Increased sympathetic nervous system activity, along with activation of the renin-angiotensin-

aldosterone system and the nonosmotic release of vasopressin, is seen in other states of arterial
underfilling. Thus, in the present study, sympathetic nervous system activity was assessed by
determining plasma norepinephrine secretion and clearance rates using a whole-body steady-state
radionuclide tracer method in 6 edematous patients with the nephrotic syndrome of various
parenchymal etiologies and 6 normal control subjects in the supine position. Patients were withdrawn
from all medications 7 days prior to study. Mean creatinine clearances and serum creatinine
concentrations were normal in both the nephrotic syndrome patients and controls. However, the
nephrotic syndrome patients exhibited significant hypoalbuminemia. The supine plasma norepinephrine
level was elevated in the patients with the nephrotic syndrome as compared with controls. More
significantly, the secretion rate of norepinephrine was markedly increased in nephrotic patients, whereas
the clearance rate of norepinephrine was similar in the two groups. Plasma renin activity and plasma
aldosterone, arginine vasopressin and atrial natriuretic peptide concentrations were not different in
nephrotic syndrome patients compared with controls. We conclude that the sympathetic nervous system
is activated in patients with the nephrotic syndrome, as assessed by the increased whole-body
norepinephrine secretion rate, prior to a significant fall in glomerular filtration rate or a marked activation
of either the renin-angiotensin-aldosterone system or the nonosmotic release of vasopressin. We
studied this phenomenon by using 109 mmol/L buffered citrate as the anticoagulant, anticipating some
increase in tolerance to underfilling. Venous blood drawn from 12 healthy subjects and 30 patients
receiving long-term oral warfarin therapy was mixed with 109 mmol/L buffered citrate solution in
proportions equivalent to filling the collection tubes from 52% to 100% of capacity. Accurate PT values
were obtained from normal specimens if the tubes were filled to 65% or more of capacity. The generally
accepted 'peripheral arterial vasodilatation hypothesis' seems to best explain the mechanism of sodium
retention and other clinical findings, such as the hyperdynamic circulation of cirrhosis. However, recent
data in pre-ascites and in early ascites do not seem to conform to the peripheral arterial vasodilatation
hypothesis. Sodium handling abnormalities can be demonstrated in pre-ascitic cirrhosis when patients
are challenged with a sodium load, in the absence of systemic vasodilatation or arterial underfilling.
Therefore, an alternative hypothesis with a direct hepatorenal interaction, acting via sinusoidal portal
hypertension and/or hepatic dysfunction as the affector mechanism, is proposed to be the initiating
event in renal sodium retention in cirrhosis. The second and later process is the development of
systemic arterial vasodilatation, possibly due to the presence of excess systemic vasodilators and/or
decreased responsiveness of the vasculature to endogenous vasoconstrictors. This, in turn, will lead to
a relatively underfilled circulation with consequent activation of neurohumoral systems, promoting
further renal sodium retention as described by the peripheral arterial vasodilatation hypothesis and
ultimately leading to ascites. When compensatory natriuretic mechanisms fail, refractory ascites
develops and hepatorenal syndrome sets in.

This underfilling of the arterial vascular compartment unloads the baroreceptors, resulting in a sequence
of events to maintain arterial circulatory integrity. Among them, the renin-angiotensin-aldosterone axis,
the sympathetic nervous system, the non-osmotic release of vasopressin and the endothelins are
activated to increase vascular resistance and enhance sodium and water renal retention.
Simultaneously, vasodilatory and natriuretic substances such as the natriuretic peptides are activated to
counterregulate these vasoconstrictors. In the initial phase of CHF, these events contribute to the
cardiorenal adaptation. However, when CHF progresses, they become maladaptive and further depress
ventricular performance and increase sodium and water retention. This vicious cycle of CHF provides
the rationale for the use of neurohormonal antagonists in CHF The beneficial effects of angiotensin
converting enzyme inhibitors in CHF are well described. Vasopressin V1 receptor antagonists have
been associated with peripheral vasodilation and improved cardiac function in some patients with CHF
In CHF animals, the vasopressin V2 receptor antagonist has been demonstrated to reverse the defect in
water excretion. Bosentan, an endothelin antagonist, is associated with an increase of cardiac index in
patients with CHF A role for exogenous natriuretic peptides is also under investigation. Eleven out of 32
patients and 12 of 21 patients lost their ascites at step 1 and step 2, respectively. The remaining nine
patients required step 3 treatment. Basal urinary sodium excretion and creatinine clearance were
significantly lower and beta-2-microglobulin was significantly higher in group 3 than those in groups 1
and 2. Elevation of basal plasma renin activity and norepinephrine was evident only in group 3. In group
1, urinary sodium excretion decreased after the treatment. In group 2, plasma alpha-atrial natriuretic
polypeptide was lowered and plasma renin activity and norepinephrine were elevated after the
treatment. These results suggest that basal renal function and plasma renin activity and norepinephrine
levels are useful indices to predict the effect of ascites treatment and that responders to sodium
restriction or potassium canrenoate may be in the state of vascular overflow, while non-responders to
potassium canrenoate may be in the state of vascular underfilling. The aim of this study was to
investigate whether and how bradykinin is involved in Na+ retention in rats with CCl4-induced liver
cirrhosis. To this end the bradykinin B2 receptor antagonist Icatibant was used. On one hand, bradykinin
has a renal natriuretic action. On the other hand, bradykinin is a potent mediator of both vasodilation
and microvascular leakage. Both vascular mechanisms, which are reported for cirrhosis, could cause
vascular underfilling and Na+ retention by activating the renin-angiotensin-aldosterone system. Icatibant
normalised Na+ retention and reduced the hyperactivity of the renin-angiotensin-aldosterone system,
suggesting a bradykinin-induced vascular disturbance. Icatibant had no significant effect on the mild
hypotension which developed with CCl4 treatment. However, there was indirect evidence for enhanced
microvascular leakage that was strongly inhibited by Icatibant.

O-2 diving incidents investigated by our laboratory were related to improper filling of the soda lime
canister in closed-circuit oxygen rebreathers. We studied the effect of overfilling or underfilling the
canister on CO2 absorption using a continuous flow of 5% CO2. With a full canister in the Oxyger 57,
CO2 began to rise at 130-160 min, reaching 1% at 240 rnin and 1.5% at 270 min. Similar results were
obtained after a reduction of 100 g in the quantity of soda lime packed into the canister. After reductions
of 200, 300 and 400 g, the rise in CO2 concentration occurred earlier as a function of the amount of the
reduction. The level of CO2 in the OxyNG 2 began to rise after 250 min with a full canister, reaching 1%
at 340 min and 1.5% at 370 min. After a reduction of 100 g there was a delay in the rise of CO2, which
reached 1.5% at 390 min. However, when the reduction was 200, 300 and 400 g, the rise in co2
concentration tended to occur earlier as a function of the amount of the reduction. For both rebreathers,
when the quantity of soda lime was reduced by 200 g or more, there was a considerable difference in
timing between the two test measurements for each weight reduction, due to variations in channeling.
For an excess of soda lime, moderate pressure was applied manually to achieve a full canister plus 300
g in the OxyNG 2. The initial rise in CO2 concentration started early, at 60 min with a full canister plus
300 g compared to 150 min with a full canister; 1% CO2 was reached at 120 min, compared to 210 min
with a full canister.