Kinetic model for gentamicin dosing with the use of individual patient parameters.

Multiple-infusion dosing regimens for gentamicin were established for 84 patients with the use of individually calculated values of elimination kinetic parameters. Serum level-time data obtained after a single infusion were used to determine the patient's gentamicin half-life (t 1/2) and distribution volume. Patients with serum creatinine (Cr) less than 1.2 mg per 100 ml had t 1/2 (mean, 2.25 hr) and total body clearances (mean, 0.082 L/hr/kg) significantly different from those with Cr greater than or equal to 1.2 mg/100 ml (means, 5.3 and 0.039, respectively). Distribution volumes were not significantly different (means, 0.22 and 0.21 L/kg, respectively). Calculations of dosing intervals and infusion rates, based on each patient's kinetic parameters and desired steady-state peaks and nadirs, assumed a one-compartment model with first-order elimination and 1-hr constant-rate input at fixed intervals. Follow-up steady-state peak and nadir levels were measured in 63 of the regimens. Differences between predicted and measured peak levels averaged --0.05 mug/ml with 60% of the measured values falling within 1 mug/ml of that predicted. Predicted-measured nadir differences averaged --0.62 mug/ml (significantly different from zero) indicating slight bias in the model. Fifty-six percent of these nadirs were within 1 mug/ml of that predicted.

The necessity of increased doses of amikacin in burn patients.

Extended periods (6 to 9 hours) of subtherapeutic serum amikacin levels were observed in five burn patients receiving the recommended intravenous dose of 7.5 mg/kg every 12 hours. Kinetic studies revealed an unusually short half-life, especially in younger patients. This more rapid elimination necessitated a shorter dosing interval (every 6 hours), resulting in an increased daily dose (30 mg/kg/day). In this study of 10 patients with normal renal function, an intravenous dosage regimen of 7.5 mg/kg every 6 hours resulted in therapeutic peak concentrations and shortened intervals of subtherapeutic serum concentrations. A transient episode of tinnitus without cochlear damage occurred in one patient after the first dose. Neither ototoxicity nor nephrotoxicity occurred in any of the patients. Because of interpatient variability in amikacin elimination, frequent monitoring of serum levels with necessary dosage changes is imperative to provide optimal serum concentrations. However, it must be emphasized that these increased dosage regimens of amikacin are not suggested for routine use without previously measuring serum levels.

Acute reversible renal failure following jejunoileal bypass for morbid obesity: a clinical and pathological (EM) study of a case.

A patient who underwent jejunoileal bypass for morbid obesity developed servere renal failure associated with hyperoxaluria and renal oxalosis. Renal function improved and oxalate excretion decreased following hemodialysis and restoration of gastrointestinal continuity.

The mortality associated with pelvic fractures.

The mortality among 604 patients with pelvic fractures was 12%. Pedestrian accidents were the etiologic agent in 27% of the patients, but accounted for 49% of the deaths and for 73% of the deaths primarily due to pelvic fractures. Although 71 of the 72 patients who died sustained concomitant major injuries (mean, 3.1), 60% of the deaths (43 patients) were attributed entirely or in part to pelvic fractures. Of particular interest were the 26 patients in whom the pelvic fracture was the primary cause of death. Ninety-three percent were in shock or had clinical evidence of hypovolemia at the time of admission. Eighteen patients (69%) exsanguinated from their pelvic fractures shortly after hospital admission (mean, 9 hours). They were more elderly than the eight patients who survived their initial resuscitation, but subsequently died of sepsis or of renal failure (mean, 62 vs. 38 years). Sepsis arising in the pelvic hematoma and acute renal failure induced by pelvic hemorrhage and/or pelvic sepsis each accounted for 15% of the deaths. Ninety-one percent of the patients who died primarily of their pelvic fracture had a single or double break in the pelvic ring. Thirty-one precent had open pelvic fractures, and injury associated with a 50% mortality. Twenty-three percent had pelvic fracture related iliac or femoral vessel disruptions, an injury associated with a 75% mortality. Mortality in these patients clearly resulted from ineffective control of pelvic hemorrhage and from the inability to prevent sepsis in the pelvic hematoma.

Increased burn patient survival with individualized dosages of gentamicin.

The clinical effect of measuring serum gentamicin concentrations and individualizing each patient's dosage regimen was determined 105 burn patients with severe gram-negative sepsis. Thirty-nine patients (conventionally dosed group) received the recommended dosage regimen of 3 to 5 mg/kg/day from 1972 to 1974. From 1974 to 1976, serum concentrations were measured in 66 patients (individually dosed group), and each patient's dose was individually calculated to obtain therapeutic serum concentrations. All patients had normal renal function prior to initiation of gentamicin therapy. For each group, 16 independent variables were compared that may have influenced treatment response. The patients in the individually dosed group required an average dose of 7.4 mg/kg/day to achieve therapeutic concentrations, compared to the average dose of 4.4 mg/kg/day for the patients receiving conventional doses (P less than 0.001). An abrupt increase in patient survival occurred with the implementation of individualized regimens. Patient survival rates for the entire hospital course were 33% and 64% for the conventionally dosed and individually dosed groups, respectively (P less than 0.005). Survival rates for the first septic episode were 51.3% and 86.4%, respectively (P less than 0.001). Individualized gentamicin regimens, age, percent burn, and sex were the statistically significant variables related to patient survival for the first episode of sepsis. Age, percent burn, individualized dosing, complications during hospitalization, and a positive blood culture were significant factors related to patient survival for the entire hospital course. These data confirm the need for measuring serum gentamicin concentrations and adjusting dosages to ensure therapeutic levels and maximal efficacy of gentamicin in burn patients.

Rapid gentamicin elimination in obstetric patients.

Wide interpatient variation in gentamicin elimination rates and dosage requirements was demonstrated in 67 obstetric patients with normal serum creatinine levels. A poor correlation occurred between the elimination rate of gentamicin and creatinine clearance (r = .23). A higher correlation was found between the drug's elimination rate and distribution volume (r = -.62), which suggests that the changing fluid status associated with pregnancy affects the kinetic parameters of gentamicin. Gentamicin dosage regimens were systematically calculated for each patient from serum concentration-time data to obtain desired serum levels. These individualized regimens demonstrated considerable variability, ranging from 3.0 to 11.6 mg/kg/day. Clinical ototoxicity and nephrotoxicity were not observed. Because of the wide interpatient variation, these increased dosages are not routinely suggested unless serum concentrations are previously measured and each patient's regimen is calculated. These results emphasize the need to measure serum concentrations and make necessary dosage adjustments to ensure therapeutic levels in obstetric patients.

Ecthyma gangrenosum: survival with individualized antibiotic therapy.

Five burn patients with ecthyma gangrenosum were treated with gentamicin sulfate in an individualized aminoglycoside regimen. Dosages greater than the currently recommended 3 to 5 mg/kg/day were necessary and ranged from 15 to 30 mg/kg/day. These increased dosages cannot be used routinely but only as serum level data indicate the need. Four of the five patients survived their course of ecthyma gangrenosum. The single fatality received a much smaller dosage of gentamicin as compared with the other four patients. No ototoxic or nephrotoxic reactions were noted in any of the patients.

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.

Systematically individualizing tobramycin dosage regimens.

Tobramycin dosage regimens were individually calculated from serum concentration-time data in 64 patients. Tobramycin pharmacokinetic parameters and dosage requirements demonstrated wide interpatient variation. The tobramycin half-life varied from 0.5 to 8.6 hours in patients with normal serum creatinines. The mean (+/- S.D.) distribution volume was 0.22 (+/- 0.09) liter/kg for all patients. Dosage requirements were higher for the younger patients, however, considerable variability existed within age groups. In patients with normal serum creatinines, an 8-hour dosing interval was optimal in only 17 of the 46 patients. A multiple regression model using age, weight, and creatinine clearance could explain only 44.2% of the variance in tobramycin clearance. Measured steady-state peak and trough concentrations compared favorably with desired peak and trough concentrations. The mean (+/- S.D.) desired peak was 7.2 (+/- 1.8) microgram/ml, and the mean (+/- S.D.) measured peak was 7.1 (+/- 2.0) microgram/ml. The mean (+/- S.D.) desired trough was 1.1 (+/- 0.9) microgram/ml, and the mean (+/- S.D.) measured trough was 1.3 (+/- 0.8) microgram/ml. Many patients required dosage regimens exceeding those commonly recommended; however, no cases of ototoxicity or nephrotoxicity were encountered. This model proved successful in calculating dosage regimens of tobramycin to obtain optimal serum concentrations.

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.

The emergency management of trauma.

For effective care, the severely injured patient may require the cooperative effort of many physicians and paramedical personnel. In the individual with isolated maxillofacial injury, adequate management may be provided by one or several specialists. In any event, there should be a plan for emergency, semiurgent, and delayed treatment. It is also important for each individual caring for the patient to understand and appreciate the problems within and outside his area of expertise. There is a logical progression of evaluation, with particular attention to the more severe and significant area of trauma. Hemmorrhage, shock, and airway problems take priority. Often the definitive treatment, from a cosmetic and functional standpoint, is delayed.

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.

The transparent face mask.

Fabrication of an accurate transparent mask for total contact pressure to the healed burned face proved helpful in controlling scarring. Wearing the mask for 20 hours daily, secured by elastic straps giving 35-mmHG pressure to the scar, can prevent the original facial contours from being distorted by contracting scar tissue.

Blunt injury to the colon and rectum.

One hundred nine patients suffering blunt injury to the colon or rectum were treated between 1 January 1970 and 31 December 1980. Vehicular accidents accounted for 90% of the injuries and 91% of the fatalities. Multiple system injury predominated, with survivors averaging 1.9 and nonsurvivors 3.8 injuries/patient. Six cases were complicated by abdominal sepsis directly related to their colon injury. There were no deaths and no episodes of colon-related abdominal sepsis among patients with isolated colon trauma. Of the 32 patients not surviving, four (3.7%), died as a direct result of their colon injury. Three of the four deaths appear to have been preventable.

Antacid therapy and nutritional supplementation in the prevention of Curling's ulcer.

The incidence of clinically evident Curling's ulcer among 109 potentially salvageable severely burned patients was reviewed. These patients, who had greater than a 40 per cent body surface area burn, received one of these three treatment regimens: antacids hourly until autografting was complete, antacids hourly during the early postburn period followed by nutritional supplementation with Vivonex until autografting was complete or no antacids during the early postburn period but subsequent nutritional supplementation with Vivonex until autografting was complete. Clinically evident Curling's ulcer occurred in three patients. This incidence approximates the lowest reported among severely burned patients treated prophylactically with acid-reducing regimens to minimize clinically evident Curling's ulcer. In addition to its protective effect on Curling's ulcer, Vivonex, when used in combination with a high protein, high caloric diet, meets the caloric needs of the severely burned patient. Probably, Vivonex, which has a pH range of 4.5 to 5.4 protects against clinically evident Curling's ulcer by a dilutional alkalinization of gastric secretion.

Brachial artery disruption following closed elbow dislocation.

Although elbow dislocation occurs frequently, associated brachial artery injury is rare. Adequate treatment of this injury includes prompt arteriography, reduction of the dislocation, vascular repair, and transarticular fixation of the reduction. A case report and review of the literature are presented.

The natural history of electrical injury.

The natural history of electrical injury, exclusive of electrical flash burns, was determined in 64 patients. These patients sustained relatively small burns (x=11%); only nine patients (14%) had burns greater than 25%. Forty-six patients suffered 114 major complications. EKG abnormalities occurred in 36%, including major cardiac arrhythmias in ten patients. One-fourth of the patients developed neurologic sequelae (CNS-8, peripheral-8). Electrical vascular injury with subsequent arterial occlusion was responsible for many of the major amputations. Nineteen patients required 32 amputations (digits-17, hand-1, foot-2, leg-3, arm-9). Early patient referral and vigorous fluid resuscitation minimized renal failure (1.5%) and mortality (3.1%). Early fasciotomy and vigorous debridement appeared to decrease wound sepsis (8%), but apparently had little if any effect on major limb salvage. The unsolved problems of electrical injury, namely neurological and vascular sequelae, are major contributors to the high morbidity of electrical injury.

Laser Doppler flowmetry and cardiac output in critically ill surgical patients.

Laser Doppler flowmetry (LDF) accurately measures cutaneous microcirculatory blood flow. We compared change in LDF flow to change in thermodilution cardiac output in ten critically ill surgical patients. A subset analysis of three patients with low cardiac output (cardiac index less than 2 L/min X m2) showed no correlation. We conclude that, under these study conditions, LDF microcirculatory flow did not reflect macrocirculatory flow. We conjecture that overcoming cutaneous vasoregulation with thermal vasodilation may obviate these results.