Effects of 0.5 and 1.0 MAC isoflurane, sevoflurane and desflurane on intracranial and cerebral perfusion pressures in children.

BACKGROUND: Isoflurane has been a commonly used agent for neuroanesthesia, but newer agents, sevoflurane and desflurane, have a quicker onset and shorter emergence from anesthesia and are increasingly preferred for general pediatric anesthesia. But their effects on intracranial pressure (ICP) and cerebral perfusion pressure (CPP), especially in pediatric patients with already increased ICP, have not been well documented. METHODS: We studied 36 children scheduled for elective implantation of an intraparenchymal pressure device for 24 h monitoring for suspected elevated ICP. After a standardized intravenous anesthesia, the patients were moderately hyperventilated with 60% nitrous oxide (N2O) in oxygen. The patients were then randomized to receive 0.5 and 1.0 MAC of isoflurane (Group I, n = 12), sevoflurane (Group S, n = 12) or desflurane (Group D, n = 12) in 60% N2O in oxygen. Respiratory and hemodynamic variables, ICP and CPP were recorded at baseline and after exposure to a target level of test drug for 10 min or until CPP fell below 30 mmHg (recommended lower ICP level is 25 mmHg in neonates, rising to 40 mmHg in toddlers). RESULTS: When comparing baseline values with values at 1.0 MAC, mean arterial pressure (MAP) decreased (P < 0.001) in all groups, with no differences between the groups. ICP increased (P < 0.001) with all agents, mean +2, +5, and +6 mmHg in Group I, S and D, respectively, with no differences between the groups. Regression analyzes found no relationship between baseline ICP and the increases in ICP from baseline to 1.0 MAC for isoflurane or sevoflurane. However, increased baseline ICP tended to cause a higher ICP increase with 1.0 MAC desflurane; regression coefficient +0.759 (P = 0.077). The difference between regression coefficients for Group I and Group D were not significant (P = 0.055). CPP (MAP-ICP) decreased (P < 0.001) in all groups, mean -18, -14 and -17 mmHg in Group I, S and D, respectively, with no significant difference between the groups. CONCLUSIONS: 0.5 and 1.0 MAC isoflurane, sevoflurane and desflurane in N2O all increased ICP and reduced MAP and CPP in a dose-dependent and clinically similar manner. There were no baseline dependent increases in ICP from 0 to 1.0 MAC with isoflurane or sevoflurane, but ICP increased somewhat more, although statistically insignificant, with higher baseline values in patients given desflurane. The effect of MAP on CPP is 3-4 times higher than the effect of the increases in ICP on CPP and this makes MAP the most important factor in preserving CPP. In children with known increased ICP, intravenous anesthesia may be safer. However, maintaining MAP remains the most important determinant of a safe CPP.

Hypertonic saline and dextran in normovolaemic and hypovolaemic healthy volunteers increases interstitial and intravascular fluid volumes.

BACKGROUND: Hypertonic saline (HS) is increasingly used for fluid resuscitation in hypovolaemic patients. Although the effects of HS have been investigated in animal models, controlled studies in healthy human individuals are few. AIM: The effects of i.v. hypertonic saline 75 mg.ml-1 in dextran 70, 60 mg.ml-1 (HSD) infusion on fluid shifts between the interstitial and intravascular fluid spaces, diuresis and haemodynamics were studied in normovolaemic and moderately hypovolaemic healthy volunteers. MATERIAL AND METHODS: Nine fasting subjects received 4 ml.kg-1 HSD as a 10-min infusion in a normovolaemic situation. Seven days later they served as their own controls in a hypovolaemic situation after 10% of the calculated blood volume had been withdrawn during a 15-min period. Before and after the HSD infusion, interstitial colloid osmotic pressure (COPi) and interstitial fluid hydrostatic pressure (Pi) were measured on the lateral part of the thorax. During the study, blood sampling and pressure measurements were performed through a radial artery cannula, and central venous pressure measured through a catheter in the cubital vein. RESULTS: In these awake and normovolaemic healthy volunteers, HSD infusion caused a transitory unpleasant sensation of headache and heat in the thorax up to the throat. A transitory haemodynamic effect was found with increased heart rate (HR), increased mean arterial pressure (MAP) from 77 +/- 5 mmHg to 92 +/- 13 mmHg (P < 0.05) and CVP increase from 5 +/- 1 mmHg to 8 +/- 1 mmHg (P < 0.05) after end of infusion. A haemodilution with increase in calculated blood volume lasting longer than the MAP increase was observed, with decreased COPi from 14.4 +/- 2.2 mmHg to 12.1 +/- 2.0 mmHg (P < 0.05). The diuresis measured at 180 min was higher in the normovolaemic than in the hypovolaemic situation. More pronounced effects of the infused fluid (HSD) on calculated blood volume, interstitial compartment and CVP were observed during moderate hypovolaemia. CONCLUSIONS: HSD infusion resulted in increased calculated blood volume with increased HR, MAP, and CVP. These effects were greater in a hypovolaemic situation. The haemodilution was most likely caused by fluid shifts from the intracellular compartment to the interstitial and vascular fluid spaces, eventually increasing diuresis.

[Treatment of hypovolemia with hypertonic saline solutions]. / Behandling av hypovolemi med hypertone saltløsninger.

Clinical and experimental studies indicate that intravenous infusion of small volumes of hypertonic saline may be beneficial in the treatment of acute hypovolemia. After infusion, cardiac output is increased and systemic vascular resistance is lowered. The effect is transient, however, but can be prolonged by adding a colloid solution. Infusion of small volumes of hypertonic saline (7.5% NaCl) does not significantly influence serum osmolality or serum sodium concentration.

[Dietary factors and risk of colon cancer]. / Kosthold og risiko for coloncancer.

Epidemiological and experimental studies indicate that certain dietary habits are associated with increased frequency of cancer in the large bowel. The article presents recent studies on the effects of fiber, fat and calcium on risk of cancer of the large bowel. A low fiber/high fat diet seems to enhance the risk of developing a colonic neoplasm. Increased intake of calcium may be beneficial in high-risk populations.

Further studies on the biological characteristics of an endogenous colon mitosis inhibitor: comparison with some structurally related peptides.

Previous work indicates that the colonic epithelial cell proliferation in mice is reversibly inhibited by the tripeptide pGlu-His-GlyOH found in aqueous extracts of the intestine. In the present study we examined the possible tissue specificity of the colon mitosis inhibitor. The mitotic rate in the small intestine, epidermis and forestomach in mice was registered after a single i.p. injection of the tripeptide. A significantly reduced rate of cell renewal was found at 18 h in the epidermis whereas no inhibition was observed in the forestomach or ileal epithelium. To investigate whether the amino acid sequence of the tripeptide is essential for the inhibitory effect, three structurally related bioactive peptides were tested and compared to the effect of CMI. CMI showed a bell-shaped dose-response relationship as previously shown, whereas the mitotic rate was not reduced in the colonic epithelium after treatment with either an epidermal mitosis inhibitory pentapeptide, or the dipeptide pGlu-GlyOH, or an analogue of luteinizing hormone-releasing hormone. The efficacy of the tripeptide was dependent on the basal rate of cell renewal in the colonic epithelium. When the tripeptide was given at the circadian nadir of cell proliferation a delayed reduction of proliferative activity was observed at 6 h after treatment, whereas treatment when the rate of cell proliferation was at its circadian zenith gave an immediate mitotic inhibition.

An endogenous colon mitosis inhibitor reduces proliferation of colon carcinoma cells (HT 29) in serum-restricted medium.

Extracts of mouse intestine contain a colonic epithelial mitosis inhibitor that has recently been purified and identified as a tripeptide (pGlu-His-GlyOH). In order to elucidate further the biological characteristics of this peptide, the effect of the tripeptide on cell proliferation in a human colon carcinoma cell line (HT 29) was examined. The incorporation of tritiated thymidine was significantly reduced at 20-30 h after addition of the tripeptide. The dose-response relationship was bell-shaped with loss of inhibitory effect at high or low doses. The number of cells were significantly reduced at a peptide concentration of 10(-8) M at 24 h, but not at 48 or 72 h after addition of the peptide. The inhibition was reversible, and was only observed when the cells were grown in a serum-restricted medium (1%). The inhibitory effect was abolished by increasing the serum content to 10% or adding insulin to the medium.

An endogenous colon mitosis inhibitor reduces the increased cell proliferation in colonic epithelium induced by dietary cholic acid and treatment with 1,2-dimethylhydrazine.

We have recently purified and identified a tripeptide (pGlu-His-GlyOH) in mouse intestinal extracts which reversibly inhibits normal colonic epithelial cell renewal in mice. We also found a similar response to a single injection of the peptide during bile-acid-induced hyperproliferation in the colonic epithelium. To investigate the effect of repeated injections of the same dose of the inhibitor under various pathological conditions of the colonic mucosa we either fed mice low-calcium cholic acid diet, treated the animals with a single injection of the colon carcinogen 1,2-dimethylhydrazine (DMH), or gave both treatments. The peptide reduced the mitotic rate and the labelling indices in the colonic epithelium during the first 5 days of feeding the low-calcium cholic acid diet, and the size of the proliferative compartment was reduced. Proliferating cells were found significantly closer to the base of the crypts in the peptide-treated animals. The mitotic rate was also reduced by each of repeated peptide injections during the first 72 h in the DMH-treated animals; the labelling indices at 48 and 72 h only. By feeding DMH-treated animals low-calcium cholic acid diet, similar results were obtained. However, in all carcinogen-treated animals the tripeptide had no effect on the size and localization of the proliferating cells in the colonic crypts.

An endogenous colon mitosis inhibitor and dietary calcium inhibit the increased colonic cell proliferation induced by cholic acid.

We have previously reported that a single intraperitoneal injection of the tripeptide pGlu-His-GlyOH (colon mitosis inhibitor (CMI] is followed by a transient reduction of cell proliferation in the colonic epithelium in mice. The effect of the tripeptide on accelerated cell proliferation in the colonic epithelium was tested during the acute response of the epithelial cells to a diet supplemented with cholic acid. The kinetics of this response was first examined with different amounts of calcium in the feed. We found an increased labeling index (LI) and mitotic rate 2 days after changing the diet, and this response was stronger in animals with a low-calcium cholic acid diet than in animals with cholic acid diet with a standard amount of calcium or a high-calcium cholic acid diet. After 2 weeks of treatment cell proliferation remained significantly elevated only in the animals with low-calcium cholic acid diet. The effect of CMI was tested 7 days after the change to a low-calcium cholic acid diet. Under these conditions a single dose of CMI (10(-12) mol per animal) was still followed by a transient reduction in the proliferative indices in the colonic epithelium. However, the decreases in LI was observed earlier after CMI treatment (at 2 h) in the animals fed a low-calcium cholic acid than in animals with a standard diet.

Kidney extract reversibly inhibits compensatory cell proliferation after unilateral nephrectomy.

Unilateral nephrectomy (uNX) in mice is followed by a transitory increase in cell proliferation in the remaining kidney. To examine whether this response could be related to a negative feedback control of kidney epithelial cell renewal, water extracts were made of kidney homogenate. Five mg freeze-dried extract was injected 18 h post-operatively, and the animals were sacrificed at intervals during the following 54 h. The mitotic rate and the incorporation of tritiated thymidine (3H-TdR) into DNA were measured in the remaining kidney. The results show that the kidney extract reduces both the mitotic rate and the incorporation of 3H-TdR into DNA. In the tubular epithelium in the kidney, the strongest inhibitory effect was found by injecting the extract at 18 or 39 h postoperatively.

Compensatory cell proliferation in the kidney after unilateral nephrectomy in mice.

The compensatory cell proliferation in kidney cortex after unilateral nephrectomy in hair-less mice was evaluated by registration of the mitotic rate, thymidine incorporation into DNA, and labelling indices (LI) over a period of 120 h after surgery. Maximal specific activity of DNA and LI were found at 30-36 h postoperatively and preceded the maximal mitotic rate by 6-12 h. The influence of age, sex and diurnal variations was examined.