissue damage and inflammation apparently overcome the effects of extensive epidural block on stress response and immune function in radical esophagectomy.     

Counterregulatory hormone responses preserved after long-term intravenous insulin infusion compared to continuous subcutaneous insulin infusion

The counterregulatory hormone responses of cortisol, growth hormone, glucagon, epinephrine, norepinephrine, and dopamine to a fixed hypoglycemic stimulus (50 mg/dl for 1 h) were studied in five type I (insulin-dependent) diabetic subjects during conventional insulin therapy (CT), after 3 mo of continuous subcutaneous insulin infusion (SC), and after 3 mo of continuous intravenous insulin infusion (IV). During the two infusion periods, the overall mean levels of preprandial blood glucose (116 +/- 6 SC vs. 114 +/- 5 mg/dl IV) and glycosylated hemoglobin (6.1 +/- 2 SC vs. 5.9 +/- 2% IV) were virtually identical, but there were more hypoglycemic episodes and greater variability of preprandial blood glucose levels during SC than with IV. During the last 30 min of the hypoglycemic clamps, the mean levels of epinephrine and cortisol were significantly lower after 3 mo of SC (epinephrine, 268 +/- 80 pg/ml; cortisol, 14 +/- 1 microgram/dl) than with both CT (epinephrine 485 +/- 80 pg/ml; cortisol, 20 +/- 2 micrograms/dl) and IV (epinephrine, 443 +/- 62 pg/ml; cortisol, 19 +/- 2 micrograms/dl)(P less than .05). The mean growth hormone level was significantly (P less than .05) lower after SC (37 +/- 9 ng/ml) than after IV (79 +/- 12 ng/ml), but it did not reach statistical significance compared with CT (66 +/- 12 ng/ml). The mean glucagon, dopamine, and norepinephrine levels during the same period of hypoglycemia were not different when all treatment regimens were compared. We conclude that intensified insulin therapy with SC leads to significant blunting of the counterregulatory hormone response to hypoglycemia, whereas IV does not.(ABSTRACT TRUNCATED AT 250 WORDS)