Continuous intravenous infusion state

In the previous discussion of the one- and two-compartment models we have loaded the system with a single-dose D at time zero, and subsequently we observed its transient response until a steady state was reached. It has been shown that an analysis of the response in the central plasma compartment allows to estimate the transfer constants of the system. Once the transfer constants have been established, it is possible to study the behaviour of the model with different types of input functions. The case when the input is delivered at a constant rate during a certain time interval is of special importance. It applies when a drug is delivered by continuous intravenous infusion. We assume that an amount Z) of a drug is delivered during the time of infusion x at a constant rate (Fig. 39.10). The first part of the mass balance differential equation for this one-compartment open system, for times t between 0 and x, is given by ... 

In the limit, when the interval 0 between administrations becomes extremely small in comparison with the elimination half-life 0.693/kp, the steady-state solutions are reduced to those already derived for a continuous intravenous infusion (eq. (39.35)) ... 

A drug with a half-life of 12 hours is administered by continuous intravenous infusion. How long will it take for the drug to reach 90% of its final steady-state level ... 

During continuous intravenous infusion at an average rate of 41 ig/kg/ minute to 31 subjects, a mean steady-state plasma concentration of 2.2 pg/ ml was reported norketamine and dehydronorketamine attained mean peak plasma concentrations of 1.1 pg/ml and 0.7 pg/ml, respectively, in about 3 hours the subjects awoke at an average plasma concentration of 0.64 pg/ml (J. Idvall et al., Br. J. Anaesth., 1979, 51,1167-1173). Following an intramuscular injection of 0.5 mg/kg to 6 subjects, peak plasma concentrations of 0.10 to 0.43 pg/ml (mean 0.24) were attained in about 0.3 hour norketamine attained a mean peak plasma concentration of 0.09 pg/ml at about 1 hour (J. A. Clements et al., J. pharm. Sci., 1982, 71, 539-542). 

A mean steady-state plasma concentration of 12.7)j.g/ml was reported during the continuous intravenous infusion of l.Omg/kg/min to 6 subjects following continuous intravenous infusion of 1.5 mg/kg/min to a further 6 subjects, a mean steady-state plasma concentration of 42.7 pg/ ml was reported (A. B. Seifen et al., Anesth. Analg. curr. Res., 1979, 58, 382-386). 

After a bolus intravenous injection of 2 mg/kg followed by continuous intravenous infusion to provide a maintenance dose of 2 mg/kg to 1 neonate, plasma concentrations attained a steady-state of 7 to 8 pg/ml and declined with a half-life of 5 hours at the end of the infusion (V. Rovei et al., J. Chromat., 1982,231 Biomed. Appl., 20, 210-215). 

Half-life less than 3 h. Dosing at intervals equal to the t/ would be so frequent as to be unacceptable, and the answer is to use continuous intravenous infusion if the tj is very short, e.g. dopamine t), 2 min steady-state plasma concentration will be reached in... 

In six patients with severe congestive heart failure and renal insufficiency being treated with continuous veno-venous hemofiltration, the pharmacokinetics of milrinone 0.25 mg/kg/minute by continuous intravenous infusion were different from those that have been previously reported in patients with normal renal function, with a prolonged half-life and a raised mean steady-state concentration, suggestive of reduced clearance (20). The half-hfe of milrinone was 20 hours, compared with reported half-lives of around 3 hours. 

Figure 6 Time-course blood concentration of xenobiotic following continuous intravenous infusion or pulmonary inhalation until steady state.

When a drug is administered by continuous intravenous infusion, the infusion rate (Ro) required to provide a desired steady-state plasma concentration is... 

As the rate of absorption increases, the concentration maxima approach 2 and tiie minima approach 1 during tiie steady state. The black line depicts the pattern during administration of equivalei dosage by continuous intravenous infusion. Curves are based on the one-compartment model. Average concentration (Css) when tiie steady state is attained during intermittent drug administration is... 

B. Cyanide toxicity, manifested by altered mental status and metabolic (lactic) acidosis, may occur with rapid high-dose infusion (> 10-15 mcg/kg/min) for periods of 1 hour or longer. Patients with depleted thiosulfate stores (eg, malnourished) may have elevated cyanide levels at lower infusion rates. Continuous intravenous infusion of hydroxocobalamin, 25 mg/h (see p 453 note caution with preservative), or thiosulfate (p 505) has been used to limit cyanide toxicity. If severe cyanide toxicity occurs, discontinue the nitropmsside infusion and consider antidotal doses of thiosulfate and sodium nitrite (p 476) or high-dose hydroxocobalamin (p 453 note concentrated fona not available in the United States). 

This physiological approach to defining volume is useful to help explain which drug might be more likely to reside outside the blood based on tissue affinity (fup/ fut), but does not readily lend itself to a calculation because of the difficulty in determining either free or total concentrations in the tissue. A simpler mathematical expression of Vss would be one related to equilibrium conditions achieved with a continuous intravenous (IV) infusion (R0) at steady-state where ... 

The acidosis was treated by intravenous infusion of bicarbonate, and he recovered consciousness. Over the next few days he continued to show signs of acidosis (rapid respiration), and even after a meal he showed ketonuria. His plasma lactate, pyruvate and ketones remained high plasma glucose was in the low normal range and his plasma insulin was normal both in the fasting state and after an oral glucose load. 

Intravenous ribavirin decreases mortality in patients with Lassa fever and other viral hemorrhagic fevers if started early. High concentrations inhibit West Nile virus in vitro, but clinical data are lacking. Clinical benefit has been reported in cases of severe measles pneumonitis and certain encephalitides, and continuous infusion of ribavirin has decreased virus shedding in several patients with severe lower respiratory tract influenza or parainfluenza infections. At steady state, cerebrospinal fluid levels are about 70% of those in plasma. 

After intravenous administration of 175 mg/70 kg to five individuals, the average peak serum concentration was 1.0 mg/L achieved at 12 min.2 The concentration declined by 50% within 30 min. The plasma half-life is reported to be 3 to 4 h with a volume of distribution of 3 to 5 L/kg.1 Continuous infusion of 41 pg/kg/min after a 2-mg/kg bolus produced an average (n = 31) steady-state plasma concentration of 2.2 mg/L.3... 

---