Renal Function in Older Hospital Patients Is More Accurately Estimated Using the Cockcroft-Gault Formula Than the Modification Diet in Renal Disease Formula

OBJECTIVES: To compare the accuracy of the two most popular creatinine clearance (CrCl) estimation formulae (Cockcroft-Gault (CG) and Modification Diet in Renal Disease (MDRD)) in older hospitalized patients.
DESIGN: Prospective, cross-sectional, observational study.
SETTING: Two hospital geriatric wards.
PARTICIPANTS: Consecutive patients aged 70 and older with an indwelling urinary catheter for the purpose of care.
MEASUREMENTS: CrCl was determined according to three methods: measured CrCl from plasma and urine creatinine and 24-hour urine volume, CG (CG-CrCl), and MDRD (MDRD-CrCl). Results were expressed as median and interquartile range (IQR). Moderate and severe renal impairment were defined as a CrCl between 30.0 and 59.9 mL/min and less than 30.0 mL/min, respectively.
RESULTS: One hundred twenty-one patients were included (46% male). Mean age was 86.1±6.7 (range 72–100). Median measured CrCl was 43.8 mL/min (IQR 33.6–61.1 mL/min), CG-CrCl was 40.9 mL/min (IQR 31.0–52.6 mL/min), and MDRD-CrCl was 61.3 mL/min (IQR 49.4–77.0 mL/min). The biases of CG-CrCl and MDRD were −3.5±22.5 and 20.1±28.2, respectively ( P <.001). Misclassification of renal impairment (absent/moderate/severe) occurred in 33% of patients according to CG-CrCl, and concordance was mild to moderate (kappa=0.50). Misclassification occurred in 50% of patients according to MDRD-CrCl, and concordance was poor (kappa=0.33). Bias was significantly related to bed confinement for both formulae and to plasma creatinine for MDRD.
CONCLUSION: In elderly hospitalized patients, CG slightly underestimates CrCl, and MDRD strongly overestimates it. CG gave a better prediction of measured CrCl than MDRD.     

Pharmacokinetics of guanfacine in patients with impaired renal function and in some elderly patients

The effects of renal impairment and age on the pharmacokinetics of guanfacine were evaluated. In normal subjects, guanfacine was found to be rapidly and completely absorbed, with an absolute bioavailability close to 100% and therefore no evidence of a noticeable first-pass effect. Its kinetics were best described by a 2-compartment model, with an elimination half-life of the beta phase of 17 hours. The major route of excretion was in the urine, with urinary excretion of 80% of a given dose within 4 days. Linearity of dose and thus predictability of blood levels were observed for single doses and at steady state. Although cumulative urinary excretion and renal clearance of unchanged guanfacine were reduced in patients with renal insufficiency, total clearances, serum levels, elimination rates constants and elimination half-lives differed very slightly, or at most by a factor of 1.5 to 2 between patients with normal and severely impaired renal function. Age-related decreases in urinary excretion and renal clearance of guanfacine were observed in 6 elderly patients and were accompanied by an increased proportion of metabolites to parent drug, confirming the significant nonrenal clearance of the drug. Based on pharmacokinetic studies in these target groups and on the dual renal and nonrenal clearance of guanfacine, the drug may, most probably, be administered to elderly patients and patients with renal insufficiency without dosage adjustment.     

Renal impairment and anaemia in a population-based study of older people

Abstract
Background: Established renal failure is a known cause of anaemia. However, the association between more modest levels of renal impairment and anaemia is unclear.
Aims: The aim of the present study was to investigate the association between mild renal impairment and anaemia in the general population.
Methods: A population-based, cross-sectional study was conducted in the general community in an urban area of the Blue Mountains, just west of Sydney, Australia. The study included 3222 people aged ≥49 years (mean age 65 years). Serum creatinine and haemoglobin were measured using standard laboratory techniques. Creatinine clearance was estimated from serum creatinine, body weight, sex and age.
Results:  Two hundred and seventy subjects (8.4%) had serum creatinine levels ≥125 µmol/L and estimated ­creatinine clearances were <0.84 mL/s (50 mL/min) in 894 subjects (27.7%) and <0.50 mL/s (30 mL/min) in 120 subjects (3.7%). There was a strong association between reduced renal function and anaemia. Compared to those with serum creatinine <125 µmol/L, the age-adjusted relative risk (RR) of anaemia in women (haemoglobin <12.0 g/dL) with serum creatinine ≥125 µmol/L was 5.5 (95% confidence interval (CI) 2.9−10.7) and the RR of anaemia in men (haemoglobin < 13.0 g/dL) was 3.1 (95% CI 1.6−6.0). Estimated ­creatinine clearance <50 mL/min was associated with a three-fold increased risk of anaemia in women and a five-fold increased risk in men.
Conclusions: The results of the present study suggest that even modestly impaired renal function is associated with anaemia in older men and women. The possibility of renal impairment should be considered in the diagnosis and management of anaemia in people aged>50 years. (Intern Med J 2004; 34: 20−23)     

Drug dosage in patients with renal failure optimized by immediate concurrent feedback

OBJECTIVE: To examine the impact of immediate concurrent feedback on dose adjustment in patients with renal failure. DESIGN: Prospective 12-month study in patients with various degrees of renal failure, with comparison to a retrospective control group. SETTING: A 39-bed unit of a university hospital providing primary and tertiary care. PATIENTS: Patients with renal failure (estimated creatinine clearance < or = 50 mL/min) receiving at least 1 pharmacologically active drug. INTERVENTIONS: Education of physicians and immediate concurrent feedback on the ward giving estimated creatinine clearance and dose recommendations for renally eliminated drugs adjusted to individual renal function. MEASUREMENTS AND MAIN RESULTS: The percentage of dosage regimens adjusted to renal function and cost assessment of drug therapy were calculated. Overall, 17% of the patients had at least 1 estimated creatinine clearance < or = 50 mL/min. In the intervention group, the dose of 81% of renally eliminated drugs was adjusted to renal function, compared with 33% in the control group ( P <.001). The mean difference in cost between standard and adjusted dose of renally eliminated drugs in the intervention and control groups was 5.3 +/- 12.3 and 0.75 +/- 2.8 Swiss francs (approximately US$3.5 and US$0.5), respectively ( P <.001), accounting for 16.5% and 2.8%, respectively, of daily medication costs of all drugs. CONCLUSIONS: The proportion of doses of renally eliminated drugs adjusted to renal function can be substantially increased by immediate concurrent feedback. This saves drug costs and has the potential to prevent adverse drug reactions.     

RIFLE classification as predictive factor of mortality in patients with cirrhosis admitted to intensive care unit

Background and Aim:  To evaluate the association of the Risk, Injury, Failure, Loss and End-stage renal failure (RIFLE) score on mortality in patients with decompensated cirrhosis admitted to intensive care unit (ICU).
Methods:  A cohort of 412 patients with cirrhosis consecutively admitted to ICU was classified according to the RIFLE score. Multivariable logistic regression analysis was used to evaluate the factors associated with mortality. Liver-specific, Acute Physiology and Chronic Health Evaluation (APACHE) II, Sequential Organ Failure Assessment (SOFA) and RIFLE scores on admission, were compared by receiver–operator characteristic curves.
Results:  The overall mortality during ICU stay or within 6 weeks after discharge from ICU was 61.2%, but decreased over time (76% during first interval, 1989–1992 vs 50% during the last, 2005–2006, P  < 0.001). Multivariate analysis showed that RIFLE score (odds ratio: 2.1, P  < 0.001) was an independent factor significantly associated with mortality. Although SOFA had the best discrimination (area under receiver–operator characteristic curve = 0.84), and the APACHE II had the best calibration, the RIFLE score had the best sensitivity (90%) to predict death in patients during follow up.
Conclusions:  RIFLE score was significantly associated with mortality, confirming the importance of renal failure in this large cohort of patients with cirrhosis admitted to ICU, but it is less useful than other scores.     

One-week losartan administration increases sodium excretion in cirrhotic patients with and without ascites

Background. Losartan, a highly selective angiotensin II type 1 receptor antagonist, has been reported to have a significant portal hypotensive effect in cirrhotic patients. A recent study also showed that losartan exerted a dramatic natriuretic effect in preascitic cirrhosis. The influence of losartan on renal hemodynamics and sodium homeostasis in cirrhotic patients with ascites is unclear. This study was undertaken to evaluate the renal effects of 1-week losartan treatment in cirrhotic patients with and without ascites. Methods. All 12 patients in the study received a daily oral dose of 25 mg losartan for 7 consecutive days. Effective renal plasma flow, urine volume, creatinine clearance, 24h urine sodium excretion and fractional excretion of sodium, blood urea nitrogen, and serum creatinine were measured before and after treatment. Results. In cirrhotic patients without ascites, creatinine clearance, 24-h urinary sodium excretion, and fractional excretion of sodium were significantly increased after losartan administration. Effective renal plasma flow and serum creatinine showed almost no change after treatment. In cirrhotic patients with ascites, creatinine clearance, 24-h urinary sodium excretion, fractional excretion of sodium, and effective renal plasma flow were significantly increased after losartan administration. In addition, the magnitudes of the increases in the fractional excretion of sodium and in the 24-h urinary sodium excretion were greater in cirrhotic patients with ascites than in those without ascites. Conclusions. One-week treatment with losartan increases sodium excretion in association with an improvement of renal function in cirrhotic patients with and without ascites. The natriuretic effect was more profound in cirrhotic patients with ascites than in those without ascites. Received: May 1, 2001 / Accepted: August 24, 2001     

Sotalol proarrhythmia: a report of five cases and an audit of the use of sotalol in a teaching hospital

Abstract Background: Polymorphic ventricular tachycardia is an uncommon complication of sotalol use.
Aims: The aims of this study were: (1) to report five cases of sotalol proarrhythmia and (2) to audit the use of sotalol in a teaching hospital population.
Methods: Five patients with sotalol proarrhythmia (defined as new ventricular arrhythmias associated with sotalol administration) were identified over an 18 month period. Sotalol use for patients admitted to the John Hunter Hospital was audited over a six month period with 85 patients (55 males) identified from die pharmacy database. Medical records were reviewed and the details of treatment including sotalol dose and indication determined. Creatinine clearance was estimated by the Cockcroft and Gault regression equation.
Results: The audit indicated that sotalol was prescribed predominantly for management of atrial arrhythmias (80%). Paroxysmal atrial fibrillation was the most common indication (71%). Although female patients were older (72±13 vs 62+15 years, p<0.001) and had a lower creatinine clearance (55±24 vs 82±32 mg/minute, p<0.001) than male patients, they were prescribed similar doses of sotalol (206±112 vs 193±93 mg/day). The ratio of sotalol dose to creatinine clearance was higher in female patients (4.0±2.6 vs 2.16±1.5, P<0.01). The five patients with proarrhythmia (torsades de pointes in four patients and polymorphic ventricular tachycardia in one patient) were all female. Daily sotalol dose (odds ratio for each 160 mg tablet 4.9 [95% confidence interval 1.5–16] and female gender (p<0.01) were significant risk factors for proarrhythmia'.
Conclusion: Sotalol dose was not appropriately adjusted for creatinine clearance which is age and gender dependent. Female patients have an increased risk of proarrhydimia and should receive lower doses of sotalol.     

Metformin‐associated lactic acidosis in patients with renal impairment solely due to drug accumulation?

Aim:  We suspect that the life-threatening complication of metformin-associated lactic acidosis, solely due to drug accumulation following renal impairment, occurs more frequently than that previously reported and is not necessarily associated with other predisposing factors for lactic acidosis.
Methods:  During a period of 13 months, at a tertiary referral centre, the incidence of lactic acidosis of any aetiology was 12.8% [67 of 524 total intensive care unit (ICU) admissions]. Metformin-associated lactic acidosis solely as the result of drug accumulation was diagnosed in 6% of all the patients suffering from lactic acidosis (4 of 67 patients).
Results:  These patients presented with severe circulatory shock due to lactic acidosis. We could not identify any predisposing factor for lactic acidosis other than renal impairment. Intercurrent deterioration of diabetic nephropathy was suspected to be responsible for the accumulation of metformin followed by lactic acidosis, finally resulting in multiorgan failure. The diagnosis was supported by extensively elevated serum levels of metformin. Two patients died during ICU treatment.
Conclusions:  Our data indicate that the incidence of metformin-associated lactic acidosis solely due to metformin accumulation is possible and underestimated. Symptoms of metformin-associated lactic acidosis are unspecific and physicians should be aware that metformin, if prescribed in patients with renal impairment, can cause fatal lactic acidosis due to drug accumulation.     

Renal underexcretion of uric acid is present in patients with apparent high urinary uric acid output

OBJECTIVE: To compare renal handling of uric acid in patients with primary gout with that of a control group. METHODS: A case-control study of 100 patients with primary gout and 72 healthy controls was undertaken. Creatinine clearance, uric acid clearance, 24-hour uric acid urinary excretion, fractional excretion of uric acid, excretion of uric acid per volume of glomerular filtration, urinary uric acid to creatinine ratio, and glomerular uric acid filtered load were calculated using 24-hour urine samples. After treatment with allopurinol to achieve similar glomerular filtered load of uric acid, patients were again compared with controls. RESULTS: Patients with gout showed lower uric acid clearance, fractional excretion of uric acid, excretion of uric acid per volume of glomerular filtration, and urinary uric acid to creatinine ratio than controls at baseline, when patients showed hyperuricemia. Although the glomerular uric acid filtered load was much higher in patients with gout than controls, 24-hour uric acid excretion was not statistically different. After treatment with allopurinol, and achieving similar uric acid filtered loads, patients still showed lower figures than controls. When patients with 24-hour urinary uric acids levels >700 mg/day were compared with controls, they had lower uric acid clearance and fractional excretion of uric acid than controls, both at baseline and after achieving similar filtered loads with allopurinol therapy. CONCLUSIONS: Renal underexcretion is the main mechanism for the development of primary hyperuricemia in gout, but even patients showing apparent high 24-hour uric acid output show lower uric acid clearance than controls, indicating that relative, low-grade underexcretion of uric acid is at work.     

Extracorporeal shock wave lithotripsy of large difficult common bile duct stones: Efficacy and analysis of factors that favor stone fragmentation

Background and Aim:  Difficult common bile duct stones (CBD) are those not amenable to extraction by the standard technique of sphincterotomy followed by use of a Dormia basket or balloon. The role of extracorporeal shock wave lithotripsy (ESWL) in stone fragmentation and clearance of difficult CBD stones and the factors which favor fragmentation were prospectively evaluated in the present study.
Methods:  A total of 283 patients with large CBD stones were subjected to ESWL. A maximum of 5000 shocks was delivered per session until CBD stones were fragmented to less than 5 mm diameter. CBD was cleared by biliary endotherapy using a basket or balloon. Outcome was assessed by CBD clearance.
Results:  Total CBD clearance was achieved in 239 patients (84.4%) and partial CBD clearance in 35 patients (12.3%). Three or fewer sessions of ESWL were required in 74.6% of patients. Minor complications were seen in 45 patients (15.9%). There was no procedure-related mortality. Epidural anesthesia, shock frequency of 90/min, radiolucent calculi and presence of fluid around the calculus helped in better fragmentation.
Conclusion:  A high success rate, negligible complications and non-invasive nature of the procedure make ESWL a useful tool for removing large CBD stones.     

Utility of a weight-based heparin nomogram for patients with acute coronary syndromes

Abstract
Background:  Unfractionated heparin has been pivotal in the management of acute coronary syndromes (ACS), and continues to be used widely despite the emerging role of low molecular weight heparins (LMWH). The apparent superiority of LMWH over unfractionated heparin may, at least partially, reside in its more predictable achievement of therapeutic effect, with high rates of non-therapeutic activated partial thromboplastin time (APTT) results being observed in the intravenous heparin treatment groups.
Aim:  To evaluate the impact of introduction of a weight-based heparin nomogram developed for use in patients with ACS on frequency of 'therapeutic' APTT results.
Methods:  The effectiveness of an existing non-weight-based heparin nomogram in achieving a therapeutic APTT was compared sequentially with that of a weight-based heparin nomogram in 89 and 84 consecutive patients admitted with a diagnosis of ACS.
Results:  Patients in whom heparin dosage adjustment was weight based rapidly achieved therapeutic APTT. The median time to achieve an APTT within the target range was 8.75 h in the weight-based group versus >24 h in the non-weight-based group. Utilization of a weight-based nomogram was associated with markedly increased proportions of readings within the therapeutic APTT range at 6 h and at 24 h (51% vs . 26% and 72% vs . 36%, respectively).
Conclusions:  The current study confirms the marked superiority of the weight-based heparin regimen for treatment of patients with ACS. The nomogram dramatically facilitated the attainment of therapeutic APTT, and may represent the optimal method for titration of heparin dosage to individual heparin requirements in patients with ACS. (Intern Med J 2003; 33: 18−25)     

Incidence of adverse drug reactions in geriatric units of university hospitals

Background:   Adverse drug reactions (ADR) in elderly people are often attributed to functional decline and polypharmacy.
Methods:   In this study, a multi-institutional retrospective survey was undertaken to investigate the current status of ADR in geriatric units of university hospitals. The inpatient databases from 2000 to 2002 for five university hospitals were studied, and a total of 1289 patients were analyzed.
Results:   The incidence of ADR, as determined by attending physicians, was 9.2% on average, but varied from 6.3 to 15.8% among the institutions. Factors significantly related to ADR were the number of diagnoses, the number of geriatric syndromes, the number of prescribed drugs, an increase of two or more drugs during hospitalization, longer hospital stay, emergency admission, depression and apathy.
Conclusion:   These results are mostly consistent with previous reports and provide important information on drug treatment in elderly people.     

Decline of outpatient asthma management in Argentina

Background and objectives:   To assess management of adult patients admitted with acute asthma and compare the results obtained with a similar study 5 years earlier.
Methods:   A cross-sectional survey of 211 consecutive patients admitted to hospital during a 12-month period was conducted. Patients were surveyed using a validated management questionnaire and the results compared with those of the previous survey.
Results:   There were 211 patients in the present survey and patient demographics were similar in both populations studied. Comparison of the previous to the current survey showed significant differences in predicted FEV₁% at admission (30.2 ± 10.7 vs 23.9 ± 8.9, respectively, P  < 0.001), and the average number of hospital admissions in the year prior to the survey (0.7 ± 1.2 vs 1.3 ± 0.7, P  < 0.0001). In the present survey, more patients changed their medication after acute exacerbation and more received an action plan. Compared with the previous survey, there were no significant differences between the mean number of emergency department visits, need for mechanical ventilation, number of patients prescribed inhaled corticosteroids and other related variables.
Conclusion:   Compared with the previous study the severity of asthma at the time of admission was worse. Some of the recommended international asthma management programmes appear to have been followed.     

Representative drug susceptibility patterns for guiding design of re-treatment regimens for multidrug-resistant tuberculosis in Iran

Background and objective:   The prevalence of multidrug-resistant tuberculosis (MDR-TB) has increased substantially in the past 20 years, however, there are no data specific to Iran. This study investigated patients suspected to have MDR-TB, attending the TB referral hospital in Iran.
Methods:   All patients suspected of having MDR-TB on hospital admission in the period 2003–2005 were included in this study. Sputum from all patients was tested for smear and culture, and drug sensitivity testing was performed using the proportion method. Patients were categorized into three groups based on their history of medical treatment. Group I consisted of patients with CAT I regimen failure; Group II consisted of patients with a history of CAT II regimen failure and Group III comprised patients with a history of more than two courses of irregular CAT I anti-TB regimen.
Results:   There were 105 patients recruited; 32 in Group I, 53 in Group II and 20 in Group III. There were no significant differences between the three groups in their resistance to first-line anti-TB drugs. Fifty-five patients were diagnosed with MDR-TB. The prevalence of MDR-TB was 56% (18 cases) in group I, 49% (26 cases) in group II and 55% (11 cases) in group III. No significant difference in the pattern of drug resistance was observed between the three groups.
Conclusion:   The prevalence of MDR-TB was high in this study. The lack of response of MDR-TB patients to CAT II treatment indicates that antibiotic sensitivity testing is essential in patients with CAT I treatment failure.     

Renal tubular events following passage from the supine to the standing position in patients with compensated liver cirrhosis: loss of tubuloglomerular feedback

BACKGROUND AND AIMS: Patients with preascitic liver cirrhosis display significant renal sodium retention in the upright posture and an exaggerated natriuresis during recumbency. To date, intrarenal sodium handling in these patients has not been studied using lithium clearance and fractional excretion techniques during recumbency and orthostatism. METHODS: Ten patients with preascitic (Child-Pugh A) liver cirrhosis and 10 healthy subjects underwent the following measurements during recumbency and then after four hours of standing: (a) active renin and aldosterone plasma levels; and (b) renal clearance of creatinine, sodium, potassium, and lithium (an index of fluid delivery to the loop of Henle). RESULTS: Unlike the control group, in the upright posture patients had significantly lower values of lithium clearance and fractional excretion compared with recumbency (21.6 (8.6) v 30.5 (10.2) ml/min (p<0.03) and 12.8 (4.4)% v 20.8 (4.9)% (p<0.01), respectively). Our patients showed maintenance of the glomerular-tubular balance-that is, the correlation between creatinine clearance and proximal tubular reabsorption of fluid-during both recumbency and in the upright posture (r=0.96, p<0.001; r=0.97, p<0.001, respectively). In contrast, patients displayed tubuloglomerular feedback only in the supine position. This was demonstrated by the observation of a negative correlation between lithium fractional excretion (a measure of the fractional delivery of sodium to the distal nephron) and filtered sodium load only in recumbency (r=-0.73; p< 0.03) and not during standing (r=0.22; p> 0.05). CONCLUSIONS: This study suggests that both the reduction in fluid and sodium delivery to the distal nephron and loss of tubuloglomerular feedback (the mechanism increasing glomerular filtration rate when the distal tubule is reached by a reduced sodium load) contribute towards the tendency to sodium retention in compensated cirrhosis during prolonged upright posture.