A retrospective study of sodium nitroprusside use and assessment of the potential risk of cyanide poisoning.

Sodium nitroprusside (SNP) is an effective vasodilator but is potentially dangerous due to its cyanide content. Infusion rates above 2 micrograms/kg/minute may cause cyanide to accumulate to toxic concentrations in critically ill patients. Coadministration of thiosulfate with SNP effectively and safely prevents cyanide toxicity. This study determined if patients at our institution were treated with SNP infusion rates that could cause cyanide toxicity and whether those patients were administered thiosulfate. We reviewed the charts of 36 critically ill patients treated with SNP during the previous 12 months. In 72% of patients the SNP infusion rates were above 2 micrograms/kg/minute. In 47% the rates were greater than 2 micrograms/kg/minute for 6 hours or more, and in 20% they were greater than 5 micrograms/kg/minute for up to 11 hours. None of the patients was administered thiosulfate. In a significant number of patients the infusion rates of SNP potentially exposed them to significant risk of cyanide toxicity including death.

Anti-infective agents and hepatic disease.

Numerous factors such as changes in plasma protein binding, tissue binding, hepatic blood flow, hepatic metabolism, and distribution may occur in hepatic disease. The impact of these physiologic changes on pharmacokinetic and pharmacodynamic parameters of anti-infective agents is likely to be clinically significant. Unfortunately, these issues have not been thoroughly investigated. Even within the same type of liver disease, there is considerable interpatient variability in pharmacokinetic variables, rendering it difficult to predict drug disposition accurately. Pharmacokinetics of selected anti-infective agents are altered in hepatic disease, necessitating careful monitoring and dosage titration to avoid enhanced drug concentrations and risk of toxicity.

Physiologic response of stress and aminoglycoside clearance in critically ill patients.

OBJECTIVE: To examine the relationships between aminoglycoside clearance and physiologic parameters associated with the physiologic response to injury. DESIGN: Cross-sectional study of surgical patients receiving aminoglycoside pharmacokinetic monitoring and parenteral nutritional support. SETTING: An adult surgical ICU. PATIENTS: Fifty-four surgical/trauma patients who had Gram-negative sepsis. INTERVENTIONS: Measurements of the physiologic stress response to injury were associated with aminoglycoside clearance in 54 surgical/trauma patients who had Gram-negative sepsis. Measurements used to estimate the magnitude of the stress response included a 24-hr urinary urea nitrogen excretion, blood urea nitrogen, peak temperature, serum albumin, bilirubin, and transferrin concentrations. MEASUREMENTS AND MAIN RESULTS: Mean drug clearance rate (4.4 +/- 2.5 [SD] L/hr) was related to the physiologic measurements using correlation and regression techniques. Collectively, all physiologic indices (utilized) explained 59% of the variance in drug clearance (p < .001), an amount similar to the variance explained by creatinine clearance alone (53%). When all six physiologic measurements were included into a multiple regression model that included creatinine clearance, the total variance explained increased to 73%. CONCLUSIONS: Along with renal function estimates, the physiologic response to stress should be considered when treating critically ill patients with aminoglycosides and other, similar, renally eliminated drugs.

Individualizing amikacin regimens: accurate method to achieve therapeutic concentrations.

Amikacin's pharmacokinetics and dosage requirements were studied in 98 patients receiving treatment for gram-negative infections. A wide interpatient variation in the kinetic parameters of the drug occurred in all patients and in patients who had normal serum creatinine levels or normal creatinine clearance. The half-life ranged from 0.7 to 14.4 h in 74 patients who had normal serum creatinine levels and from 0.7 to 7.2 h in 37 patients who had normal creatinine clearance. The necessary daily dose to obtain therapeutic serum concentrations ranged from 1.25 to 57 mg/kg in patients with normal serum creatinine levels and from 10 to 57 mg/kg in patients with normal creatinine clearance. In four patients (4%), a significant change in baseline serum creatinine level (greater than 0.5 mg/dl) occurred during or after treatment, which may have been amikacin-associated toxicity. Overt ototoxicity occurred in one patient. The method of individualizing dosage regimens provided a clinically useful means of rapidly attaining therapeutic peak and trough serum concentrations.

Amikacin pharmacokinetics: wide interpatient variation in 98 patients.

The disposition of amikacin was studied in 98 patients receiving treatment for severe gram-negative sepsis. Several factors were identified which were significantly related to the drug's elimination rate. These included renal function (r = .67), age (r = -.55), distribution volume (r = .34), and weight (r = -.31). These variables explain 62% of the variance (R2) in elimination rate constant when combined in a multiple regression model. The drug's half-life demonstrated considerable interpatient variation in patients with a normal serum creatinine (.68-14.4 hrs) or with a normal creatinine clearance (.68-7.2 hrs). The drug's distribution volume ranged from .08 to .48 L/Kg. The drug's clearance varied from 6.5 to 200 mL/hr/kg for patients with a normal serum creatinine and 17.8 to 200 mL/hr/kg for patients with a normal creatinine clearance. The interpatient variation in the drug's kinetic parameters is a concerning clinical problem. Measuring serum amikacin concentrations and adjusting dosage regimens are necessary to achieve desired peak and trough serum concentrations.

Initial dosage regimens of gentamicin in patients with burns.

For 95 patients with burns the gentamicin dosage regimen necessary to achieve optimal serum concentrations was determined. Individual elimination rates and distribution volumes for gentamicin were determined and correlated with renal function parameters and age. In patients with burns who had normal serum creatinine levels (less than 1.5 mg/dl), gentamicin clearance and thus dosage regimens can be stratified by age. Gentamicin's clearance decreased inversely with age. Initial dosage guidelines were calculated for different age groups of patients with normal levels of serum creatinine. The guidelines were developed to assist the clinician in attaining therapeutic concentrations with initial doses of gentamicin. Therapeutic serum concentrations were reached in most patients with burns dosed by these guidelines. Serum gentamicin concentrations should always be monitored during therapy, and dosages should be adjusted to ensure optimal concentrations during the course of therapy.

Thermal injury effects on drug disposition: a prospective study with piperacillin.

The disposition of piperacillin was prospectively evaluated in nine severely burned patients who had normal renal and hepatic function. Wide interpatient variations were demonstrated in the drug's distribution volume, half-life, and clearance, with mean (+/- SD) values of 55.0 (+/- 44.2) liters, 3.6 (+/- 5.2) hours, and 14.9 (+/- 6.3) liters/hour, respectively. Piperacillin clearance was best explained by patient factors other than age, renal function, and the percentage of body surface area burns. Piperacillin disposition was related to the patients' serum albumin, total bilirubin, blood urea nitrogen, and the amount of urea nitrogen excreted daily in urine. Altered piperacillin disposition thus appeared to occur secondary to changes in the patients' physiologic and metabolic state caused by injury-related stress and fluid therapy. The patient's physiologic and metabolic response to injury, along with age and renal function, should be considered when instituting treatment with piperacillin or other agents cleared from the body in a similar manner.

Aminoglycosides: another perspective.

Despite the introduction of several new classes of antimicrobial agents, aminoglycosides are still recognized as first-line therapeutic agents in the management of severe gram-negative sepsis. The major obstacle limiting the use of aminoglycoside antibiotics has been, and continues to be, the possibility of drug-induced ototoxicity and nephrotoxicity. This review critically examines the definitions used to establish the diagnosis of aminoglycoside-induced nephrotoxicity and ototoxicity and the clinical significance of these adverse reactions. The review also focuses on the practical and economic issues surrounding therapeutic drug monitoring practices. We conclude that aminoglycoside antibiotics remain an effective and economical form of therapy for severe infections and that if careful criteria are used in the selection of these agents, the benefits of therapy outweigh the risk of toxicity.

Effects of treatment and the metabolic response to injury on drug clearance: a prospective study with piperacillin.

The disposition of piperacillin was prospectively evaluated in 11 critically ill surgical patients who had no evidence of pre-existing renal and hepatic disease. Interpatient variations were demonstrated in the drug's half-life, distribution volume, and clearance, with values of 1.50 +/- 2.05 (SD) h, 25.0 +/- 17.2 L, and 23.8 +/- 17.2 L/h, respectively. Variations in piperacillin disposition were best explained by serum concentrations of albumin, total protein, and bilirubin, and the amount of urea nitrogen excreted daily in urine. Age and renal function were moderately associated with piperacillin elimination rate and clearance. Altered piperacillin disposition thus appeared to occur as secondary to changes in the patients' physiologic and metabolic state caused by injury-related stress and fluid/colloid therapy. These alterations may necessitate dosage modifications to achieve optimal patient response when treating patients with piperacillin as well as with other similar drugs eliminated via renal and nonrenal routes.

Protamine sulfate and fatal anaphylactoid shock.

A 73-year-old male underwent uneventful three-vessel coronary artery bypass grafting after which he received iv protamine sulfate for reversal of systemic heparinization. Shortly thereafter, the patient developed and succumbed to an anaphylactoid reaction attributed to protamine. The patient had none of the previously reported risk factors for hypersensitivity to the drug and was therefore not considered at high risk for such a severe adverse reaction. Although uncommon, the fatal outcome of this low-risk patient seriously addresses the need for alternative measures for heparin reversal.

Sustained-release diltiazem compared with atenolol monotherapy for mild to moderate systemic hypertension.

The daily administration of 240 to 360 mg of diltiazem lowered blood pressure in a dose-related pattern similar to that seen in patients taking a daily dosage of 50 to 100 mg of atenolol. Sustained-release diltiazem was administered twice daily and atenolol once. Goal blood pressure was defined as less than 90 mm Hg or a reduction of greater than or equal to 10 mm Hg for patients with baseline pressures of 95 to 99 mm Hg in the supine position and was achieved in 60% of diltiazem-treated and 63% of atenolol-treated patients. The mean diltiazem dosage at the end of the study was 329 mg daily; for atenolol it was 80 mg daily. Adverse reactions considered possibly or probably drug related were reported by 26% of diltiazem patients and 38% of atenolol patients. Although both drugs were associated with a slower heart rate, atenolol patients showed a significantly greater negative chronotropic effect. Diltiazem, in a sustained-release form taken twice daily, is as effective as atenolol as a sole antihypertensive agent. It has a favorable side-effect profile and may be a useful alternative antihypertensive medication compared with existing beta-blocker therapy with atenolol.

Relationship between intensity of hospital services and pharmacy workload.

The relationship between hospital census variables and pharmacy department workload was studied; intensity, which measures services provided per hospitalized patient per day, was used as the workload indicator. Quarterly data on inpatient pharmacy workload and hospital census were statistically analyzed for 1981 through 1985. Number of patient days, number of admissions, average length of stay (LOS), and pharmacy work units were examined. A work unit was one unit of inpatient pharmacy activity, such as one order for oral medication or one i.v. admixture; clinical services were excluded. Intensity was defined as the number of work units per patient day. Intensity as a function of intensive-care-unit (ICU) patient days was also analyzed. The number of pharmacy work units per quarter more than doubled from 1981 to 1985, while the number of admissions remained relatively constant. The average LOS decreased from 8.4 days in 1981 to 6.3 days in 1985, and the number of patient days decreased 27%. Quarterly workload intensity increased from 1.4 to 4.37 over the five-year period. Statistical analysis showed a strong inverse relationship between intensity and average LOS; LOS accounted for 92% of the variability in intensity. The number of ICU patient days, which increased 21%, had a significant effect on pharmacy workload; 30% of the variation in pharmacy workload was explained by ICU days. Intensity measures are useful in predicting pharmacy department workload.

Increased dosage requirements of tobramycin and gentamicin for treating Pseudomonas pneumonia in patients with cystic fibrosis.

The pharmacokinetic behavior of tobramycin and gentamicin was evaluated in 27 patients who had cystic fibrosis (CF). A previously studied, age-matched group of 334 patients who had been treated with gentamicin and who did not have CF served as controls. The CF patients, who ranged in age from 2 to 32 years and who had normal renal function, received 36 treatment courses with either tobramycin (19) or gentamicin (17) to treat Pseudomonas pneumonia. Serum concentrations were determined after a 1.5-mg/kg dose to compute half-life (t 1/2), elimination rate constant (k), and apparent volume of distribution (V). From these values, doses were calculated to produce steady-state peak concentrations of 8.0 micrograms/ml with a dosing interval of every six hours. For tobramycin the mean (+/- SD) t1/2 was 1.0 (0.4) hours, V was 0.18 (0.06) l/kg, total body clearance (TBC) was 2.19 (0.71) ml/min/kg, and the calculated dose was 8.2 (2.1) mg/kg/day. For gentamicin t1/2 was 1.1 (0.5) hours, V was 0.20 (0.06) l/kg, TBC was 2.28 (0.89) ml/min/kg, and the calculated dose was 8.8 (2.4) mg/kg/day. The pharmacokinetic parameters were not statistically different between the two drugs, but the mean values of t1/2 and TBC of CF patients differed significantly from those of the control group. The calculated doses were larger than the manufacturer's maximum recommended dose of 7.5 mg/kg/day for 63% of tobramycin and 71% of gentamicin treatment courses. A dosing interval change to every four hours would have been appropriate in 28 of the 36 treatment courses (78%).(ABSTRACT TRUNCATED AT 250 WORDS)

Theophylline therapy. Titrating dosage requirements.

Theophylline has long been a cornerstone of bronchodilator therapy for asthma and chronic obstructive lung disease, but until recently its use carried the risk of serious, even fatal, toxicity. With recent advances in understanding of this drug's pharmacologic properties and pharmacokinetic characteristics, serious toxicity now can usually be avoided. The dosage requirements for theophylline demonstrate wide interpatient and intrapatient variation. Several factors responsible for this variation, most notably age, have been identified and used in definition of dosage guidelines for different patient groups. However, substantial variation still exists within these groups, necessitating measurement of serum concentration in selected patients. The measurements obtained are used to titrate the patient's dosage requirement in such a way as to maximize therapeutic response while minimizing risk of toxicity.

Aminoglycoside therapy. Improving patient response and safety.

The aminoglycosides have long been effective antibiotics in treatment of serious gram-negative infections. However, ototoxicity and nephrotoxicity have been of major concern because of the narrow therapeutic range of these agents and the wide variability in pharmacokinetics among patients. With recent advances in aminoglycoside monitoring techniques, the risk of toxicity has been greatly reduced. Automated methods are now available to quickly and precisely measure aminoglycoside concentration in serum, and by applying pharmacokinetic principles to serum concentration-time data, the clinician can readily calculate the correct dosage for each patient. Programs for computers and programmable calculators, also now available, can assist in these calculations.

Determination of theophylline bioavailability using saliva theophylline concentrations.

Substantial error occurs when individual saliva theophylline concentrations are used to predict serum theophylline concentrations. However, the use of saliva theophylline concentrations to determine product bioavailability has never been evaluated. Subjects in this study were 18 stable patients (20-51 yr) with a history of chronic obstructive pulmonary disease. Three preparations--a capsule (Elixophyllin 400 mg), elixir (Elixophyllin 373 mg), and tablet (Theolair 375 mg)--were administered in a randomized crossover design. Serum and saliva samples were obtained pre-dose and 0.25, 0.5, 1, 2, 4, 6, and 8 hours after theophylline administration. The saliva AUC0-infinity and serum AUC0-infinity were highly associated for the elixir (r = 0.84) tablet (r = 0.89), and capsule (r = 0.89). The bioavailability of the tablet and capsule calculated from elixir saliva and elixir serum AUC0-infinity were not significantly different (p = 0.2). The bioavailability of the tablet calculated from saliva and serum was 93% and 102%, respectively. The bioavailability of the capsule calculated from saliva and serum was 113% and 102% respectively. Our data suggests that theophylline bioavailability can be reliably estimated from saliva theophylline concentrations. However, study designs that include larger sample sizes and more frequent sampling may be necessary when determining bioavailability from saliva.

Clinical use of a one-compartment model for determining netilmicin pharmacokinetic parameters and dosage recommendations.

To determine netilmicin pharmacokinetic parameters and to evaluate the use of a one-compartment pharmacokinetic model, 32 patients receiving netilmicin for suspected gram-negative sepsis were enrolled in our study protocol. Dose and dosage interval for each patient were determined by one-compartment pharmacokinetic analysis of six postinfusion netilmicin serum samples (0.16, 0.33, 0.5, 1, 2, and 3 h) measured by radioimmunoassay. In patients with a normal serum creatinine, mean (+/- SD) half-life and distribution volume were 1.9 +/- 1.1 h and 0.2 +/- 0.8 L/kg, respectively. The average daily dose and mean days of therapy were 5.1 +/- 1.9 mg/kg/day for 7.3 +/- 2.8 days. Serum creatinine changes of greater than 0.5 mg% occurred in 2 of 28 (7%) patients. Substantial variability in half-life and distribution volume occurred in patients. Initial dosages of 5-7 mg/kg/day in divided dosages seem appropriate for adult patients with normal renal function. Monitoring of serum levels and adjustment of dose and dosage interval are necessary to maintain therapeutic antibiotic concentrations. As with other aminoglycosides, the one-compartment pharmacokinetic model proved to be an acceptable method for measuring netilmicin pharmacokinetic parameters and individualizing therapy.

Wide interpatient variations in gentamicin dose requirements for geriatric patients.

Substantial interpatient variations were demonstrated in the daily doses required to obtain therapeutic gentamicin sulfate serum concentrations in 417 elderly patients. Dosages ranged from 0.3 to 22.0 mg/kg/day in patients with a normal serum creatinine level. Twenty-five percent of these patients required daily doses higher than the standard regimen of 5 mg/kg/day, and 33% required less than 3 mg/kg/day. The drug half-lives in these patients ranged from 0.3 to 32.7 hours, compared with previous reports of 2.5 to four hours. The distribution volumes of these patients ranged from 0.07 to 0.53 L/kg, compared with reported values of 0.20 to 0.25 L/kg. These wide variations in kinetic variables in elderly patients and the need to obtain narrow ranges in serum concentrations required measuring serum concentrations and individually calculating each patient's dosage requirement early in the treatment course. Doing this consistently produced optimal peak and trough serum levels. Ototoxicity did not occur in any of the patients, and nephrotoxicity may have been drug related in 2% of the elderly patients.

Gentamicin dosing errors with four commonly used nomograms.

Four methods for calculating gentamicin sulfate dosage requirements were evaluated in 96 patients and compared with an individualized method. The pharmacokinetic parameters of gentamicin were determined from serum concentration time data and used to calculate individualized dosage regimens. Doses were determined in each patient using the "predictive methods" (Sarubbi-Hull, Dettli, "rule of eights," and Chan). Resultant serum concentrations were calculated from doses arrived at by each method. These dosing methods resulted in a large proportion of patients with subtherapeutic or potentially toxic concentrations, or both. The Dettli and Chan methods produced therapeutic concentrations in more patients than the Sarubbi-Hull and rule of eights methods. Desired therapeutic concentrations were attained in significantly more patients with the individualized method than with the predictive methods, and, in addition, larger doses were required. The use of predictive dosage methods should be followed with serum concentration determinations and dosage adjustment to ensure therapeutic concentrations early in treatment.