The Effect of Barbiturates in Patients With Liver Disease 1

Abstract

Although sedatives are frequently required in the treatment of patients with liver disease, barbiturates are believed to be contraindicated in the face of impaired hepatic function. Three points are advanced in support of this belief: First, patients with advanced liver disease have remained comatose for long periods of time after receiving a barbiturate; second, animals after chloroform induced hepatic damage or partial liver extirpation have shown an increased sensitivity to anesthetic doses of barbiturates (1, 2); and third, animals are alleged to show a greater than normal retention of pentobarbital and barbital in their blood and tissues after chloroform anesthesia (3). These points of evidence, however, are far 'from conclusive. The natural progression of hepatic coma from a stage of restlessness to one of somnolence, and the spontateous fluctuations that occur in the course of liver disease reduce the significance of temporal correlations in determining the part any single factor plays in causing hepatic coma. As far as animal experiments are concerned, they are not necessarily applicable to man, particularly if the type of liver damage and the barbiturate dosage are not comparable to the usual clinical situation. Finally, methods of barbiturate analysis are difficult and non-specific. Since the evidence incriminating the use of barbiturates in liver disease seemed circumstantial, a study to obtain direct evidence was undertaken. Three questions in particular seemed worthy of consideration:

Metabolism of amylobarbitone in patients with chronic liver disease

“…Nine years later the first controlled study demonstrated a significantly increased duration of thiopentone effect in patients with liver disease (Shideman, Kelly, Lee, Lowell & Adams, 1949), and Dundee (1952) reported similar observations. The decay of serum pentobarbitone concentration during the first hour after intravenous administration was not slowed in patients with advanced liver disease (Sessions, Minkel, Bullard & Ingelfinger, 1954).…”

“…The total score was thus a function of both the intensity and the duration of the drug effects. The method was similar to that adopted by Sessions et al (1954) when studying the effects of pentobarbitone.…”

“…Sessions et al (1954) reported that patients with chronic liver disease were no more affected by pentobarbitone than were healthy control subjects. These findings were, however, contrary to those reported for thiopentone by Shideman et al (1949) and Dundee (1952).…”

Influence of liver disease on the elimination of drugs

“…Sessions et al (70) recorded clinical symptoms after varying doses of sodiumpentobarbital in 28 control subjects of varying diagnosis and 15 patients with liver disease. A barbiturate index, based on the degree and duration of side effects, such as nystagmus, two-point discrimination, slurred speech, and change in mood, did not show any significant difference between both groups.…”

Liver

“…Disappearance of BSP and of rose bengal from plasma follows a simple exponential course to 80 to 90 per cent disappearance, slow ing thereafter (141,142,143). Anesthesia affects neither estimated hepatic blood flow nor BSP extraction efficiency greatly in dogs (145,146). In cirrhotic livers (144, 145) BSP extraction is re duced, possibly as a result of reduced vascular cross section and consequent short transit time.…”