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Role of pharmacist during COVID-19 pandemic: A retrospective study focused on critically ill COVID-19 patients

Background and aim During the Coronavirus 2019 (COVID-19) crisis, there has been a huge demand for medications and unprecedented utilization of intensive care unit (ICU) services that subsequently and profoundly impacted the quality of medical care provided to COVID-19 patients. This study aimed to shed light on the role of pharmacists on the health care provided to critically ill COVID-19 patients. Methods A retrospective study, was conducted in Diriyah hospital in Riyadh, Saudi Arabia on all COVID-19 patients admitted to the ICU between June 27th and August 15th, 2020 until patients were transferred to the medical ward, discharged, or deceased. All medication related interventions performed by pharmacists have been documented electronically, collected and subsequently categorized and analyzed. Results The mean age of patients was 58.8 years (±12.98 SD), with age of >64 years in approximately 37%. Four hundred and seventy interventions (470) were made by pharmacists of which 32%, 11.7%, 4%, 2.6%, 2.1% were due to error in dosing regimens, drug duplication, missing drug information, drugs requiring prior authorization, and missing critical information, respectively; while 40.6% were due to medication shortage of which 40.3% were substituted with alternative medications. Based on the analysis of drugs involved in interventions, medication groups that were mainly associated with interventions included antibiotics (16.8%), electrolytes/minerals (11.7%) and vitamins (9.4%). Conclusion During health crises such as COVID-19 pandemic, the role of pharmacists in the ICU services becomes extremely crucial for providing better patients’ outcomes. Further studies should be conducted to follow up these findings in the context of COVID-19 pandemic.


Introduction
Declaring Coronavirus 2019  pandemic by the World Health Organization on March 11, 2020 (Tang et al., 2020;World Health Organization), imposed a significant challenge on the global healthcare services and resources. During this crisis, there has been a huge demand for medications and unprecedented utilization of intensive care unit (ICU) services (World Health Organization, 2020), that has subsequently and profoundly impacted the quality of medical care provided to COVID-19 patients. Although respiratory distress and failure caused by SARS-CoV-2 is known to jeopardize the patients' lives, medication errors (MEs) and adverse drug events (ADEs) represent additional life-threatening factors.
All ICU cases are complicated in the sense that they require more parameters monitoring, multiple high-risk medications administration and are subjected to more frequent changes in therapeutic plans (Cullen et al., 1997;Moyen et al., 2008;Klopotowska et al., 2010). However, with COVID-19 pandemic, the situation has become more complex that consequently made the critically ill COVID-19 patients more vulnerable to MEs and ADEs.
Medication errors (MEs) represent a major concern globally. Early studies have estimated that MEs account for 7000 deaths annually in the United States (Phillips et al., 1998(Phillips et al., , 2001. Whereas recent reports have shown that the number is underestimated as MEs may account for up to 251,000 deaths a year in the U.S. (Makary and Daniel, 2016;Anderson and Abrahamson, 2017). Drug related mortality and morbidities have a major economic burden on the American health care system, as their cost was estimated to exceed $177 billion annually (Ernst and Grizzle, 2001). This underlines the significant role that pharmacists can play to provide the most economically saving therapies and more importantly ensure patients' safety during the treatment process.
Pharmacists have a crucial role in emergency medical services (EMS), including the ICU, through participation in planning pharmacotherapies and decisions related to clinical parameters evaluation and drug monitoring (Kane et al., 2003). Their interventions represent the first line defense that prevents MEs and ADEs from occurring in the first place, ultimately improving the medication safety. Beyond this, their presence in the ICU and consultation with ICU physicians have shown to reduce the consumed quantities of drugs, which was correlated with a reduction in the cost of drug therapy (Aljbouri et al., 2013;Montazeri and Cook, 1994), and prevent inappropriate drug use or ADEs, thus avoiding their attributable cost (MacLaren et al., 2021;MacLaren and Devlin, 2019). More details regarding contribution of pharmacists in the ICU is discussed elsewhere (Preslaski et al., 2013).
Despite the wealth of literature with the role of ICU pharmacists in general, there is a paucity of research on the role of pharmacists on the ICU admitted COVID-19 patients. This study aimed to explore the role of pharmacists in the ICU services provided to the critically ill COVID-19 patients. The overall goal of the study was to highlight the major types of pharmacists' interventions and MEs that pharmacists experience during caring for critically ill COVID-19 patients to draw the practitioners' attention to areas where they need to be more vigilant to warrant patients' safety during this pandemic.

Method
This retrospective study was conducted in Diriyah hospital in Riyadh, Saudi Arabia on all COVID-19 patients admitted to the ICU between June 27th and August 15th, 2020. Patients who were admitted before June 27th and after August 15th were excluded from the study. All patients' cases had been followed between June 27th and August 15th, until patients were transferred out of the ICU, i.e. transferred to the medical ward, discharged, or died. Baseline characteristics including demographic data, medical and disease history as well as pharmacists' interventions were collected by two on-duty pharmacists and two volunteering pharmacists with no need to informed consent from patients as the study was performed retrospectively. Ten out of twelve on-duty pharmacists provided therapeutic interventions during the study period. Pharmacist intervention in our study is defined as any action taken by the pharmacist on medications ordered to these patients that might have potential measurable impact on the quality of care provided to them during their stay in the ICU (Alderman and Farmer, 2001;Dooley et al., 2004;Mongaret et al., 2018). Following their collection, thery were counted and classified according to the predefined types of interventions built into the utilized software at the hospital. Medication groups or classes corresponded to these interventions were determined. A designed collection sheet was utilized to gather all required information. Data related to pharmacists' interventions and medications would be reviewed by one junior and 2 senior pharmacists, to ensure interventions align with the type or class provided by the software. Data were analyzed using Microsoft Excel 2019.

Baseline characteristics
During the study period, one hundred and nine patients were considered, of which thirty were excluded [9 admitted to the medical ward; 16 with inaccessible files since their transfer to Diriyah hospital was cancelled; 3 with inaccessible clinical notes; 2 patients with missing medication lists] that resulted in 79 patients to be included in the study. The mean age of patients was 58.8 years (±12.98 SD), with age of >64 years in approximately 37%, as shown in Table 1. Male patients represented 84.8% and all were non-Saudis. Diabetes and hypertension were the most prevalent comorbidities which were diagnosed in 59.5% and 58% of the Table 1 Clinical baseline characteristics of participants (N = 79).

Characteristic
Number ( patients, respectively. Obesity existed in 38% of the patients, while 29% of patients were classified as overweight. Most of the patients were sedated and mechanically ventilated (87% and 90%, respectively). Further details on baseline characteristics are provided in Table 1.

Classification of pharmacists' interventions based on their types
Four hundred and seventy interventions were made by pharmacists, as shown in Table 2. Of these interventions and based on the predefined types built into the software, 11.7%, 4%, 32%, 2.1% and 2.6% were due to drug duplication, drug information, error in dosing regimen, missing critical information about the patients and absence of prescriber's privilege, respectively. In addition, 40.6% of the interventions were related to medication shortage as they were out of stock or being nonformulary drugs, of which pharmacists suggested alternatives for 40%, while 60% were left without suggestions due absence of alternative medications, yet they were requested and supplied by the Saudi Ministry of Health (MOH) or other governmental hospitals falling under MOH umbrella. Interventions related to drug order rejection represented only 2%. Further analysis of the interventions under error in dosing regimens type revealed that 53% and 21% were associated to dose and frequency adjustments, respectively. Additional information related the types of interventions, corresponding number of recipients and example for each intervention are provided in Table 2.

Classification of pharmacists' intervention based on the pharmacological category of involved medications and their numbers
Many pharmacological groups were associated with the interventions. However, antibiotics (16.8%), electrolytes/minerals (11.7%) and vitamins (9.4%) are considered the most involved categories. Further details are provided in Table 3.
Regarding the number of interventions per patient, it ranged between none in 3 patients to 22 interventions in 1 patient, while many had 3 to 4 interventions, as shown in Table 4.

Health complications in COVID-19 patients during ICU stay and patients' survival
Cardiovascular and respiratory complications were found the most common in this cohort (25.5% and 26%, respectively), as shown in Table 5.
Patients were also categorized based on their survival. Unfortunately, 74.7% (59 patients) died, while only 20.3% (16 patients) survived at the end of the study. Interestingly, when BMI was compared between patients who survived and discharge (12 patients) vs. those who died (51 patients), no significant difference was observed (mean BMI 30.30 kg/m 2 vs. 31.2 kg/m 2 , respectively), as provided in Fig. 1. It is worth to mention that a total of 16 patients from the cohort were excluded from this analysis because of missing BMI and/or survival data (4 patients), missing BMI data only (10 patients) or being transferred to another hospital where survival data could not be obtained (2 patients).

Discussion
Many studies have been conducted investigating the essential services delivered by pharmacists during COVID-19 pandemic.
Pharmacists had the likely to show a superior role during this pandemic in multiple aspects, such as providing drug information for healthcare providers (Dhahri et al., 2020;Louiselle et al., 2020), patients counseling (Meng et al., 2020), suggestion alternative therapy (Ong et al., 2020), therapeutic drug monitoring (Mongaret et al., 2018), drug supply administration (Ong et al., 2020;Tan et al., 2020) and safety measures for infection control (Ong et al., 2020;Zuckerman et al., 2020). This study sheds light on the services provided by pharmacists to the critically ill COVID-19 patients in Riyadh, Saudi Arabia.
Since the beginning of this pandemic, researchers all over the world started searching different aspects of this novel disease. As the available peer reviewed literature regarding the services of pharmacists provided to COVID-19 patients in the ICU setting has been scarce, it has become of our interest to assess that during the pandemic. Understanding how pharmacists have contributed in providing services to the critically ill COVID-19 patients would highlight their achievements and more importantly expose any gap in their practice giving ample opportunity for future improvements.
Only one study conducted on 22 ICU-admitted COVID-19 patients in China investigating this topic and was published recently by Wang et al. (2021). Wang et al. (2021) have shown that drug discontinuation was the most common recommendation (31.5%; 35 out of 111) while dose adjustment accounted for 15.3%. Despite the slight difference in type of interventions at drug level compared to our study, most of the recommendation based on their observation were related antibiotics (57.7%) which aligns with the current reported results (16.8%; 79 of 470) in spite of the lower rate. As studies discussing this matter are rarely reported (Wang et al., 2021), it becomes challenging to compare our findings to additional studies. Nevertheless, a quick glance on types of interventions made by pharmacists on the critically ill COVID-19 patients reveled some similarities with their interventions at different critical care units. For instance, a study focused on the impact of pharmacists' interventions with respect to drug-related problems (DRPs) in the ICU has shown 28.9% and 14.3% were related to wrong dosing regimen and no indication for drug use, respectively (Al-Jazairi et al., 2008). Additional study assessing the role of clinical pharmacy services in the oncology ward showed that 26.6%, 21.5% and 10.3% of pharmacist's interventions were related to drug discontinuation, drug dosing adjustments, and therapeutic drug monitoring (Delpeuch et al., 2015). Further findings from the oncology ward revealed 27.1%, 20.0%, 6.2%, 5.1% of the pharmacist interventions were secondary to drug dosing modifications, therapy discontinuations, recall of the treatment, and replacement of a drug with another one, respectively (Moukafih et al., 2021). Another study conducted by Faqeer and colleagues on identifying DRPs in the oncology ward, showed that addition of medications (38.7%), then discontinuation of medications (25%) were the most common types of interventions followed by dose adjustment secondary to wrong dose (3.7%) (Faqeer et al., 2021). In the internal medical ward, Abunahlah and colleagues showed that inappropriate drug use (44.79%), inappropriate dose (27.61%), and inappropriate medication treatment procedures (21.47%) were the most common interventions identified by the clinical pharmacists (Abunahlah et al., 2018). Although Molino and colleagues' study was conducted in the outpatients' setting, they reported similar rate of our interventions related to drug duplication (11.29%), and lower rate of those associated to dose adjustment (20.05%) (Molino Cde et al., 2014).
Comparing with the current literature, our results are in agreement with the type of ICU pharmacists' interventions seen in the current pharmacy practice in hospitals, reiterating the notion that more attention should be directed towards errors in the prescribed regimens that are mainly attributed to wrong dose and/or frequencies. Our results also showed approximately 60% of the interventions associated to medication shortage were left with no alternative suggestions (117 of 191). Despite that, these medications were requested and supplied by MOH, either directly or via other MOH-operated hospitals.
By looking at the complications that COVID-19 patients developed during ICU admission, respiratory complications were found to be the most prominent (26%) among which pneumonia, tachypnea, ARDS, hypoxia, and metabolic acidosis which were more frequent, followed by the cardiovascular complications (25.5%), which were mainly hypotension, septic shock and bradycardia/tachycardia. These results are in agreement with Hajjar et al study that was focused on the intensive care management of COVID-19 patients (Hajjar et al., 2021). Finally, and unexpectedly, when BMI was compared between the survived and deceased patients, there was no significant difference between the two groups.

Conclusion
Our findings highlight that pharmacist's attention should be amplified towards errors in dosing regimens and drug duplications throughout caring of critically ill COVID-19 patients. In addition, with medication shortage that potentially occur during the pandemic, pharmacist as a medication expert should be proactive in providing information about drugs and their alternatives, if necessary, for healthcare providers. Studies focused on significance of pharmacists' interventions on health outcomes of critically ill COVID-19 patients and their acceptance by physicians should be conducted to follow up these findings.

Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. A. Alwhaibi, A. Alrwaished, Shoug Majed Binobydaan et al. Saudi Pharmaceutical Journal 29 (2021) 1050-1055