Delirium in older patients with COVID-19: Prevalence, risk factors and clinical outcomes across the first three waves of the pandemic.

OBJECTIVES: Delirium is a serious condition, which poses treatment challenges during hospitalisation for COVID-19. Improvements in testing, vaccination and treatment might have changed patient characteristics and outcomes through the pandemic. We evaluated whether the prevalence and risk factors for delirium, and the association of delirium with in-hospital mortality changed through the pandemic. METHODS: This study was part of the COVID-OLD study in 19 Dutch hospitals including patients ≥70 years in the first (spring 2020), second (autumn 2020) and third wave (autumn 2021). Multivariable logistic regression models were used to study risk factors for delirium, and in-hospital mortality. Differences in effect sizes between waves were studied by including interaction terms between wave and risk factor in logistic regression models. RESULTS: 1540, 884 and 370 patients were included in the first, second and third wave, respectively. Prevalence of delirium in the third wave (12.7%) was significantly lower compared to the first (22.5%) and second wave (23.5%). In multivariable-adjusted analyses, pre-existing memory problems was a consistent risk factor for delirium across waves. Previous delirium was a risk factor for delirium in the first wave (OR 4.02), but not in the second (OR 1.61) and third wave (OR 2.59, p-value interaction-term 0.028). In multivariable-adjusted analyses, delirium was not associated with in-hospital mortality in all waves. CONCLUSION: Delirium prevalence declined in the third wave, which might be the result of vaccination and improved treatment strategies. Risk factors for delirium remained consistent across waves, although some attenuation was seen in the second wave.

Een succesvol geautomatiseerd medicatiebewakingssysteem om ontbrekende maagprotectie toe te voegen bij gebruik van NSAID's en salicylaten.

Richtlijnen adviseren het voorschrijven van een maagbeschermer naast een NSAID of salicylaat in geval van risicofactoren voor gastro-intestinale complicaties (GIC). In het Catharina Ziekenhuis Eindhoven maakt men gebruik van een geautomatiseerd medicatiebewakingssysteem ofwel "computerized clinical decision support system" (CCDSS) Dit systeem alarmeert wanneer een maagbeschermer ontbreekt bij klinische patiënten, die hiervoor wel een indicatie hebben. In deze studie analyseerden we welke risicofactoren voor GIC het vaakst voorkwamen in de door de CCDSS gegenereerde meldingen bij patiënten van 60 jaar en ouder die in 2019 opgenomen waren en welk deel van deze meldingen leidde tot toevoeging of dosisaanpassing van een maagbeschermer. In totaal werden 762 meldingen geïncludeerd, waarvan 334 (44%) NSAID gebruikers betrof en 428 (56%) salicylaat gebruikers. In de NSAID groep was een hoge dosering (van NSAID) de meest voorkomende additionele risicofactor (59%) en in de salicylaat groep leeftijd ≥70 in combinatie met duale trombocytenaggregatieremming (38%). 81% van de meldingen leidde tot toevoeging of dosisophoging van een maagbeschermer, 18,5% werd verworpen met een gedocumenteerde reden en slechts 0,5% werd verworpen zonder gedocumenteerde reden. Concluderend draagt een CCDSS bij aan het voorschrijven van aanbevolen maagbeschermer bij patiënten die een NSAID of salicylaat gebruiken.

An evaluation of postoperative outcomes and treatment changes after frailty screening and geriatric assessment and management in a cohort of older patients with colorectal cancer.

INTRODUCTION: Adequate patient selection is crucial within the treatment of older patients with colorectal cancer (CRC). While previous studies report increased morbidity and mortality in older patients screened positive for frailty, improvements in the perioperative care and postoperative outcomes have raised the question of whether older patients screened positive for frailty still face worse outcomes. This study aimed to investigate the postoperative outcomes of older patients with CRC screened positive for frailty, and to evaluate changes in treatment after frailty screening and geriatric assessment. MATERIALS AND METHODS: Patients ≥70 years with primary CRC who underwent frailty screening between 1 January 2019 and 31 October 2021 were included. Frailty screening was performed by the Geriatric-8 (G8) screening tool. If the G8 indicated frailty (G8 ≤ 14), patients were referred for a comprehensive geriatric assessment (CGA). Postoperative outcomes and changes in treatment based on frailty screening and CGA were evaluated. RESULTS: A total of 170 patients were included, of whom 74 (43.5%) screened positive for frailty (G8 ≤ 14). Based on the CGA, the initially proposed treatment plan was altered to a less intensive regimen in five (8.9%) patients, and to a more intensive regimen in one (1.8%) patient. Surgery was performed in 87.8% of patients with G8 ≤ 14 and 96.9% of patients with G8 > 14 (p = 0.03). Overall postoperative complications were similar between patients with G8 ≤ 14 and G8 > 14 (46.2% vs. 47.3%, p = 0.89). Postoperative delirium was observed in 7.7% of patients with G8 ≤ 14 and 1.1% of patients with G8 > 14 (p = 0.08). No differences in 30-day mortality (1.1% vs. 1.5%, p > 0.99) or one-year and two-year survival rates were observed (log rank, p = 0.26). DISCUSSION: Although patients screened positive for frailty underwent CRC surgery less often, those considered eligible for surgery can safely undergo CRC resection within current clinical care pathways, without increased morbidity and mortality. Efforts to optimise perioperative care and minimise the risk of postoperative complications, in particular delirium, seem warranted. A multidisciplinary onco-geriatric pathway may support tailored decision-making in patients at risk of frailty.

Atypical presentation of COVID-19 in older patients is associated with frailty but not with adverse outcomes.

PURPOSE: Older patients with COVID-19 can present with atypical complaints, such as falls or delirium. In other diseases, such an atypical presentation is associated with worse clinical outcomes. However, it is not known whether this extends to COVID-19. We aimed to study the association between atypical presentation of COVID-19, frailty and adverse outcomes, as well as the incidence of atypical presentation. METHODS: We conducted a retrospective observational multi-center cohort study in eight hospitals in the Netherlands. We included patients aged ≥ 70 years hospitalized with COVID-19 between February 2020 until May 2020. Atypical presentation of COVID-19 was defined as presentation without fever, cough and/or dyspnea. We collected data concerning symptoms on admission, demographics and frailty parameters [e.g., Charlson Comorbidity Index (CCI) and Clinical Frailty Scale (CFS)]. Outcome data included Intensive Care Unit (ICU) admission, discharge destination and 30-day mortality. RESULTS: We included 780 patients, 9.5% (n = 74) of those patients had an atypical presentation. Patients with an atypical presentation were older (80 years, IQR 76-86 years; versus 79 years, IQR 74-84, p = 0.044) and were more often classified as severely frail (CFS 6-9) compared to patients with a typical presentation (47.6% vs 28.7%, p = 0.004). Overall, there was no significant difference in 30-day mortality between the two groups in univariate analysis (32.4% vs 41.5%; p = 0.173) or in multivariate analysis [OR 0.59 (95% CI 0.34-1.0); p = 0.058]. CONCLUSIONS: In this study, patients with an atypical presentation of COVID-19 were more frail compared to patients with a typical presentation. Contrary to our expectations, an atypical presentation was not associated with worse outcomes.

Shared decision-making in advance care planning among hospitalized older COVID-19 patients: a multicenter, retrospective cohort study.

BACKGROUND: In the Netherlands, it is customary to discuss directives regarding resuscitation, intubation, and ICU-admission with patients and/or their relatives upon hospital-admission. The outcome of this discussion is documented in a code status. Ideally, these advance care planning (ACP)-related decisions are made by a patient (and/or their relatives) and a professional together in a shared decision-making (SDM) process, to improve patient satisfaction and prevent undesired care. Given the bad outcomes in older COVID-19 patients, it is particularly important to discuss the code status upon admission. This study aims to describe the practice of SDM regarding code status during the COVID-pandemic. Specific aims were to find out to what extend patients took part in this decision-making process and whether all key elements of SDM for a shared decision were documented in medical reports. METHODS: In this retrospective cohort study, we included COVID-19 patients aged 70 years and older, admitted to two large teaching hospitals in the Netherlands, during the first months of the COVID-19 pandemic in 2020. Data about code status and the decision-making process were extracted from electronic healthcare records. RESULTS: Code status was documented for 274 of 275 included patients. Patient participation in the decision-making process was described in 48%. In 19% all key elements of shared decision-making have been described. Key elements of SDM were defined as the presence of a completed code status form, the presence of clinical notes showing that both patient's wishes and values and the opinion of the healthcare professional about the predicted outcome was taken into consideration and clinical notes of a patient-healthcare professional interaction during the admission. CONCLUSION: Our results show that a proper SDM process regarding code status is possible, even in hectic times like the COVID-19-pandemic. However, shared decision-making was not common practice in older patients with COVID-19 regarding code status (an ACP-related decision) in the early phase of the COVID-19 pandemic. Only in 19% of the patients, all key elements of SDM regarding code status were described.

Delirium in older COVID-19 patients: Evaluating risk factors and outcomes.

OBJECTIVES: A high incidence of delirium has been reported in older patients with Coronavirus disease 2019 (COVID-19). We aimed to identify determinants of delirium, including the Clinical Frailty Scale, in hospitalized older patients with COVID-19. Furthermore, we aimed to study the association of delirium independent of frailty with in-hospital outcomes in older COVID-19 patients. METHODS: This study was performed within the framework of the multi-center COVID-OLD cohort study and included patients aged ≥60 years who were admitted to the general ward because of COVID-19 in the Netherlands between February and May 2020. Data were collected on demographics, co-morbidity, disease severity, and geriatric parameters. Prevalence of delirium during hospital admission was recorded based on delirium screening using the Delirium Observation Screening Scale (DOSS) which was scored three times daily. A DOSS score ≥3 was followed by a delirium assessment by the ward physician In-hospital outcomes included length of stay, discharge destination, and mortality. RESULTS: A total of 412 patients were included (median age 76, 58% male). Delirium was present in 82 patients. In multivariable analysis, previous episode of delirium (Odds ratio [OR] 8.9 [95% CI 2.3-33.6] p = 0.001), and pre-existent memory problems (OR 7.6 [95% CI 3.1-22.5] p < 0.001) were associated with increased delirium risk. Clinical Frailty Scale was associated with increased delirium risk (OR 1.63 [95%CI 1.40-1.90] p < 0.001) in univariable analysis, but not in multivariable analysis. Patients who developed delirium had a shorter symptom duration and lower levels of C-reactive protein upon presentation, whereas vital parameters did not differ. Patients who developed a delirium had a longer hospital stay and were more often discharged to a nursing home. Delirium was associated with mortality (OR 2.84 [95% CI1.71-4.72] p < 0.001), but not in multivariable analyses. CONCLUSIONS: A previous delirium and pre-existent memory problems were associated with delirium risk in COVID-19. Delirium was not an independent predictor of mortality after adjustment for frailty.

Lessons Learned From the COVID-19 Pandemic as Experienced by Older Adults Treated for COVID-19.

Background: In order to provide the best care, the perspective of older COVID-19 patients must be involved in the development of treatment protocols. This study describes the experiences of older adults affected by COVID-19 who recovered in the hospital or at home. Methods: Qualitative semi-structured interviews were conducted with 23 older adults affected by COVID-19. A content-based thematic analysis was conducted. Results: Nine categories were identified as recurring topics, which were grouped into three major themes. The first theme describes experiences in the first phase of the disease when older adults fell ill. The second theme includes experiences during the illness, ranging from illness severity to participation in decision-making, communication barriers and isolation effects. The final theme covers the recovery course, residual symptoms and social aspects. Conclusion: Older adults treated for COVID-19 experienced a feeling of being in a fast-paced whirlwind and lost total control over the situation. Extra attention should be paid to shared decision making, coordinated information provision and the instalment of a primary contract to the patient. The uncertainty of their situation, isolation measures and fears could result in psychological consequences and hinder rehabilitation in older adults.

Characteristics and outcomes of older patients hospitalised for COVID-19 in the first and second wave of the pandemic in The Netherlands: the COVID-OLD study.

BACKGROUND: as the coronavirus disease of 2019 (COVID-19) pandemic progressed diagnostics and treatment changed. OBJECTIVE: to investigate differences in characteristics, disease presentation and outcomes of older hospitalised COVID-19 patients between the first and second pandemic wave in The Netherlands. METHODS: this was a multicentre retrospective cohort study in 16 hospitals in The Netherlands including patients aged ≥ 70 years, hospitalised for COVID-19 in Spring 2020 (first wave) and Autumn 2020 (second wave). Data included Charlson comorbidity index (CCI), disease severity and Clinical Frailty Scale (CFS). Main outcome was in-hospital mortality. RESULTS: a total of 1,376 patients in the first wave (median age 78 years, 60% male) and 946 patients in the second wave (median age 79 years, 61% male) were included. There was no relevant difference in presence of comorbidity (median CCI 2) or frailty (median CFS 4). Patients in the second wave were admitted earlier in the disease course (median 6 versus 7 symptomatic days; P < 0.001). In-hospital mortality was lower in the second wave (38.1% first wave versus 27.0% second wave; P < 0.001). Mortality risk was 40% lower in the second wave compared with the first wave (95% confidence interval: 28-51%) after adjustment for differences in patient characteristics, comorbidity, symptomatic days until admission, disease severity and frailty. CONCLUSIONS: compared with older patients hospitalised in the first COVID-19 wave, patients in the second wave had lower in-hospital mortality, independent of risk factors for mortality.The better prognosis likely reflects earlier diagnosis, the effect of improvement in treatment and is relevant for future guidelines and treatment decisions.

Identifying adverse drug reactions from free-text electronic hospital health record notes.

BACKGROUND: Adverse drug reactions (ADRs) are estimated to be the fifth cause of hospital death. Up to 50% are potentially preventable and a significant number are recurrent (reADRs). Clinical decision support systems have been used to prevent reADRs using structured reporting concerning the patient's ADR experience, which in current clinical practice is poorly performed. Identifying ADRs directly from free text in electronic health records (EHRs) could circumvent this. AIM: To develop strategies to identify ADRs from free-text notes in electronic hospital health records. METHODS: In stage I, the EHRs of 10 patients were reviewed to establish strategies for identifying ADRs. In stage II, complete EHR histories of 45 patients were reviewed for ADRs and compared to the strategies programmed into a rule-based model. ADRs were classified using MedDRA and included in the study if the Naranjo causality score was ≥1. Seriousness was assessed using the European Medicine Agency's important medical event list. RESULTS: In stage I, two main search strategies were identified: keywords indicating an ADR and specific prepositions followed by medication names. In stage II, the EHRs contained a median of 7.4 (range 0.01-18) years of medical history covering over 35 000 notes. A total of 318 unique ADRs were identified of which 63 were potentially serious and 179 (sensitivity 57%) were identified by the rule. The method falsely identified 377 ADRs (positive predictive value 32%). However, it also identified an additional eight ADRs. CONCLUSION: Two key strategies were developed to identify ADRs from hospital EHRs using free-text notes. The results appear promising and warrant further study.

Frailty is associated with in-hospital mortality in older hospitalised COVID-19 patients in the Netherlands: the COVID-OLD study.

BACKGROUND: During the first wave of the coronavirus disease 2019 (COVID-19) pandemic, older patients had an increased risk of hospitalisation and death. Reports on the association of frailty with poor outcome have been conflicting. OBJECTIVE: The aim of the present study was to investigate the independent association between frailty and in-hospital mortality in older hospitalised COVID-19 patients in the Netherlands. METHODS: This was a multicentre retrospective cohort study in 15 hospitals in the Netherlands, including all patients aged ≥70 years, who were hospitalised with clinically confirmed COVID-19 between February and May 2020. Data were collected on demographics, co-morbidity, disease severity and Clinical Frailty Scale (CFS). Primary outcome was in-hospital mortality. RESULTS: A total of 1,376 patients were included (median age 78 years (interquartile range 74-84), 60% male). In total, 499 (38%) patients died during hospital admission. Parameters indicating presence of frailty (CFS 6-9) were associated with more co-morbidities, shorter symptom duration upon presentation (median 4 versus 7 days), lower oxygen demand and lower levels of C-reactive protein. In multivariable analyses, the CFS was independently associated with in-hospital mortality: compared with patients with CFS 1-3, patients with CFS 4-5 had a two times higher risk (odds ratio (OR) 2.0 (95% confidence interval (CI) 1.3-3.0)) and patients with CFS 6-9 had a three times higher risk of in-hospital mortality (OR 2.8 (95% CI 1.8-4.3)). CONCLUSIONS: The in-hospital mortality of older hospitalised COVID-19 patients in the Netherlands was 38%. Frailty was independently associated with higher in-hospital mortality, even though COVID-19 patients with frailty presented earlier to the hospital with less severe symptoms.

[The use of telemedicine with frail elderly patients in the Netherlands - experience of caregivers in an outpatient setting]. / Teleconsulten op de polikliniek geriatrie in Nederland ­ ervaringen van zorgverleners.

The use of telemedicine (telephone and video consultations) has increased over the past decades and has grown substantially during the COVID-19 pandemic. Multimorbidity, visual - and hearing impairment, cognitive impairment and lack of technical skills might complicate the use of telemedicine in frail elderly patients. Limited research on this topic is has been performed. The aim of this article is to investigate which elements of care could be performed by telemedicine and what patient characteristics are useful in selecting patients for telemedicine. To get more information about the use of telemedicine in frail elderly patients, an online survey was conducted amongst caregivers working in geriatric outpatient care departments in the Netherlands. 67 caregivers completed the survey. The results indicate there is limited experience in video consultations in this population. The experience so far is mainly positive. Caregivers indicate the following elements of care could be performed by telemedicine: follow-up consultations, taking an (hetero)anamnesis, medication review, conversations with multiple contacts or caregivers and informing about test results. Our advice is to decide in dialogue with patient and caregiver, which form of consultation is feasible, desirable and appropriate for every individual process and consultation.

Dabigatran trough concentrations in very elderly patients.

OBJECTIVES: The aim of this observational study was to explore dabigatran concentrations in elderly and very elderly patients in a real-life population. Patients aged >75 years receiving dabigatran have a significantly higher risk of gastrointestinal bleeding compared withthose receiving warfarin. High trough concentrations have an important impact on this bleeding risk. METHODS: We measured dabigatran trough concentrations in 75 patients with atrial fibrillation, divided into age categories <75, ≥75 to 84 and ≥85 years. The most important exclusion criteria were use of interacting medication and severe renal failure. We analysed absolute trough concentrations and concentrations normalised for dose. RESULTS: Trough concentrations were considerably higher in the highest age category. Dose-normalised medians were 0.66, 0.83 and 1.20 ng/mL/mg in the <75, ≥75-84 and ≥85 age groups, respectively (p=0.004). CONCLUSION: Clinicians should be aware of higher dabigatran concentrations in elderly patients despite dose reduction.

[Medication reconciliation: a hell of a job]. / Overdracht van medicatiegegevens.

Transitions of care pose a risk to medication safety. To reduce patient harm, medication reconciliation is advised. However, implementation of medication reconciliation is difficult due to time constraints. We present two female patients aged 82 and 84 years. In both women, unintentional discrepancies arose, went undetected and led to patient harm. Accurate information transfer is essential for continuity of patient care. Medication reconciliation comprises four steps, i.e. verification (identify discrepancies), clarification (check the collected list), reconciliation (document the reason for medication changes) and transfer (communicate the updated list). This article discusses the steps of medication reconciliation and those medication errors that arise during a patient's transfer from the home setting to hospitalization or a clinic visit. We show that medication reconciliation is not merely an administrative task. As the patient is the only constant factor in health care, patient participation is essential.

Psychotropic Drug Prescription and the Risk of Falls in Nursing Home Residents.

BACKGROUND: Falling is a common and serious problem in the elderly. Previous studies suggest that the use of psychotropic drugs increases the risk of falling. However, the contribution of these drugs on fall risk has not been quantified on a daily basis among the general population of nursing homes until now. OBJECTIVE: To assess the association between fall incidence and the prescription of psychotropic drugs and different categories of psychotropic drugs (antipsychotics, antidepressants, and benzodiazepines) among a general nursing home population. DESIGN: Retrospective observational study, data collection per person-day. SETTING: 9 nursing homes in Eindhoven, the Netherlands. PARTICIPANTS: 2368 nursing home residents, resulting in 538,575 person-days. MAIN OUTCOME MEASURE: Association between the prescription of psychotropic drugs and falls. RESULTS: A total of 2368 nursing home residents were included, which resulted in a data set of 538,575 person-days. Prescription of at least 1 psychotropic drug per day occurred during a total of 318,128 person-days (59.1%). Scheduled prescriptions with or without an as-needed prescription were involved in a total of 270,781 person-days (50.3%). The prescription of psychotropic drugs on a scheduled basis was found to be associated with almost a 3-fold increase in fall incidence (OR 2.88; 95% CI 1.52-5.44). An increase in fall incidence was found following the prescription of antipsychotics (OR 1.97; 95% CI 1.51-2.59) and antidepressants (OR 2.26; 95% CI 1.73-2.95). This increased fall risk was found for prescriptions on a scheduled basis as well as for prescriptions on an as-needed basis. CONCLUSION: The prescription of psychotropic drugs is associated with a strongly increased risk of falling among nursing home residents. To our knowledge, this is the first study among the general nursing home population in which the association between daily falls and daily prescriptions of psychotropic drugs and groups of psychotropic drugs was specified.

[Falling due to vitamin B12 deficiency]. / Vallen door een vitamine B12-deficiëntie.

BACKGROUND: Ataxia due to a vitamin B12 deficiency can be a cause of falls in elderly patients. CASE DESCRIPTION: An 86-year-old woman presented with functional decline and gait problems. She had been falling regularly. The patient's gait was ataxic and she was unable to stand without support. Additional laboratory tests showed a volume macrocytic blood picture and a severe vitamin B12 deficiency, as well as antibodies directed against intrinsic factor and parietal cells. We diagnosed her as having falls and ataxia caused by vitamin B12 deficiency. Vitamin B12 supplementation resulted in improvement of gait. CONCLUSION: Ataxia due to vitamin B12 deficiency is a rare problem which in 20-25% of cases is not accompanied by anaemia. Prompt treatment reduces the chance of neurological sequelae.

Systems that prevent unwanted represcription of drugs withdrawn because of adverse drug events: a systematic review.

Represcription of medication that was withdrawn after the occurrence of an adverse drug event (including allergy), is a recognized medication safety issue on a patient level. We performed a systematic review to identify systems (electronic and nonelectronic) that can prevent the represcription of drugs withdrawn because of an adverse drug event and the effects of these systems. The review was performed using PRISMA and Cochrane guidelines. PubMed and Embase were searched for articles describing systems that can prevent represcription of drugs that had been withdrawn for causing an adverse drug event. Information on the characteristics of the studies, systems, and if present results achieved with such systems, was extracted. The results showed that of 6793 articles screened, 137 full-text articles were assessed for eligibility. A total of 45 studies describing 33 systems (28 electronic) were included. The five nonelectronic systems used allergy bracelets or allergy labels on hospital medical records or on drug orders. Systems differed in the way adverse drug events were documented and how users were alerted to drug represcription. Most systems functioned within a specific healthcare setting. Of 12 studies that compared pre- and post-intervention periods or wards with and without intervention, 7 showed a reduction in represcription after adverse drug event. In conclusion, several systems have been developed that can prevent the represcription of drugs that elicited an adverse drug event, but the evidence that these systems are effective is limited.

An electronic system to document reasons for medication discontinuation and to flag unwanted represcriptions in geriatric patients.

BACKGROUND: Earlier studies have shown poor documentation of the reasons for medication discontinuation during hospitalization. Communication of reasons for discontinuation, e.g. adverse drug reactions (ADRs), to general practitioners and pharmacists was also found to be insufficient, leading to a rate of represcription after an ADR of 27% during the first 6 months after discharge. OBJECTIVE: The aim of this study was to develop and implement a user-friendly electronic clinical decision support system to document reasons for medication discontinuation in hospitalized geriatric patients and to flag potentially undesirable represcriptions. METHODS: The electronic clinical decision support module was developed using the Gaston framework. Pop-up windows force physicians to document reasons for medication discontinuation, and the system alerts physicians to the represcription of drugs withdrawn because of an ADR. We interviewed users regarding the acceptability of the system. RESULTS: On a 20-bed geriatric ward, the electronic system documented 2,228 medication discontinuations and the reasons for them over 11.4 months and alerted physicians to represcription of drugs associated with an ADR 20 times. The system was considered to be user-friendly. CONCLUSIONS: This clinical decision support system fulfilled its aims of documenting the reasons for medication discontinuation and alerting physicians to potentially undesirable represcription of previously withdrawn drugs. It was found to be user-friendly.

Recurrence of adverse drug reactions following inappropriate re-prescription: better documentation, availability of information and monitoring are needed.

Adverse drug reactions (ADRs) are a common, and often preventable, cause of hospital admission, especially in the elderly, and can occur during hospitalization. In this current opinion article, we present three cases of recurrence of a serious ADR due to re-prescription of a withdrawn medication that highlight the need for a system to prevent the undesirable re-prescription of medications withdrawn because of an ADR. In addition, we describe an electronic system that could help prevent undesirable re-prescription following an ADR. Such a system should document ADRs systematically at the patient level, make this information available to relevant healthcare providers and the patient, and flag re-prescription of the offending drug. The effectiveness and cost effectiveness of such a system would need to be determined.

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) or hyponatraemia associated with valproic Acid: four case reports from the Netherlands and a case/non-case analysis of vigibase.

The Netherlands Pharmacovigilance Centre Lareb received four cases of severe symptomatic hyponatraemia or syndrome of inappropriate antidiuretic hormone secretion (SIADH) in association with valproic acid use, in which a causal relationship was suspected. This study describes these cases and gives support for this association from Vigibase, the adverse drug reaction (ADR) database of the WHO Collaborating Centre for International Drug Monitoring, the Uppsala Monitoring Centre. Cases of hyponatraemia in valproic acid users are described. In a case/non-case analysis, the strength of the association between reported cases of hyponatraemia and the use of valproic acid in Vigibase was established by calculating a reporting odds ratio, adjusted for possible confounding by concomitant medication. Four females aged 57, 67, 71 and 88 years developed symptomatic hyponatraemia or SIADH after starting valproic acid. Despite concomitant medication or co-morbidity, a causal relationship was plausible. In Vigibase, valproic acid is disproportionally associated with hyponatraemia and SIADH (corrected reporting odds ratio 1.83 [95% CI 1.61, 2.08]). Based on the described cases and the reports from Vigibase, a causal relationship between valproic acid use and hyponatraemia or SIADH can be suspected. The mechanism by which valproic acid could cause hyponatraemia or SIADH has not been fully elucidated. Valproic acid use could lead to reduced sensitivity of hypothalamic osmoreceptors. It also might directly affect tubular cell function, thereby leading to SIADH. It might be expected that a combination of effects on the osmoreceptors and a lack of compensation of the salt-water unbalance by the nephrons causes SIADH in some patients using valproic acid. It could be a dose- or concentration-related adverse effect. In this report, severe symptomatic hyponatraemia and SIADH have been associated with the use of valproic acid. With this study, not only is the number of published cases doubled, but also the data from Vigibase strongly support the association. Since hyponatraemia and SIADH have a high morbidity, health professionals should be aware of this potential ADR.