INTRODUCTION

Chronic kidney disease (CKD) has globally become of substantial health and economic burden. An estimated 5-10 million people die annually from kidney disease.¹ In Lebanon, 10% of the population suffers from kidney disease at various stages, of whom 3500 patients are on dialysis.¹ With decreased renal function, the pharmacokinetics of many drugs are significantly altered so that the effect of usual doses becomes either augmented or diminished.²,³,⁴ Moreover, the patient’s response may be changed due to the disease effect on multiple organ systems, making patients more susceptible to the effect of drugs.^{2 3}-⁴ CKD patients are subject to significant accumulation of renally eliminated drugs.⁴,⁵ When a drug accumulates, the risk of side effects increases, and may lead to toxicities. In contrary, under-dosing in dialysis patients may decrease efficacy and result in suboptimal response. In hospitalized patients, toxic or ineffective doses increase the length of hospitalization and cost of treatment, and thus, increase burden on both patient and healthcare systems.¹ Although adverse outcomes can often be delayed or prevented by inexpensive interventions, different studies have showed that during hospital stay, drug doses in patients with CKD are not adjusted properly in 25-77% of cases.⁶,⁷ In order to improve drugs’ prescription in CKD patients, it would be necessary to have collaboration between all healthcare providers.⁸ The primary objective of the current study was to assess adherence to dosing guideline in hospitalized patients with renal impairment, whereas the secondary objective was to assess appropriateness of drug dosing adjustment in those patients recruited from two university hospitals in Beirut, Lebanon.

METHODS

RESULTS

A total of 2138 patients with CKD were identified during the twelve-month study period. Based on the inclusion criteria, a total of 223 patients were considered for evaluation (10.4% of screened subjects). Those patients were prescribed 578 orders of our study medications. The clinical and demographic characteristics of all study patients (n=223) are summarized in Table 1. The study population consisted of 124 (55.6%) males and 99 (44.4%) females. The mean age was 65.78 years (range 19-96); the mean actual body weight was 76.3 kg; 27 (12.1%) were admitted for a renal reason. Most of the patients 104 (46.6%) were admitted to internal medicine (IM) floor; 84 (37.7%) and 94 (42.2%) patients were in G4 and G5 stages of CKD, respectively. Patients receiving hemodialysis were 95 (42.6%) of study group.

DISCUSSION

Several studies conducted worldwide have focused on the evaluation of medication dosing in patients with renal impairment. Yet, none of the published studies was, to our knowledge, carried in Lebanese hospitals. Our objective was to assess whether proper medication dosing was practiced at two university hospitals in Lebanon. The results of our study demonstrate that among 578 medication orders only 37% of prescription orders were adjusted adequately, and the remaining 63% of inappropriately dosed orders were divided into a majority adjusted inadequately with a rate of 49%, and 19% not adjusted at all. Moreover, among the 223 patients selected in our study, 84.3% received at least one medication without the correct adjustment dose.

Our results were comparable to those obtained by Decloedt et al. who reported that 32% of 117 prescription entries were adequately adjusted at a hospital in South Africa, and a slightly lower adequate adjustment rate when compared to 49% found by Getachew et al. in Addis Ababa, Ethiopia.¹⁰,¹⁶ Several studies had described rates of inappropriately dosed drug orders: Alahdal et al., in a study conducted at a university hospital in Saudi Arabia, reported a rate of 53.1%, and another study in Paris by Salmon et al., showed a rate of 34%, both rates were lower than the 63% obtained in our study.¹⁷,¹⁸ Altunbas et al. reported significantly lower rates of 12.6%, but the rate was explained by authors by the fact that the study patients had higher degrees of renal dysfunction, compared to other studies, and thus required nephrology consultation and more careful drug prescription.¹⁹ Another similar study was carried out at a governmental hospital in Palestine, indicated that only 26.42% of medications were found to be appropriately adjusted, compared to 73.58% inappropriately adjusted medication orders.²⁰

The rate of inappropriate prescriptions obtained in our study is considered to be high. Several reasons may contribute to inappropriate drug dosing in renal failure.¹⁶,¹⁹,²¹ These include not reviewing renal function tests before prescribing, which was reflected by the high number of exclusions due to missing serum creatinine level in our patients’ charts. Moreover, physicians’ lack of knowledge concerning all drugs that require dosage adjustment which was revealed here by the high rates of drugs “not adjsusted at all”. Furthemore, underestimating the impact of mild renal disease by physicians resulted in higher rates of inadequate adjustment in G3a/3b CKD stages versus more advanced disease stages.

We found a positive association between age greater than 65 years and inadequate dose adjustment; this can be attributed to polypharmacy and incorrect GFR estimation.¹⁰,²² It was noticed that patients admitted to the CCU had higher rates of inadequate adjustment. The latter finding can be explained by the fact that beta-blockers were among the most commonly prescribed class of medication requiring adjustment similar to the results obtained by Bailie et al.²³ Furthermore, the inadequate adjustment rate of beta-blockers in the present study was 83.6% far more than the 3.78% attained with Altunbas et al.¹⁹

Other finding in our study reported that dialysis patients had lower rates of inadequate adjustment. It seems that physicians were more careful in medication prescription, made appropriate dose adjustments, and more nephrologist consultations among dialysis patients were noted.²¹

This study was subject to some limitations. It was confined to two hospitals, which limits the generalizability of the results. The study was planned as a retrospective, cross sectional study, and thus, data collection may be vulnerable to missing and incomplete data, the method which prescribers used to assess the severity of renal impairment could not always be determined, and we did not evaluate the outcomes. The SCr value of 1.2 mg/dL is considered cut off point for patient inclusion, and this value, alone, cannot confirm the presence of renal impairment as those below 1.2 mg/dL may have severe renal impairment particularly in some special population such as very old or amputated patients. However, because hospital data lack consistent CrCl estimation rates, a cutoff point to start with was necessary. A cutoff point lower than 1.2 would have included huge number of non-CKD patients. Physicians may have referred to guidelines that are different from the ones we used in our study. In addition, the dose of some medications may be adjusted based on different endpoints other than estimated GFR. Moreover, the experience with the use of certain medications in renal dialysis patients is limited and no clear adjustment guidelines.²⁴ Lastly, GFR may become extremely difficult to estimate and unreliable in critically ill patients who experience rapidly changing renal function.¹⁶

In consideration of the high prevalence of CKD among medical inpatients, and the significant impact of improper dosing of medications, several methods have been suggested to improve drug dose adjustment recommendations. The collaboration with clinical pharmacists, who are uniquely trained in therapeutics and provide comprehensive drug management to both patients, physicians, and all members of the care team, has been shown to be a vital step towards improving patient care.¹⁷,²⁵ Moreover, improving education, via standardization of prescription sources, updated prescription protocols, and pocket tables with dosing guidelines, as a complete interventional program, have been showed by Martinez-Anton et al. to reduce the rate of prescribing errors from 34.2% to 21.7%.²⁶ Furthermore, computerized systems are becoming significantly helpful in this area. It has been shown that using computerized physician order entry and clinical decision support system was able to decrease rates of medication dosing errors.¹⁹

CONCLUSIONS

In conclusion, the frequency of appropriate dosing adjustment as to renal clearance for all non-antimicrobial drugs in patients with CKD at two Lebanese university hospitals was low. Although the rates of inappropriate dosing were relatively low in statins and ACE inhibitors, it was fairly high in bisoprolol and ranitidine dosing. In Lebanon, problems at the organizational and professional levels are contributing to the incidence of medical errors and the associated suboptimal responses.²⁷ Therefore, increasing nephrology consultation rate and implementation of physician education programs may be helpful to reverse this trend.