Anders Helldén

Adverse Drug Reactions and Impaired Renal Function in Elderly Patients Admitted to the Emergency Department: A Retrospective Study

BackgroundAdverse drug reactions (ADRs) are common in elderly patients. There are various reasons for this, including age- and disease-related alterations in pharmacokinetics and pharmacodynamics as well as the common practice of polypharmacy. The decline in renal function in elderly patients may also predispose them to pharmacological ADRs (type A, augmented). Patients receiving home healthcare may be at even higher risk.ObjectivesTo study ADRs as a cause of acute hospital admissions in a defined cohort of elderly patients (aged ≥65 years) registered to receive home healthcare services, with special reference to impaired renal function as a possible risk factor.MethodsThis was a retrospective study of 154 elderly patients aged ≥65 years admitted to the emergency department of a university hospital in Stockholm, Sweden, in October–November 2002. Estimated creatinine clearance (eCLCR) was calculated from the Cockcroft-Gault formula, and estimated glomerular filtration rate (eGFR) by the Modification of Diet in Renal Disease (MDRD) equation. ADRs were defined according to WHO criteria. All medications administered to patients at admission and at discharge were collated. These and other data were collected from computerized hospital records.ResultsADRs were judged to contribute to or be the primary cause of hospitalization in 22 patients, i.e. 14% of 154 patients registered to receive home healthcare. Eleven of the 22 patients were women. All but one ADR were type A. Excessive doses or drugs unsuitable in renal insufficiency were present in seven patients in the ADR group compared with only four patients in the group without ADRs (p=0.0001). Patients with ADRs did not differ significantly from those without ADRs in relation to age, plasma creatinine, eCLCR, weight or number of drugs prescribed at admission. However, women with ADRs were significantly older than women without ADRs (mean±SD age 88.8±5.7 years vs 82.5±8.0 years, respectively; p=0.014) and had significantly lower mean±SD eCLCR values (25.5±10.8 and 37.1±17.1 mL/min, respectively; p=0.035). Median MDRD eGFR was significantly higher than median eCLCR (59 [range 6–172] mL/min/1.73 m2 vs 38 [range 5–117] mL/min, respectively; p=0.0001).ConclusionsIn elderly patients registered to receive home healthcare, 14% of hospital admissions were primarily caused by ADRs. One-third of these ADRs were related to impaired renal function, generally in very old women. These ADRs may be avoided by close monitoring of renal function and adjustments to pharmacotherapy (drug selection and dose), particularly in very elderly women.

Erratum to: Adverse Drug Reactions and Impaired Renal Function in Elderly Patients Admitted to the Emergency Department

Background Adverse drug reactions (ADRs) are common in elderly patients. There are various reasons for this, including age- and disease-related alterations in pharmacokinetics and pharmacodynamics as well as the common practice of polypharmacy. The decline in renal function in elderly patients may also predispose them to pharmacological ADRs (type A, augmented). Patients receiving home healthcare may be at even higher risk.

Renal function estimations and dose recommendations for dabigatran, gabapentin and valaciclovir: a data simulation study focused on the elderly

Objectives The thrombin inhibitor dabigatran is mainly excreted by the kidneys. We investigated whether the recommended method for estimation of renal function used in the clinical trials, the Cockcroft-Gault (CGold) equation and the estimated glomerular filtration rate (eGFR) modification of diet in renal disease equation 4 (MDRD4), differ in elderly participants, resulting in erroneously higher dose recommendations of dabigatran, which might explain the serious, even fatal, bleeding reported. The renally excreted drugs gabapentin and valaciclovir were also included for comparison. Design A retrospective data simulation study. Participants Participants 65 years and older included in six different studies. Main outcome measure Estimated renal function by CG based on uncompensated (‘old Jaffe’ method) creatinine (CGold) or by MDRD4 based on standardised compensated P-creatinine traceable to isotope-dilution mass spectrometry, and the resulting doses. Results 790 participants (432 females), mean age (±SD) 77.6±5.7 years. Mean estimated creatinine clearance (eCrCl) by the CGold equation was 44.2±14.8 ml/min, versus eGFR 59.6±20.7 ml/min/1.73 m2 with MDRD4 (p<0.001), absolute median difference 13.5, 95% CI 12.9 to 14.2. MDRD4 gave a significantly higher mean dose (valaciclovir +21%, dabigatran +25% and gabapentin +37%) of all drugs (p<0.001). With MDRD4 58% of the women would be recommended a full dose of dabigatran compared with 18% if CGold is used. Conclusions MDRD4 would result in higher recommended doses of the three studied drugs to elderly participants compared with CG, particularly in women, and thus increased the risk of dose and concentration-dependent adverse reactions. It is important to know which method of estimation of renal function the Summary of Products Characteristics was based on, and use only that one when prescribing renally excreted drugs with narrow safety window. Doses based on recently developed methods for estimation of renal function may be associated with considerable risk of overtreatment in the elderly.

Pulmonary embolism associated with the use of anabolic steroids

We present the case of a 56-year-old man with deep vein thrombosis (DVT) and pulmonary embolism (PE). He had been given intramuscular injections of testosterone and the anabolic-androgenic steroid nandrolone, due to a muscle injury, a total of three times prior to manifestation of the symptoms. An ultrasonographic examination of the right leg revealed a DVT and computed tomography of the pulmonary arteries showed PE. The thromboembolic episodes in this previously healthy patient were in all probability associated with intramuscular injections of testosterone and nandrolone, to which there is a clear correlation in time.

Fluconazole-induced intoxication with phenytoin in a patient with ultra-high activity of CYP2C9

PurposeThe cytochrome P450 enzyme CYP2C9 metabolizes several important drugs, such as warfarin and oral antidiabetic drugs. The enzyme is polymorphic, and all known alleles, for example, CYP2C9*2 and*3, give decreased activity. Ultra-high activity of the enzyme has not yet been reported.MethodsWe present a patient with Behçet’s disease who required treatment with high doses of phenytoin. When fluconazole, a potent inhibitor of CYP2C9, was added to the treatment regimen, the patient developed ataxia, tremor, fatigue, slurred speech and somnolence, indicating phenytoin intoxication. On suspicion of ultra-high activity of CYP2C9, a phenotyping test for CYP2C9 with losartan was performed.ResultsThe patient was shown to have a higher activity of CYP2C9 than any of the 190 healthy Swedish Caucasians used as controls.ConclusionsOur finding of an ultrarapid metabolism of losartan and phenytoin may apply to other CYP2C9 substrates, where inhibition of CYP2C9 may cause severe adverse drug reactions.

Aciclovir induced posterior leucoencephalopathy

Aciclovir is an extremely effective agent for the treatment of herpes simplex encephalitis and varicella–zoster infections in immunocompromised individuals.1 Encephalopathy induced by aciclovir is an infrequent but well recognised adverse effect of aciclovir.2 The predisposing factors to aciclovir induced encephalopathy (AIE) include age, acute or chronic renal failure, and other neurotoxic drugs.2 Tremors (40–58%), disorientation (40–50%), agitation (22–38%), hallucinations (25%), and delirium (25%) are common presentations of AIE, whereas seizures (10%), cerebellar ataxia (11%), sensory symptoms (9%), speech disorders (9%), fever (3%), and cranial nerve palsies (0%) are much less frequent.2 The supportive diagnostic criteria for AIE include a temporal association between the symptoms and aciclovir use, as well as acellular cerebrospinal fluid (CSF) in cases without herpes simplex or varicella–zoster encephalitis. In the majority of cases symptoms develop within 72 hours of starting aciclovir treatment, although up to 120 days has been reported.2 The clinical recovery may take several days (five days in 57% of cases) following discontinuation of aciclovir.2 The EEG typically shows diffuse slow wave activity rather than focal abnormalities.2 The radiological features are not well described in AIE. Case reports have identified multifocal white matter signal abnormalities involving the cerebellum, pons, and periventricular region as well as evidence of vascular encephalopathy on MRI.2,3 We report a case of AIE with MRI features consistent with posterior leucoencephalopathy with clinical …

Implications of serum creatinine measurements on GFR estimation and vancomycin dosing in children.

Different serum creatinine (sCr) assays may obtain different values in the same patient, causing discrepancies in estimated glomerular filtration rate (eGFR) and sCr‐based vancomycin dosing calculations.

Development of a computerised decisions support system for renal risk drugs targeting primary healthcare

Objectives To assess general practitioners (GPs) experience from the implementation and use of a renal computerised decision support system (CDSS) for drug dosing, developed for primary healthcare, integrated into the patient’s electronic health record (EHR), and building on estimation of the patients creatinine clearance (ClCG). Design Qualitative research design by a questionnaire and a focus group discussion. Setting and participants Eight GPs at two primary healthcare centres (PHCs). Interventions The GP at PHC 1, and the project group, developed and tested the technical solution of the CDSS. Proof-of-concept was tested by seven GPs at PHC 2. They also participated in a group discussion and answered a questionnaire. A web window in the EHR gave drug and dosage in relation to ClCG. Each advice was according to three principles: If? Why? Because. Outcome measures (1) The GPs’ experience of ‘easiness to use’ and ‘perceived usefulness’ at PHC 2, based on loggings of use, answers from a questionnaire using a 5-point Likert scale, and answers from a focus group discussion. (2) The number of patients aged 65 years and older with an estimation of ClCG before and after the implementation of the CDSS. Results The GPs found the CDSS fast, simple and easy to use. They appreciated the automatic presentation of the CICG status on opening the medication list, and the ability to actively look up specific drug recommendations in two steps. The CDSS scored high on the Likert scale. All GPs wanted to continue the use of the CDSS and to recommend it to others. The number of patients with an estimated ClCG increased 1.6-fold. Conclusions Acceptance of the simple graphical interface of this push and pull renal CDSS was high among the primary care physicians evaluating this proof of concept. The graphical model should be useful for further development of renal decision support systems.

Differential diagnosis of central nervous system involvement in a patient treated with acyclovir.

Acyclovir-induced neuropsychiatric symptoms (AINSs) may resemble several diseases of the central nervous system. Laboratory testing of acyclovir may be critical in supporting the diagnosis of AINSs when there is doubt. We present a case of suspected herpes encephalitis in which the diagnosis of AINSs was supported by therapeutic drug monitoring of plasma and cerebrospinal fluid concentrations of acyclovir and its main metabolite 9-carboxymethoxymethylguanine.

Ganciclovir concentrations in the cerebral extracellular space after valganciclovir treatment; a case study

Nearly all glioblastomas (GBMs), brain tumours with very poor prognosis, are infected with human cytomegalovirus (CMV). The anti-CMV drug valganciclovir (VGCV) has shown promise as a treatment option for patients with GBM, but its penetration into the central nervous system (CNS) is unknown. Here we describe a patient with GMB receiving VGCV in whom an intracerebral microdialysis catheter was implanted and ganciclovir (GCV) concentrations in brain extracellular fluid (BECF) and serum were monitored. GCV was rapidly absorbed. Cmax values (at 3 h) in serum and BECF were 19.6 and 10.2 µmol/L, T½ values were 3.2 and 4.5 h, and plasma and BECF AUC0−∞ values were 90.7 and 75.9 µmol h/L, respectively. Thus, VGCV treatment results in significant intracerebral levels of GCV that may be sufficient for therapeutic effects. Further studies of this drug in patients with GBM are warranted.