BACKGROUNDPatients with acute hypoxemic respiratory failure in the intensive care unit (ICU) are treated with supplemental oxygen, but the benefits and harms of different oxygenation targets are unclear. We hypothesized that using a lower target for partial pressure of arterial oxygen (Pao 2 ) would result in lower mortality than using a higher target. METHODSIn this multicenter trial, we randomly assigned 2928 adult patients who had recently been admitted to the ICU (≤12 hours before randomization) and who were receiving at least 10 liters of oxygen per minute in an open system or had a fraction of inspired oxygen of at least 0.50 in a closed system to receive oxygen therapy targeting a Pao 2 of either 60 mm Hg (lower-oxygenation group) or 90 mm Hg (higheroxygenation group) for a maximum of 90 days. The primary outcome was death within 90 days. RESULTSAt 90 days, 618 of 1441 patients (42.9%) in the lower-oxygenation group and 613 of 1447 patients (42.4%) in the higher-oxygenation group had died (adjusted risk ratio, 1.02; 95% confidence interval, 0.94 to 1.11; P = 0.64). At 90 days, there was no significant between-group difference in the percentage of days that patients were alive without life support or in the percentage of days they were alive after hospital discharge. The percentages of patients who had new episodes of shock, myocardial ischemia, ischemic stroke, or intestinal ischemia were similar in the two groups (P = 0.24). CONCLUSIONSAmong adult patients with acute hypoxemic respiratory failure in the ICU, a lower oxygenation target did not result in lower mortality than a higher target at 90 days.

Acute severe pain decreases insulin sensitivity, primarily by affecting nonoxidative glucose metabolism. It is conceivable that the counterregulatory hormonal response plays an important role. This may indicate that pain relief in stress states is important for maintenance of normal glucose metabolism.

We have investigated the effect of pain without tissue injury on natural killer (NK) cell activity in peripheral blood in humans and the effect of local anaesthesia on the response. Ten subjects were investigated during two sessions. First, self-controlled painful electric stimulation was applied to abdominal skin for 30 min to an intensity of 8 on a visual analogue scale (0-10). Next, the electric intensity profile was reproduced during local anaesthesia (mepivacaine 10 mg ml-1 s.c. to a total dose of 2.5 mg kg-1). NK cell cytotoxicity was measured using a 4-h 51Cr-release assay against K562 target cells. NK cell activity increased from mean 22 (SEM 4)% (baseline) to 35 (6)% and 36 (5)% after 15 and 30 min of painful stimulation, respectively (P < 0.02). A simultaneous increase in the number of CD56+ cells in peripheral blood during pain was found. Stimulation after local anaesthesia did not change either NK cell activity or number. Parallel and significant increases in concentrations of plasma epinephrine and serum cortisol were observed. These changes were abolished by local anaesthesia. We conclude that acute severe pain without tissue injury markedly increased NK cell cytotoxicity. Local anaesthesia completely abolished this immunological and hormonal response.

fect on the capacity of urea synthesis is caused by a Improvement of nitrogen balance is desirable in padecreased translation rate of the urea cycle enzymes tients with acute or chronic illlness. Both growth horcaused by GH and IGF-I's down-regulatory effect on urea mone (GH) and insulin-like growth factor-I (IGF-I) are cycle enzyme gene transcription. The findings may indipromising anabolic agents, and their combined adminiscate a novel mechanism of the protein anabolic action tration has been shown to reverse catabolism more effiof GH and IGF-I. (HEPATOLOGY 1997;25:964-969.) ciently than each of the peptides alone. This is believed to be mediated primarily through increased peripheral protein synthesis, whereas little attention has focused Improvement of nitrogen balance is desirable in patients on a possible participation of amino acid metabolism in with acute or chronic illness, and growth hormone (GH) is a the liver. Four groups of rats were given: 1) placebo; 2) promising anabolic agent.1-4 However, it cannot reverse nitro-GH (200 mg/d); 3) IGF-I (300 mg/d); and 4) both GH and gen wasting in all catabolic situations, and it may cause hy-IGF-I. After 3 days, the maximum capacity of urea-nitro-perglycemia and insulin resistance, which limits its clinical gen synthesis was determined by saturating infusion of use.5-7 Insulin-like growth factor I (IGF-I) mediates some of alanine (n Å 8 in each group), together with measure-the growth-promoting effects of GH and has been reported ments of liver messenger RNA (mRNA) levels for urea to cause an anabolic response comparable with that of GH, cycle enzymes (n Å 5 in each group) and N-contents of but it may induce hypoglycemia.8 When using GH and IGFmuscles, heart, and kidney. Basal plasma a-amino acid I simultaneously, Kupfer et al. observed an enhanced effect concentrations were similar in all groups. The capacity on overall nitrogen excretion compared with either peptide of urea-N synthesis [mmol/(min 1 100 g body weight)] alone. 9 was reduced in a stepwise manner (placebo: 8.25 { 1.2;As for the anabolic mode of action of the peptides, little GH treatment: 6.52 { 0.8; IGF-I treatment: 5.5 { 0.6; and attention has focused on the possible role of amino acid me-GH/IGF-I: 4.22 { 1.6 [P õ .001 by ANOVA]), each step tabolism in the liver, although administration of GH and, in being lower than the former. Serum IGF-I increased particular, IGF-I reduces blood urea nitrogen. [10][11][12] There are stepwise from placebo (699 { 40 to 1,579 { 96 mg/L in the conflicting data regarding the influence of GH on hepatic combined GH/IGF-I group), and was correlated nega-nitrogen metabolism. Pacatti et al. found that GH decreases tively with the capacity of urea-nitrogen synthesis (P õ hepatic uptake of amino acids in humans and rats, 11 whereas .01). mRNA levels for urea cycle enzymes in the liver Palekar et al. found that GH decreases the activities of urea decreased after GH and IGF-I treatment, and the effect cycle enzymes in rat liver. 12 In humans, we found unchanged was more ...

Growth hormone (GH) reduces the catabolic side effects of steroid treatment due to its effects on tissue protein synthesis/degradation. Little attention is focused on hepatic amino acid degradation and urea synthesis. Five groups of rats were given 1) placebo, 2) prednisolone, 3) placebo, pair fed to the steroid group, 4) GH, and 5) prednisolone and GH. After 7 days, the in vivo capacity of urea N synthesis (CUNS) was determined by saturating alanine infusion, in parallel with measurements of liver mRNA levels of urea cycle enzymes, N contents of organs, N balance, and hormones. Prednisolone increased CUNS (μmol ⋅ min−1 ⋅ 100 g−1, mean ± SE) from 9.1 ± 1.0 (pair-fed controls) to 13.2 ± 0.8 ( P < 0.05), decreased basal blood α-amino N concentration from 4.2 ± 0.5 to 3.1 ± 0.3 mmol/l ( P < 0.05), increased mRNA levels of the rate- and flux-limiting urea cycle enzymes by 20 and 65%, respectively ( P < 0.05), and decreased muscle N contents and N balance. In contrast, GH decreased CUNS from 6.1 ± 0.9 (free-fed controls) to 4.2 ± 0.5 ( P < 0.05), decreased basal blood α-amino N concentration from 3.8 ± 0.3 to 3.2 ± 0.2, decreased mRNA levels of the rate- and flux-limiting urea cycle enzymes to 60 and 40%, respectively ( P < 0.05), and increased organ N contents and N balance. Coadministration of GH abolished all steroid effects. We found that prednisolone increases the ability of amino N conversion into urea N and urea cycle gene expression. GH had the opposite effects and counteracted the N-wasting side effects of prednisolone.

The moderate acute phase response up-regulated in vivo urea synthesis but had the opposite effect on gene level. The severe acute phase response decreased the functional liver mass that attenuated the increase in urea synthesis.

. Human insulin release processes measured by intraportal sampling. Am J Physiol Endocrinol Metab 282: E695-E702, 2002; 10.1152/ajpendo.00516.2000.-Insulin is secreted as a series of punctuated secretory bursts superimposed on variable basal insulin release. The contribution of these secretory bursts to overall insulin secretion has been estimated on the basis of peripheral vein sampling in humans to encompass Ն75% of overall insulin release. A similar contribution of the pulsatile mode of release was inferred in a canine model by use of portal vein sampling. The primary regulation of insulin secretion is through perturbation of the mass and frequency of these secretory bursts. The mode of delivery of insulin into the circulation seems important for insulin action; therefore, physiological conditions that alter the pattern of insulin release may affect insulin action through this mechanism. Transhepatic intraportal shunt in humans may provide access to portal vein samples, thus potentially improving the sensitivity of detecting and quantitating the frequency, mass, and amplitude of secretory bursts along with basal release and the regularity of these variables. To establish the insulin-secretory mechanism in nondiabetic humans by the use of portal vein sampling, we here assessed the mass, frequency, amplitude, and overall contribution of pulsatile insulin secretion by deconvolution analysis of portal vein insulin profiles. We find that, in nondiabetic humans fasted overnight, the portal vein insulin concentration oscillates at a periodicity of 4.1 Ϯ 0.2 min/pulse and with secretory peak amplitudes averaging 660% of basal (interpulse) release. The frequency was confirmed by spectral and autocorrelation analyses. The punctuated insulin-secretory bursts partially overlap and are responsible for the majority (70 Ϯ 4%) of insulin release. After ingestion of a mixed meal, the insulin release was increased through amplification of the secretory burst mass (507 Ϯ 104 vs. 1,343 Ϯ 211 pmol ⅐ l Ϫ1 ⅐ min Ϫ1 , P Ͻ 0.001), whereas frequency (4.4 Ϯ 0.2 vs. 4.3 Ϯ 0.2, P ϭ 0.86) and basal secretion (62 Ϯ 14 vs. 91 Ϯ 22 pmol ⅐ l Ϫ1 ⅐ min Ϫ1 , P ϭ 0.33) were unaffected. One subject with diabetes and cirrhosis had a similar insulin-secretory pattern, whereas a subject with insulin-dependent diabetes mellitus and minimal insulin release had preserved pulsatile release. A single subject was entrained to show agreement between entrained frequency and portal vein insulin oscillations. We conclude that insulin release in the human portal vein occurs at a mean periodicity of 4.4 Ϯ 0.2 min with a high signal-to-noise ratio (pulse amplitude 660% of basal). The impact of noise on the detected high frequency cannot be excluded.C-peptide; oscillations; cirrhosis; secretion; diabetes INSULIN IS SECRETED in a pulsatile manner (4), resulting in high-frequency insulin concentration oscillations in the peripheral circulation. These high-frequency oscillations are apparently caused by interislet coordinate insulin-secretory bursts at a periodicity...

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