Andrew D. Blair

Neurologic outcome and blood glucose levels during out‐of‐hospital cardiopulmonary resuscitation

We examined the interrelations of outcome, time elapsed during cardiopulmonary resuscitation (CPR), and blood glucose levels drawn from 83 patients with out-of-hospital cardiac arrest. Levels rose significantly during CPR. Although slope and intercept of regression lines differed for those dying in the field and those admitted, regression lines were similar for those who awoke and never awoke after admission. These results suggest that the previously reported association between poor neurologic recovery and high blood glucose level on admission after cardiac arrest is best explained by prolonged CPR, leading to both higher rise of blood glucose and worse neurologic outcome.

Clinical pharmacokinetics of frusemide.

SummaryFrusemide is an anthranilic acid derivative that is pharmacologically more potent than organomercurial agents in producing natriuresis and is effective when taken orally even in acid-base disorders or advanced renal failure. The bioavailability of commercially prepared tablets is comparable to an aqueous solution of frusemide. In healthy subjects the range of oral absorption is 60 to 69%. In patients with end-stage renal disease (ESRD), absorption is reduced to values between 43 and 46%. Food decreases the rate of absorption but does not affect bioavailability. Chronic phenytoin therapy, however, does reduce bioavailability to about the level of ESRD.Plasma protein binding in healthy subjects has been demonstrated to be between 91 and 99%. Frusemide is almost exclusively bound to albumin and it competes for binding sites with other acidic drugs. In patients with reduced plasma albumin concentration or azotaemia, frusemide binding is reduced.The mean apparent volume of distribution in the steady-state ranges from 0.07 to 0.18L/kg body weight in healthy adults. It may be modestly increased in adults with cardiac failure, but is very large in neonates with fluid overload. After intravenous injection, intact frusemide is the major urinary product in the first 4 hours. After this time, frusemide glucuronide and the free amine metabolite are also found. In healthy subjects, between 6 and 18% of an intravenous dose is found in the faeces. However, in renal failure, this is increased to 60% of the injected dose.Although apparently secreted by proximal portions of the nephron, frusemide has its principal action on the luminal surface of the ascending limb of Henle’s loop. In this segment it exerts an inhibitory action on active chloride, thus producing a saluresis of both sodium and chloride. Probenecid substantially reduces the renal secretion of frusemide and the plasma clearance, and prolongs the half-life of the drug without impairing its natriuretic effect.Frusemide plasma clearance is greater than the creatinine clearance except in ESRD where it tends to be about 50% of the measured value. Elimination half-lives of 19 to 100 minutes are reported in healthy subjects but may be 8 to 15 hours in ESRD. In patients with both hepatic and renal insufficiency, reported half-lives were 11 to 20 hours. In neonates elimination half-lives of 7 to 8 hours have been reported apparently due to very large distribution volumes as well as low renal and hepatic clearance.Although the natriuretic effect of frusemide is variable and apparently dependent on the state of sodium reabsorption at the site of drug action, it appears that the saluretic response is more closely correlated with the urinary concentration of frusemide than with the plasma level. If the salt and water balance is maintained, a sigmoid-shaped dose-response curve is observed. From a therapeutic viewpoint, the maximum response with the least amount of drug would occur if the urinary excretion of frusemide were on the ‘steep’ portion of the curve. This concept has been applied in several clinical studies and probably explains the greater natriuresis seen when a divided oral dose regimen is given or small continuous infusions have been used.

Flucytosine kinetics in subjects with normal and impaired renal function

Kinetics and bioavailability of flucytosine were studied in 5 subjects with normal renalfunction. Kinetic parameters and absorption were compared after a 500‐mg dose administered in the following manner: intravenously, aqueous solution, and capsules while fasting; capsules after meals; and capsules with antacid. Encapsulation, food, and antacid decreased the absorption rate constant but the total amount absorbed orally did not differ significantly. Bioavailability assessed by the urinary recovery or comparison of the AUCo to AUCiv on the average showed 76% to 89% oral absorption. In 3 patients on hemodialysis, the serum concentrations in the β‐phase following oral flucytosine in capsules during fasting were in the same range as those after a comparable intravenous dose. The mean steady‐state distribution volume (Vdss) was 0.679 L/kg in normal subjects and ranged between 0.413 and 0.706 L/kg in 9 patients with renal failure. The mean t½β was 4.2 hr in normal subjects and the renal clearance was comparable to creatinine clearance. In renal failure, a linear regression analysis showed the t½β (hr) to be numerically about 5 times the steady‐state serum creatinine concentration (mg/dl). Under the conditions of the study, hemodialyzer clearance of flucytosine was rapid and similar to creatinine hemodialyzer clearance. Computer simulation based on the measured pharmacokinetic parameters demonstrated that a loading dose (20 mg/kg) after dialysis should result in therapeutic plasma concentrations for susceptible organisms and avoid toxic levels.

Inhibition of Renal Creatinine Secretion by Cimetidine in Humans

The renal clearance of inulin (Clin), 14C-creatinine (Cl14C.cr) and endogenous creatinine (Clcr) were measured in 6 healthy subjects before and a

Sotalol kinetics in renal insufficiency.

Kinetics of sotalol, a beta adrenoceptor blocker, was studied in 20 patients with varying renal function. In subjects with creatinine clearance (Clcr) ≥ 39 ml/min/m2, sotalol plasma clearance (x̄ ± SD) was 71 ± 31 ml/min/m2, elimination half‐life (t½) was 8.1 ± 3.4 hr, and renal clearance was 46 ± 26 ml/min/m2. In patients with moderate renal impairment (Clcr = 8 to 38 ml/min/m2) elimination t½ rose to 24.2 ± 7.5 hr, and plasma clearance fell to 24 ± 7 ml/min/m2. In patients receiving dialysis, elimination t½ rose to 33.9 ± 27.1 hr. Elimination t½ during hemodialysis was 5.8 ±2.1 hr and was associated with a 56.7 ± 21% reduction in plasma levels.

Hemodialyzer clearances of gentamicin, kanamycin, tobramydn, amikacin, ethambutol. procainamide, and flucytosine, with a technique for planning therapy

Hemodialyzer clearance studies have been undertaken on the following drugs: gentamicin, kanamycin, tobramycin, amikacin, ethambutol, procainamide, and flucytosine. The following hemodialyzers were tested: Dow model 4, Kiil, Travenol UF II, and the Extracorporeal EX-03. The studies were predominantly undertaken in vitro,permitting direct comparison between drug clearances on the same dialyzer. Protein binding studies for gentamicin, kanamycin, procainamide, and ethambutol are also reported. Nomograms to facilitate the prediction of drug dosage regimens in dialysis patients are included.

Effect of Hemodialysis on the Pharmacokinetics of Theophylline in Chronic Renal Failure

We studied theophylline elimination in 8 patients with chronic renal failure to determine the effect of hemodialysis on the pharmacokinetics of theophylline. Each subject was studied twice, once on a nondialysis day and again during dialysis. Total body theophylline clearance on the nondialysis day was similar to that reported for patients with normal renal function (57.4 +/- 27.2 ml/kg/h). Hemodialysis accelerated theophylline elimination and shortened serum theophylline half-life in all patients (nondialysis t 1/2 = 7.3 h +/- 2.3 vs. dialysis t 1/2 = 2.7 +/- 0.9 h, p less than 0.01). Dialysis clearance averaged 59.7 +/- 16.4 ml/kg/h with a fraction of drug removed of 0.4 liters in 4 h. Guidelines for theophylline management during hemodialysis are suggested.

Nephrotoxicity: A comparison in humans of gentamicin and gentamicin C1 administration

Abstract The relative nephrotoxicities of the gentamicin complex (Garamycin) and gentamicin C 1 were studied using “acute” (intravenous infusion, five normal renal function subjects) and 3-day (multiple injections for 3 days, five normal renal function subjects) administration of the drug. Inulin, creatinine, and para -aminohippurate (PAH) clearances, renal concentrating capacity, urinary alkaline phosphatase, N -acetyl-β- d -glucosaminidase and β-glucuronidase enzyme excretions, and quantitative urinary sediment counts were measured before and during treatment. Although transient elevations of urinary enzymes occurred with both drugs, these were judged neither excessive nor abnormal. Renal function indicators showed no change after drug administration and there were no significant differences between drugs. Also, urinary sediment showed no changes from normal, and the gentamicin C 1 administration was not significantly different from results after gentamicin complex administration. By the presently rather imprecise criteria defining the lower limits of nephrotoxicity, neither drug when administered by the present recommendations for the upper dose limits for therapy with gentamicin complex was shown to be toxic. The 3-day multiple-dosing schemes for both drugs results in a total dose comparable to chronic dosing for 7–10 days at more usual doses and were judged to be comparable.

Gentamicin and tobramycin kinetics

Eighty‐two hospitalized adult patients were randomized to treatment with gentamicin or tobramycin. Serum levels were compared to computer‐derived mathematically predicted levels to evaluate predictability of gentamicin and tobramycin serum levels. When comparable dosages were used mean peak gentamicin levels (4.87 μg/ml) did not differ from those after tobramycin (4.31 μg/ml). Seventy‐three percent of patients had peak levels after gentamicin >4.0 μg/ml compared to 46% after tobramycin. Factors purported to influence predictability of aminoglycoside serum levels were examined. In 46 of 74 patients whose actual body weight was 10 to 35 kg less than estimated ideal body weight levels after both drugs were lower than predicted. Serum levels were also lower than predicted in 7 of 11 patients with ascites, 6 of 7 patients receiving carbenicillin therapy, and 17 of 29 patients who had pneumonia. Neither hematocrit nor temperature appeared to influence predictability of serum levels. A comparison of methods used to obtain computer‐derived predicted levels showed that ideal body weight provided the most accurate prediction. Differences between predicted and measured levels were established when calculations were based on actual body weight (P = 0.009) or on surface area (P = 0.003 for peak and 0.023 for trough levels).

Cefadroxil kinetics in patients with renal insufficiency

SummaryKinetic parameters and bioavailability of cefadroxil were studied in 20 subjects with differing renal function as measured by endogenous creatinine clearance (CCr). Two subjects were on hemodialysis. After an overnight fast, each subject ingested two 500-mg capsules of cefadroxil. The peak serum concentration was variable (12 to 57 mg/l) and correlated inversely with the CCr. All but one patient had maximum absorption within 4 hr of ingestion and in most patients the peak was reached within the 2-hr sample. Urinary recovery within 48 hr was 45% to 106% when CCr > 8 ml/min. Even in patients with the most severe renal failure (CCr < 10 ml/min), urine concentrations of cefadroxil were adequate to treat susceptible bacteria. The rate of oral absorption, ka, was not affected by the state of renal function and was 0.76 ± 0.50 hr−1. The apparent distribution volume Vd ext was 0.28 ± 0.09 l/kg. The plasma elimination rate was dependent on CCr with a small fraction of drug being removed by nonrenal routes. Except in advanced renal failure, tubular secretion was present since renal clearance of cefadroxil exceeded CCr. The data suggest that little drug accumulation will occur with the usual 8- to 12-hr dosing schedule except when the CCr is less than 25 ml/min.ZusammenfassungCefadroxil-Kinetik bei Patienten mit Niereninsuffizienz. Die kinetischen Parameter und Bioverfügbarkeit von Cefadroxil wurden an 20 Personen mit unterschiedlicher Nierenfunktion, gemessen an der endogenen Kreatinin-Clearance (Ccr), bestimmt. Zwei Personen standen unter Hämodialyse. Nach Fasten über Nacht nahm jede Person zwei 500-mg-Kapseln Cefadroxil ein. Die Serumspitzenkonzentration variierte (zwischen 12 und 57 mg/l) und stand in umgekehrter Korrelation zur CCr. Bis auf einen Patienten fand in allen Fällen die maximale Absorption innerhalb der ersten vier Stunden nach Einnahme statt, und bei den meisten Patienten wurde das Maximum bei der 2-Stunden-Probe erreicht. Die Urin Recovery innerhalb 48 Stunden betrug 45% bis 106%, wenn die CCr > 8ml/min war. Sogar bei Patienten mit schwerster Nierenfunktionseinschränkung (CCr < 10 ml/min) reichte die Urinkonzentration für die Behandlung empfindlicher Bakterien aus. Die orale Absorptionsrate ka wurde durch den Zustand der Nierenfunktion nicht beeinflußt und betrug 0,76 ± 0,50 h−1. Das Verteilungsvolumen Vd ext betrug 0,28 ± 0,09 1. Die Plasmaeliminationsrate stand in Abhängigkeit von CCR, nur ein kleiner Anteil des Medikaments wurde auf extrarenalem Wege ausgeschieden. Außer in Fällen von fortgeschrittenem Nierenversagen fand eine tubuläre Sekretion statt, denn die renale Clearance von Cefadroxil überstieg die CCr. Die Werte lassen annehmen, daß es nur zu einer geringen Kumulation des Medikaments bei dem gewöhnlichen Dosierungsschema von 8–12stündlicher Verabreichung kommt, ausgenommen, die CCr unterschreitet 25 ml/min.Kinetic parameters and bioavailability of cefadroxil were studied in 20 subjects with differing renal function as measured by endogenous creatinine clearance (CCr). Two subjects were on hemodialysis. After an overnight fast, each subject ingested two 500-mg capsules of cefadroxil. The peak serum concentration was variable (12 to 57 mg/l) and correlated inversely with the CCr. All but one patient had maximum absorption within 4 hr of ingestion and in most patients the peak was reached within the 2-hr sample. Urinary recovery within 48 hr was 45% to 106% when CCr > 8 ml/min. Even in patients with the most severe renal failure (CCr < 10 ml/min), urine concentrations of cefadroxil were adequate to treat susceptible bacteria. The rate of oral absorption, ka, was not affected by the state of renal function and was 0.76 ± 0.50 hr−1. The apparent distribution volume Vd ext was 0.28 ± 0.09 l/kg. The plasma elimination rate was dependent on CCr with a small fraction of drug being removed by nonrenal routes. Except in advanced renal failure, tubular secretion was present since renal clearance of cefadroxil exceeded CCr. The data suggest that little drug accumulation will occur with the usual 8- to 12-hr dosing schedule except when the CCr is less than 25 ml/min. Cefadroxil-Kinetik bei Patienten mit Niereninsuffizienz. Die kinetischen Parameter und Bioverfügbarkeit von Cefadroxil wurden an 20 Personen mit unterschiedlicher Nierenfunktion, gemessen an der endogenen Kreatinin-Clearance (Ccr), bestimmt. Zwei Personen standen unter Hämodialyse. Nach Fasten über Nacht nahm jede Person zwei 500-mg-Kapseln Cefadroxil ein. Die Serumspitzenkonzentration variierte (zwischen 12 und 57 mg/l) und stand in umgekehrter Korrelation zur CCr. Bis auf einen Patienten fand in allen Fällen die maximale Absorption innerhalb der ersten vier Stunden nach Einnahme statt, und bei den meisten Patienten wurde das Maximum bei der 2-Stunden-Probe erreicht. Die Urin Recovery innerhalb 48 Stunden betrug 45% bis 106%, wenn die CCr > 8ml/min war. Sogar bei Patienten mit schwerster Nierenfunktionseinschränkung (CCr < 10 ml/min) reichte die Urinkonzentration für die Behandlung empfindlicher Bakterien aus. Die orale Absorptionsrate ka wurde durch den Zustand der Nierenfunktion nicht beeinflußt und betrug 0,76 ± 0,50 h−1. Das Verteilungsvolumen Vd ext betrug 0,28 ± 0,09 1. Die Plasmaeliminationsrate stand in Abhängigkeit von CCR, nur ein kleiner Anteil des Medikaments wurde auf extrarenalem Wege ausgeschieden. Außer in Fällen von fortgeschrittenem Nierenversagen fand eine tubuläre Sekretion statt, denn die renale Clearance von Cefadroxil überstieg die CCr. Die Werte lassen annehmen, daß es nur zu einer geringen Kumulation des Medikaments bei dem gewöhnlichen Dosierungsschema von 8–12stündlicher Verabreichung kommt, ausgenommen, die CCr unterschreitet 25 ml/min.