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Drug Utilization Evaluation of High Alert Medications in Intensive Care Units of Tertiary Care Teaching Hospital

1 Associate professor in clinical pharmacy, P Rami Reddy Memorial College of Pharmacy, Prakruthi Nagar, Utukur, Kadapa-516003. Andhra Pradesh, India 2 Assistant professor, Department of General Medicine, Rajiv Institute Of Medical Sciences (RIMS), Kadapa-516003. Andhra Pradesh, India. 3 Pharm.D Interns of P Rami Reddy Memorial College of Pharmacy, P Rami Reddy Memorial College of Pharmacy, Prakruthi Nagar, utukur, Kadapa516003.Andhra Pradesh, India


INTRODUCTION
High-alert medications are drugs that bear a heightened risk of causing significant patient harm while they are used in error. Although mistakes may or may not be more common with these drugs, the consequences of error are more devastating to patients 1,2 . When any medication can potentially cause harm, a select group of drugs "high-alert medications (HAMs)" carries a higher risk of patient injury. According to The Joint Commission (TJC), HAMs frequently are associated with harm, the harm they cause is serious, and when they're misused, the risk of serious injury or death is high 3 .
Based on the previous reports submitted to the ISMP National Medication errors Reporting Program (ISMP MERP), ISMP created an updated list of HAM's 4 . HAM's are commonly used in the emergency room (ER), intensive care unit (ICU), Because HAMs are used in emergencies, they bear a heightened risk of causing patient harm when used incorrectly 5 . Patients who are admitted to ICUs (Intensive Care Unit) are usually seriously ill, often suffer from multiple chronic illnesses and drug usage is also quite extensive. Thus the ICU represents an important platform for performing drug utilization studies. Drug utilization (DU) is defined by the World Health Organization (WHO) as the marketing, distribution, prescription, and use of drugs in society, with special emphasis on the resulting medical, social, and economic consequences 6 . DU involves a wide range of review of the patient's prescription and medication data before, during, and after dispensing to ensure appropriate medication decision making and positive patient outcomes. DU programs play a key role in helping managed health care systems understand, interpret, and improve the prescribing, administration, and use of medications. Drug utilization reviews (DUR) are categorized into three classes: Prospective -evaluation of a patient's treatment before medication is dispensed, Concurrent -ongoing monitoring of drug therapy throughout treatment, Retrospective -review of therapy after the patient has received the medication 7 .
The ultimate purposes of drug utilization studies are to contribute to the optimal quality of drug therapy by ISSN Data includes patient's demographics, past and present medical and medication history, family history, allergies, which were obtained by personnel interview. The clinical review was performed to assess the day-to-day prognosis. Periodically medication trays were examined for the proper labeling of drugs including name and expiry dates, deterioration, damages, misplacements, proper storage, etc. the observed deviations were intimated to the Concerned professionals and rectified. We also monitored the administration process of High-Alert medications the observed deviations were rectified by discussing with the concerned staff. Data was collected, analyzed and the conclusions of the program were intimated to the hospital authorities to bring changes in the utilization of High-Alert medications for the betterment of patient care. We used Descriptive statistics like Mean, SD (Standard Deviation), and Percentage of use of high alert medications by using excel.

RESULTS AND DISCUSSION
Both retrospective and prospective data of the patients who were prescribed high alert medications were collected for a period of 6 months i.e. from June to November 2019. During the study period, about 1338 cases were reviewed for 6 months, and selected 533 cases/prescriptions containing 23 high alert medications (based on the ISMP list of HAM) 8 were collected.
Out of 23 drugs, only 7 high alert medications (Atropine, Digoxin, Enoxaparin, Glimepiride, Insulin, Midazolam, Noradrenaline) met the sample size criteria and which accounts for 420 prescriptions in 362 cases and were considered for the in-depth analysis, but for DRPs and interventions, we have considered all 23 drug prescriptions.

Patient Demographics:
The demographic of the patients with gender, age, and social habits and their numeral is represented in Table-1 Of 362 subjects enrolled, 57.73 % were males and 42.26 % were females. We found that the HAMs were prescribed slightly more in males (57.73%) than females, in support of our data Manjula Devi et al 9 , also reported that prescribing of HAMs is more in males, this represents that, the males are mostly affecting with the life-threatening conditions with more severity and receiving the high alert medications. The incidence of these conditions may be more because of their lifestyles.
We found that the average age of total subjects is 53.40(+17.60). We observed that the prescribing of study drugs is more in old adults/ geriatrics i.e. 45 % next to this group 37 % of middle-aged adults have prescribed with these drugs. The results of this study were found to be in coinciding with a previous study conducted by Mitchell Kim et al., [10] where they reported that the majority of the study subjects with HAM were ≥ 60 years of age. This may be due to the reason that the age progresses the incidence of highrisk conditions will be increased which was confirmed with these results.
Of 362 subjects, 74.5% were devoid of social habit. The study results of Mitchell Kim, et. al, 10 suggest that the incidence of ICU admissions is more because of the CVS, RS, and CNS disorders associated with social habits. But in contradiction to that study, we found that only 24 % of the total subjects were having the habit of alcoholism, smoking, or both and this may not be the only risk factor in causing high-risk diseases in the study area.

HAM characteristics:
Characteristics of HAM's according to their formulation type, The number of prescriptions that are prescribed in generic and brand name, and the number of HAM's per prescription are represented in table 2. In 420 encounters, Oral and parenteral (Subcutaneous and Intravenous) formulations were used. Our data indicate that the majority of prescriptions contained parenteral preparations; this is obvious that intensive care admissions are generally required immediate management/action. In support of our data, the results of Anitta Thomas, et. al 11 show that the most frequent route of administration of HAM is parenteral (79.2 %) followed by oral route (20.7 %). The majority of ICU studies document that the parenteral route is the most frequent route of administration.
Generally, drug names in the prescription should be in their generic/active ingredient name than their brand names to avoid duplications of drug class and therapeutic class. Most of our study drugs are prescribed in Generic names. Only 2 drugs are prescribed in Brand name. i.e., Insulin as ACTRAPID AND MIXTARD whereas Enoxaparin as BIO-ENOX. In our study site, we found a majority (54.7%) of the drugs were prescribed in their generic/active ingredient name, which indicates the appropriate drug utilization.
The number of HAMs per prescription is an indicator of the severity of the high-risk diseases. A total of 420 HAM containing prescriptions were observed with 7 HAMs in 362 cases with an average of 1.62 (±0.916) HAMs per prescription. We found that majority were received single HAM (60%) and the most commonly prescribed HAM is Insulin i.e. in 125 (34.5 %) prescriptions, which indicates the majority were suffered from uncontrolled hyperglycemia. The most commonly prescribed combination of HAMs was found to be Digoxin and Enoxaparin.

ATC/DDD:
All the study drugs were classified as per the standard guidelines of the ATC (Anatomical Therapeutic Chemical) classification system along with their Defined Daily Doses (DDD). The main purpose of the ATC/DDD system is to present drug utilization statistics that improves drug usage where it has been demonstrated to be suitable for national and international comparisons, for the evaluation of long term patterns in drug use, to assess the impact of certain events on drug use, and for providing denominator data in investigations of drug safety. prescribed with standard DDD to know the differences in the prescribing habits.

Indications and ICD Codes:
As only 7 high alert medications met the sample size criteria which accounts for 420 prescriptions in 362 cases, the detailed description about their ATC/DDD, indications, ICD(International Classification of Diseases) code, and cost details were represented in table 3.

Atropine:
Atropine was prescribed in 42 prescriptions for 19 types of indications. Out of 42 prescriptions, 17 were prescribed majorly in cardiovascular conditions with or without comorbidities followed by poisoning conditions. Murat Sungur et al 12 study has shown that the OP-Poisoning cases were prescribed with intravenous atropine and oximes commonly.
The utilization of the atropine in our study site is not according to the guidelines, as the average daily dose was 1 time more than the DDD and we have found 5 DRPs i.e. overdose induced ADRs like Psychosis (3) and Tachycardia (2). And in some cases, the drug administrator has not followed the prescription i.e. they are not writing the complete dose given to the patient as and when.

Digoxin:
Digoxin was prescribed in 44 prescriptions for 14 indications, which are cardiovascular problems with or without comorbidities. CHF(Congestive Heart failure) is a common indication. In parallel to our results, Christopher et. al 13 also concluded that Digoxin was the cornerstone of therapy for patients with chronic heart failure. The average prescribed digoxin dose is as per DDD and we didn't found any harmful issues with digoxin. So, We found that digoxin use is appropriate as per guidelines in our study site.

Enoxaparin:
Enoxaparin was prescribed in 65 prescriptions for 18 types of indications. Out of 65 prescriptions, the majority of prescriptions (29) were for STEMI(ST-Segment elevated Myocardial Infarction), followed by CAD(Coronary Artery disease) i.e.,15. Similar to our results Andrea Rubboliet. al., 14 study had also reported that Enoxaparin is the most commonly prescribed in STEMI in conjunction with thrombolysis.
Though the average prescribed enoxaparin dose was not according to the guidelines i.e., higher than the defined daily dose, we did not found any negative issues in the subjects. The reason for this discrepancy is the unavailability of the exact strength.

Glimepiride:
Glimepiride was prescribed in 43 prescriptions for 3 types of indications. Out of 43 prescriptions, the majority were prescribed for diabetes mellitus with hypertension. The study by Massi Benedetti et.al., 15 states that glimepiride is an effective and well-tolerated once-daily antidiabetic drug for the management of type 2 diabetes.
We found that the average prescribed dose of glimepiride was appropriate as per the DDD. We did not found any harmful issues related to glimepiride use. Only one ADR was identified that is managed with medications and then reported to IPC PvPI.

Insulin:
Insulin was prescribed in 125 prescriptions for 9 types of indications. Out of125 prescriptions, we found that DM with HTN was a common indication treated with this drug after DM alone. The study results of Sanne G swinnen et. al 16 , states that insulin had improved treatment satisfaction and quality-of-life for type 2 diabetic patients.
Though the average prescribed daily dose of insulin is as per the DDD, the dose calculation method being followed in our study site is not common for all the prescriptions, as some prescribers fix the dose according to the GRBS values while others follow the sliding scale method, but there is no display of sliding scale at the study site. We also found ADRs related to its use which can be managed with medications and reported to IPC PVPI.

Midazolam:
In our study site, Midazolam was prescribed in 60 prescriptions for 12 types of indications. Of them, 50% were prescribed for Epilepsy/seizure disorders. The study results ofRob smith et. al 17 , specified that Midazolam was widely used as an off-label indication for Seizures, and the first-line treatment for status-epilepticus in children. But in our study, Midazolam was commonly prescribed for Epilepsy/seizure. We found that the average prescribed dose of midazolam was appropriate as per the DDD.

Noradrenaline:
In our study site, Noradrenaline was prescribed in 41 prescriptions for 21 types of indications. Of 41 prescriptions, 12 prescribed for cardiac disorders with or without comorbidities, followed by CVA and sepsis. Similar to our study, A study by Hamzaouiet. al 18 , states that nor-adrenaline is the first-line agent recommended during septic shock to correct hypotension.
The average prescribing dose of noradrenaline is as per the defined daily dose. As per the guidelines, nor-adrenaline should be diluted in 5% D, but we found in 11 cases the dilution of nor-adrenaline was done with NS, Which is incompatible, this may be due to lack of awareness regarding the dilution technique of noradrenaline.

Cost of study drugs:
One of the objectives of the DUE process is to estimate the cost of drug therapy and promote better economic treatment. Based on our study results, the Cost/amount spent on 7 HAMs was estimated and found that INR 23,075.75with an average INR 63.75/patient was spent by the government for 362 patients during the study period.
The individual cost of all the study drugs was calculated and which of total cost spent, enoxaparin (65) was listed to be the costliest drug among 7drugs and it occupied 68.26 % of the total cost of seven drugs, and digoxin was listed to be the low-cost drug and it occupied 0.41% of the total cost of seven drugs.
As this study center is a government health care center, there is no burden for the patients and no need to pay from their pocket. We have not analyzed the cost spent and outcome of the treatment, with this data we cannot conclude the right cost as we have not compared it with any other costs.

Drug-Related Problems:
A drug-related problem is anything that is involving drug therapy that interferes with the desired outcome for a patient. We have done intervention to the DRPs identified for better patient response. The DRP's we identified were derived from the standard source of information 20 . The study results by SachinRavalet.al 3 , also states that the primary focus should be on preventing the errors of HAMs with the greatest potential to improve patient safety.

ADR's
Among the 9 ADRs, 7 were common and 2 are lifethreatening reactions. All the ADRs were reported to the IPC PvPI after thorough analysis and MedDRA (Medical Dictionary for Regulatory Authority) code was given as represented in the table below.
We have represented the MedDRA code for the observed adverse drug reactions which is a standardized International medical terminology used to convert adverse event information into terminology that can be readily identified, retrieved, and analyzed. states that the clear majority of ICU prescriptions had at least one potential DDI, and the most prevalent ones were classified as moderate. Admitting that high potential for Drug-Drug Interactions in the ICU represents an important step toward improving patient safety and best therapy results. Actual drug-drug interactions: The 2 observed actual DDI's (2) were with Meropenem and linezolid. The consequences of the actual DDIs were observed in patients clinically, as it is not possible to analyze through the laboratory at our study site, so we have confirmed clinically and intervention was done for those interactions.
Potential drug-drug interactions: Of all the 133 DDI's, 131 DDI's were potential (not clinically observed in subjects). Among them, Serious DDIs were observed with 4 drug combinations and these combinations were prescribed in 24 prescriptions. Serious interactions are those interactions that are required to change the drug or avoid the use together. The most common DDI observed in this category is Digoxin along with Pantoprazole (i.e., 71 %). Fortunately, the consequences of these interactions are not observed in our study subjects.
Of 131 potential DDIs, Moderate interactions were observed with 24 drug combinations and these combinations were prescribed in 107 prescriptions. Moderate interactions are those interactions that are required to monitor the consequences closely.
Among the 362 subjects, we observed that 42% of the subjects were discharged after recovery. Around 20 % of patients died during the therapy in the ICCU and MICU. We found that one patient who was on ventilation was suspected to die due to ADR i.e. Midazolam induced breathlessness. A study result by Maharani et. al [22] , states that More than half of the patients admitted in ICU were discharged with improvement in the condition for which they were admitted.

Drug Duplication:
We observed 2 Drug duplications with our study drugs among all the prescriptions (Insulin prescribed as ACTRAPID and MIXTARD, which were prescribed in 17 prescriptions). We also observed Therapeutic duplication with one class of drugs i.e., Insulin and Glimepiride, which are prescribed in 14 prescriptions. Though there was drug duplication, we did not found any issues related to the duplication. As the blood glucose levels were not controlled in those patients, they have prescribed two hypoglycemic agents.

CONCLUSION:
Utilization of high alert medications is appropriate to the standards and criteria of the study in the majority of the prescriptions i.e appropriate ROA, almost all the HAMs are written in their active ingredient/generic names, and we found very few drug-related problems such as overdose induced ADRs. We have observed a one-off labeled indication for Midazolam and the remaining drugs were prescribed for their labeled indications. The prescribed dose of the study drugs is comparable to the WHO-DDD and appropriate to the patient's condition.
Though, the DUE of HAMs is appropriate still some issues that need to be addressed were as follows: The dose calculation method is not uniform by all the prescribers. The dilution technique being followed for noradrenaline is not as per the specifications and no information chart/dilution technique is displayed on the study site. We have observed the usage of the same strength of enoxaparin for both loading and maintenance doses. Drug administrators are not mentioning in the prescription the exact dose administered to the patient for Atropine. Maintenance of ward pharmacy is not up to the standards; there is no regular check for expiry drugs, deteriorated drugs, drug misplaces, and not following the labeling standards especially for SALA high alert drugs. Finally, we conclude that there is a need to establish a DUE committee lead by a clinical pharmacist to identify such issues in time and rectify them for the improvement of drug use especially in emergency departments like ICCU.

FUNDING:
The authors declare that no funding has been received from any source.