the tomb of the hepatologist!
Notes by dr Claudio Italiano
see on topic other link: albumina Impiego dell’albumina nella pratica clinica Ascites The patient swollen L'ascite, come curarla
The condition in which diuretic treatment, even at high doses, is not able to resolve the ascitic effusion or to prevent rapid recurrence after paracentesis is defined as "refractory ascites". In the context of refractory ascites, a diuretic-resistant ascites and a diuretic-intractable ascites are distinguished. In the first case there is a lack of therapeutic response to high doses of diuretics, in the second case there is a response to the diuretic treatment, which, however, must be interrupted by the onset of side effects. The occurrence of refractory ascites, which occurs in 5-6% of patients with ascites, is linked to a complex series of changes in hepatic function of systemic hemodynamics and renal function that depends on the progression of the disease. In particular, the progression of portal hypertension leads to a progressive aggravation of hyperdynamic circulatory syndrome with further reduction of effective volemia and activation of neuro-hormonal systems such as the RAA and SNS system. In these conditions there is a progressive increase in renal resistance and a further reduction of glomerular filtration and plasma renal flow; since there is a more marked reduction of the renal flow than of the glomerular filtrate, the filtration fraction increases, favoring the reabsorption of sodium at the proximal tubular level. Even the high levels of angiotensin II and the activation of sympathetic renal stimulate the proximal reabsorption of sodium which is particularly intense in this condition. Therefore, both for a reduction of the filtered sodium and for the increase in the proximal reabsorption of sodium there is a dramatic reduction in the amount of sodium reaching the loop of Henle and the distal tubule. It is clear that under these conditions the efficacy of diuretics acting either at the level of the Henle loop such as furosemide, or at the level of the distal tubule, such as the antialdosterones, will be greatly reduced. It is also necessary to distinguish the true refractory ascite from all those conditions in which the refractoriness is not due to a progressive deterioration of the renal function but to an incorrect therapeutic conduct.
The non-prescription of a hypododic diet or a failure to adhere to it by the
patient are frequent causes of the ineffective diuretic therapy. 
This situation should be suspected in all cases where body weight does not decrease and the ascites are not reduced despite a good response to diuretics, easily detectable through the measurement of urinary sodium excretion. In general, for ascites to be reduce, the daily sodium ingestion should be less than the natriuresis of at least 40 mEq / day. The lack of response to diuretic therapy may also be due to an inadequate use of these drugs: as already discussed previously, loop diuretics, while having an intrinsic natriuretic power much higher than antialdosterones, are much less effective than the latter in determining a natriuretic response in patients with cirrhosis and ascites. The mechanisms responsible for the reduced response to loop diuretics in this type of patient are not yet fully known. Moreover, the most probable hypothesis is that the resistance to furosemide is due to phenomena of a pharmacodynamic type. This drug, as well as other loop diuretics, would not be able to determine an increase in sodium excretion in these patients or because the amount of sodium that reaches the ascending tract of the loop of Henle is reduced due to a excessive proximal reabsorption or because the sodium that escapes the reabsorption in the loop of Henle due to the effect of furosemide is then reabsorbed into the distal tubule due to hyperaldosteronism. The importance of the latter mechanism is confirmed by the observation that patients who do not respond to furosemide are those with the highest plasma levels of aldosterone. Any therapeutic scheme used in the treatment of patients with cirrhosis and ascites should therefore include an antialdosteronic. The reduced response to diuretic therapy is linked not only to pharmacodynamic but also pharmacokinetic reasons.
The volume of drug distribution has increased
due to both a reduced link with albumin and the passage of the drug into the
ascitic fluid. These alterations cause a part of the drug to be seized and
therefore a smaller quantity of it reaches the tubule. The reduction of the
renal flow is reflected in the renal clearance of the drug, so that a smaller
amount of the drug can reach the lumen of the renal tubule. Finally, in patients
with cirrhosis and ascites the use of non-steroidal anti-inflammatory drugs (aspirin,
phenylbutazone, indomethacin, ibuprofen, naproxen and others) also causes a
marked reduction in renal perfusion, glomerular filtration, the ability to
eliminate water and sodium and of the diuretic response to furosemide and
antialdosterones. All of these effects, due to the ability of these drugs to
inhibit renal synthesis of prostaglandins, were rapidly reversible after drug
withdrawal. Once they are certain that the patient has a true refractory ascite,
therefore, alternative choices to the diuretic treatment are required for the
clinician, which involve the use of repeated paracentesis, shunt of LeVeen or
the intrahepatic transgíugular portosystemic shunt (TIPS). Repeated paracentesis
is the treatment of choice for refractory ascites. This orientation is confirmed
by a recent controlled study in which the efficacy of repeated paracentesis and
peritoneo-venous shunt was evaluated in a group of patients with refractory
ascites. Both treatments are equally effective in mobilizing ascites. Of course,
patients treated with paracentesis required more re-admissions to the hospital,
but the overall length of hospitalization, incidence of complications and
survival were similar in the two groups.
These studies clearly indicate that the paracentesis and the infusion of albumin
is more
effective than the diuretic treatment (97% of successes compared to 73%) in
obtaining the complete resolution of the effusion, without this leading to a
greater incidence of side effects affecting the hepatic and renal function and /
or hydro-electrolyte balance. Furthermore, the period of hospitalization is
significantly shorter in patients treated with paracentesis, while the need for
new hospitalizations for recurrence of effusion, survival and causes of death
were not different in the two groups. Paracentesis and consequent removal of
ascitic fluid is followed by changes in systemic hemodynamics, renal function
and the arrangement of the main hormonal systems. In fact, after an initial
improvement of the systemic hemodynamics, which occurs in the first three hours
after paracentesis, there is, between 12 and 24 hours, a reduction in cardiac
output, central venous pressure, pulmonary pressure and an occluded catheter. ,
creatinine clearance and serum sodium concentration. These haemodynamic changes
are associated with activation of the RAA system and a reduction in circulating
levels of atrial factor. Such alterations are evidently due to a sharp reduction
of the effective volemia, which is probably secondary to a rapid accumulation of
ascitic fluid in the peritoneal cavity after paracentesis. It is therefore
evident that the administration of albumin is an effective therapeutic aid, capable of preventing the reduction of effective volemia and therefore the
potential complications that follow this event. To confirm this hypothesis, in
patients whose paracentesis is not accompanied by albumin, there is a
significantly higher incidence of complications such as hyponatraemia and renal
failure.
Since the use of albumin may be limited by high costs, the use of other plasma
expander such as emagel or dextran 70 has also been proposed: in a recent
controlled study a large group of patients with cirrhosis and ascites, which was
subjected to paracentesis, was randomized to receive albumin, dextran 70 or
emagel. No significant differences were observed between the three drugs in
terms of major complications. However, the authors considered in the study a
particular marker of effective volemia, that is, plasma renin activity, which
was evaluated 6 days after paracentesis. In patients who had a renin increase
greater than 50% compared to the levels observed before paracentesis, or higher
than 4 ng / ml / h, the increase in reninemia tended to persist over time and
above all was associated with a worse prognosis. The incidence of this
alteration was significantly lower in patients treated with albumin than in
those treated with dextran or emagel.