One way to reach a therapeutic drug level in a patient as rapidly as possible is with a

Loading Dose

A loading dose is typically administered at the time of initiation of PCA as a means of quickly achieving a serum opioid concentration that provides effective pain control. After administration of a loading dose, patients can then self-administer additional opioid doses via the demand mode to maintain satisfactory analgesia. A loading dose should generally be prescribed when patients are experiencing significant pain upon starting PCA because use of the demand feature alone is unlikely to allow for timely establishment of sufficient analgesic serum opioid concentrations.

Loading doses can be given before PCA is initiated as multiple small opioid doses, repeated at frequent intervals until adequate analgesia is achieved (e.g., in the postanesthesia care unit [PACU]). It is vitally important to understand that PCA should be initiated only after the patient has achieved pain relief that is “in the ballpark of adequate analgesia.”

Warfarin Daily Loading Doses (Approximately 3–5 Days)

Dosage and Administration

Loading doses are not recommended with disopyramide. The usual effective dosage for disopyramide is 100 to 200 mg three to four times daily, up to a maximum dose of 800 mg/day. Dosages up to 1600 mg/day have been required for some refractory arrhythmias. Therapy should be very carefully titrated, beginning with low doses and allowing ample time for achievement of steady state equilibrium.

Although rapid fluctuations in plasma concentration are undesirable, they are difficult to avoid because of disopyramide's saturable protein binding. The controlled-release form of disopyramide may be useful in reducing adverse effects by decreasing fluctuations in the concentration of free disopyramide in plasma.139 Because of saturable protein binding,140 the generally accepted therapeutic range for total disopyramide in plasma of 2 to 5 µg/mL should not be relied on with confidence. Although monitoring the plasma concentrations of free disopyramide has been recommended,141 the range of concentrations associated with arrhythmia suppression has not been clearly delineated and overlaps with that associated with adverse effects.

Individualization of Dosage

Loading doses are not recommended with disopyramide because of saturable protein binding. The usually effective dosage for disopyramide is 100 to 400 mg three to four times daily, to a maximal dose of 800 mg daily. Therapy should be titrated, beginning with low doses (100 mg three times daily) and allowing ample time (2 to 4 days) for achievement of steady-state equilibrium.

Although rapid fluctuations in plasma concentration are undesirable, they are difficult to avoid because of the saturable protein binding of disopyramide. The controlled-release form of disopyramide may be useful in reducing adverse effects by decreasing fluctuations in the concentration of free disopyramide in plasma.62 Because of saturable protein binding,63 the generally accepted therapeutic range for total disopyramide in plasma of 2 to 5 mcg/mL should not be strictly relied on. Although monitoring of the plasma concentrations of free disopyramide has been recommended,64 the range of concentrations associated with arrhythmia suppression has not been clearly delineated and overlaps with that causing adverse effects.

For Rapid Intravenous Therapeutic-Dose Anticoagulation:

Loading dose: ±0.2 mg/kg IV bolus*

Maintenance: 0.05 to 0.10 mg/kg/hr IV,†‡ with adjustments to maintain PTT at 1.5 to 2.0 times the mean of the normal laboratory range

IV, Intravenous; PTT, partial thromboplastin time; sCR, serum creatinine.

Treatment

Dosage and Administration

A loading dose of 1.5 mg/kg is administered over 2 to 3 minutes, followed by a maintenance infusion rate of 1 to 4 mg/min. Since the bolus dose has a half-life of 15 minutes and the maintenance infusion requires 2 to 3 hours to achieve a steady state, repeated boluses may be required to achieve the desired effect.44 A reduced dose is necessary in liver impairment or heart failure. Lidocaine can also be injected intramuscularly at a dose of 4 to 5 mg/kg, achieving therapeutic concentrations more reliably via the deltoid than the gluteal muscle.44

Antimicrobial Agents

Inappropriate loading dose reduction resulting in ineffectively low plasma concentration is a significant danger in patients with renal impairment. A single loading dose of antibiotic, equivalent to the usual maintenance dose for patients with normal renal function, should almost always be given to patients with impaired renal function. Subsequent doses and dose intervals can be individualized based on relative importance of maintaining therapeutic peak or trough concentrations (see earlier discussion). Uremia may mask the clinical presentation of infection and the signs of antibiotic toxicity in patients with renal failure. Adverse reactions to antimicrobial treatment in patients with impaired renal function are usually caused by the accumulation of drugs or their metabolites to toxic levels with repeated doses; any organ system may be affected. Drug toxicity should be considered in antibiotic-treated patients with renal insufficiency who develop new symptoms, and therapeutic drug monitoring is essential in all patients with renal impairment to avoid toxicity to the kidney and other organs. Specific care should be taken with the use of aminoglycosides as nephrotoxicity can occur even in the context of “normal” serum levels. Antiviral agents may also be problematic. Acyclovir, valacyclovir, and ganciclovir accumulate in renal failure, resulting in increased cerebrospinal fluid levels of both parent compound and metabolites, resulting in neuropsychiatric side effects.

Heparinization

A loading dose of heparin is administered intravenously (70 units/kg) after groin puncture, and 5 minutes later, the activated coagulation time is obtained. The guide catheter is placed in the ICA or VA only after a therapeutic level of heparinization has been achieved. The activated coagulation time should be kept between 250 and 300 seconds for the duration of the procedure. Continuous irrigation of the guide with heparinized saline (5000 units of heparin per 500 mL of saline) is important to avoid thrombus formation. A three-way stopcock connects the heparinized saline flush line to a rotating hemostatic valve to allow continuous infusion of saline through the guide and microcatheter while other devices are being inserted. More recently, we are using a COPILOT Bleedback Control Valve (Guidant Corporation, St. Paul, MN) in the place of a rotating hemostatic valve with the guide catheter because it has a one-way valve that prevents back-bleeding from the rotating hemostatic valve during exchange of devices through the guide.

Doses

A loading dose of 200 to 400 mcg of levothyroxine (T4) may be given intravenously followed by a maintenance dose of 1.6 mcg/kg body weight per day, reduced to 75% if being intravenously administered. Within 24 hours, serum T4 levels may approach the normal reference range and a decrease in TSH levels should be observed. Following improvement in the overall general condition of the patient, we may switch to oral therapy. Larger doses of T4 probably have no advantage and may, in fact, be more dangerous.31 Due to its conversion from T4, a progressive increase in serum T3 is seen after a dose of 300 to 600 mcg of T4, as has been described by Ridgway et al.31

Although the therapeutic approach of administering a bolus followed by maintenance therapy has been more widely accepted as optimal, the initial amount of the dose of T4 is still debated. In a retrospective study analyzing 11 patients with myxedema coma, it was observed that those patients who died had received larger amounts of thyroid hormone and had circulating levels of T3 that were 1.9 times higher than the surviving patients.3 Together with advanced age, high serum levels of T3 were associated with a fatal outcome. It was on this basis that Hylander et al. suggested that the use of T4 instead of T3 would lead to lower serum levels of T3, which are probably less stressful for the patients.3

In a more recent prospective study, 11 patients were randomized to receive either a 500-mcg loading dose of intravenous T4 followed by a 100-mcg daily maintenance dose, or only the maintenance dose. The overall mortality rate was 36.4%, and despite the absence of statistically significant results between the two groups, a lower mortality was noted in the high-dose group (17%) versus the low-dose group (60%).32 Factors associated with a worse outcome included a decreased level of consciousness, lower Glasgow coma score, and increased severity of illness on entry as determined by an APACHE II score of more than 20.32