Medication is one of the frequently used modalities to treat illnesses throughout the world. However, improper medication use has a catastrophic impact on patients increasing adverse events (AEs), morbidity, prolonged hospital stays, costs, and mortality (Al Hamid et al., 2014; Aderemi-Williams et al., 2015; Watanabe et al., 2018; Formica et al., 2018; Giardina et al., 2018) Patient safety is one of the fundamental patient rights and should be ensured during the health care provision process.

According to the World Health Organization (WHO), AEs are included in the top 10 leading causes of death and disability worldwide (WHO, 2019a). Overall, 10% of hospital admissions are reported to be due to AEs following medication (WHO, 2015). More recently among countries in the Organization for Economic Co-operation and Development (OECD), it has been estimated that 15% of total hospital expenditure resulted from AEs (Slawomirski et al., 2017). In addition, in high-income countries, one out of every 10 hospitalized patients were harmed with AEs, with half of them considered preventable (WHO, 2019a). In the United States, more than 7 million hospitalized patients are affected by medication errors (MEs), and MEs are estimated overall to cost $40 billion annually (Tariq et al., 2020). In the United Kingdom, 2.37 million MEs are reported with an economic burden of £98.5 million per year (Hodkinson et al., 2020). The situation is even worse in low-middle income countries (LMICs) where more than 134 million AEs are reported due to unsafe medication, with more than 2.6 million deaths every year (WHO, 2019a). Patient safety is a key concern in the Eastern Mediterranean region where 18% of hospitalizations are associated with AEs; 3% lead to permanent disability or deaths with more than 80% AEs considered preventable (WHO, 2015).

Approximately two decades ago, the WHO instigated activities to enhance patient safety and proposed active debate in World Health Assembly (WHA). The subsequent resolution on patient safety urged Member States to take initiatives against patient harm. This campaign led to the development of safe medication programs across the world (WHO, 2019b). In 2021, again, a resolution presented in the 72nd WHA demonstrated the need to improve patient safety by implementing continuous training and skill development among health care professionals (WHO, 2021).

High alert medications (HAMs) are a special class of medicines bearing a greater risk of patient harm than other medicines when prescribed or administered inappropriately (Labib et al., 2018; Salman et al., 2020). HAMs include chemotherapeutic agents, cardiovascular medicines, anticoagulants, opioids and their derivatives, insulin, neuromuscular blocking agents, benzodiazepines, and certain electrolytes in high concentrations (Zyoud et al., 2019). Consequently, prescription, administration, storage, and handling of HAMs should require specific protocols and regulations to reduce or prevent harm related to their prescribing. The prevalence of MEs due to HAMs ranges from 3.8% to 100% in hospital settings with a pooled prevalence rate of 16.3% (Alves et al., 2021). The severity of these errors in this systematic review ranged from 0.1% to 19.2% for moderate errors and 0.2% to 15.4% for serious errors, and 1.9% lead to death (Alves et al., 2021). MEs related to HAMs can occur due to multiple factors including poor communications between health professionals and patients, the improper passage of medication information, organizational factors, interruption during the medication process, psychological impairment of staff, overburden on healthcare professionals (HCPs), lack of regulation and policies, and insufficient awareness among HCPs (Keers et al., 2013; Sessions et al., 2019).

Pakistan is a LMIC located in South Asia with a struggling health care delivery system due to poor governance, inconsistent health policies, and insufficient resources (Kurji et al., 2016). Despite this, there have been a number of initiatives facilitated by the Government and others in Pakistan to enhance patient safety (Jafree et al., 2017); however, patient safety is challenging. It is recently reported that more than half a million deaths occur in Pakistan every year due to MEs, substantially higher than in the United States where the number of causalities due to MEs range between 7,000 and 9,000 per year (Dawn newspaper, 2017; Tariq et al., 2020). A previous study conducted by Mahmoud et al. among low-middle income Asian countries including Pakistan revealed that more than 95% of MEs were prescribing errors (Mahmoud et al., 2020).

A previous study undertaken in the United States indicated that most of the HCPs did not obtain sufficient training on HAMs during their education regarding medication use and HAMs. More specifically, the involvement of prescribers in the training on HAMs was reported to be lower among physicians compared with pharmacy and nursing personnel (Engels and Ciarkowski, 2015). Being an important member of multidisciplinary health care provision teams, physicians need to be informed about all aspects regarding medicines including their administration and potential harm.

Overall, physicians are a key player in addressing issues relating to patient safety as they are recognized as often initiators of the medication use process across sectors after examining the patients according to their needs. In addition, they often need to play the role of an expert in prescribing the right drug for the right patient with the right dose via the right route of administration (Maxwell, 2016). While there are multiple factors that contribute to MEs (Mutair et al., 2021), these are reduced in high-risk situations if they are properly educated, trained, and equipped to prevent such medicine-related harms (Wittich et al., 2014). Consequently, their knowledge regarding administration, regulations, and practices related to HAMs is of considerable importance to prevent HAMs-related errors among patients. Recently, the death of a 9-month-old baby girl due to abrupt administration of 15% potassium chloride (KCl) enhanced issues of HAMs errors in Pakistan (Salman et al., 2020). In view of this, the objectives of this study were to evaluate the awareness of Pakistani physicians about HAMs administration, regulations, and practices during their routine work. We have previously reported on HAM knowledge among nurses (Salman et al., 2020), and we are aware of previous publications regarding concerns with medication safety among physicians and pharmacists in Pakistan (Jafree et al., 2017; Mahmoud et al., 2020). We wanted to build on this to provide future guidance.

We believe this is the first study of its kind in Pakistan to evaluate the knowledge and practices on HAMs-related administration and regulations among physicians throughout Pakistan, building on our previous study among nurses (Salman et al., 2020). There were areas of encouragement. However, we identified a number of areas of concern that need to be addressed. Epinephrine is recommended as first-line therapy in anaphylaxis, and it should be administered at a dose of 0.1 mg in the diluted form via slow infusion (in 5–15 min). However, one-fourth of the Pakistani physicians in our study were unable to administer this HAM according to these guidelines. Our previous study conducted among registered nurses revealed similar findings about the administration of epinephrine (Salman et al., 2020). Our findings though are in line with a recent study reported by Wijekoon et al. (2021) from Sri Lanka who revealed that majority of the study population knew that epinephrine is the first-line drug to treat anaphylaxis along with correct dose in children and adults (Wijekoon et al., 2021). Encouragingly, our findings are better than previous studies reported from the United Kingdom, where 15% of physicians were familiar with the recommended way of epinephrine administration in anaphylaxis (Droste and Narayan, 2010; Droste and Narayan, 2012; Tyree et al., 2012).

Similarly, CaCl₂, another HAM, indicated for electrolytes abnormalities to advance cardiac life support (Chakraborty and Can, 2021), carries the potential of cutaneous burning sensation and peripheral vasodilation when administered via intravenous (IV) push. Consequently, it is recommended to administer CaCl₂ slowly (in 5–10 min) and repeat the same if necessary (Lindner et al., 2020). The concentration of calcium in CaCl₂ is three times than that present in calcium gluconate, and hence they cannot be replaced by each other. However, one-third of physicians in our study were not aware of the right way of CaCl₂ administration and even considered that CaCl₂ can be replaced with calcium gluconate. These findings though are in line with the previous study from the United Kingdom (Powell et al., 2013) that reported poor knowledge among doctors about the IV administration of different IV fluids including CaCl₂.

Abrupt administration of concentrated KCl carries the risk of arrhythmias, cardiac arrest, and even deaths reported throughout the world (Grissinger, 2011; Bertol, et al., 2012). Consequently, physicians must prescribe KCl in a diluted form and administer it slowly to avoid complications. However, one-third of our study population were not aware of the right way of KCl administration, and less than half of the participants agreed to add KCl in Ringer's solution despite the chances of metabolic alkalosis. These findings though are similar to the results of a previous study from Japan that reported inadequate physicians' knowledge about the KCl administration necessitating interventions for improvement (Nakatani et al., 2019). Another HAM, insulin, needs to be administered carefully with the right dose usually calculated in international units. Moreover, it should be administered using a dedicated insulin syringe. However, of concern is that nearly half of the physicians in our study were unaware that dose expression for insulin is in international units and not in “ml.” Our findings are contrary though to those of Bain et al. (2019) who reported a better understanding of insulin-related factors among junior doctors, pharmacists, and nurses from the United Kingdom where more than two-thirds of consultant physicians possessed good knowledge about insulin and its administration (Bain et al., 2019).

Incorrect dose calculation, especially among children, is one of the major contributing factors in the emergence of adverse drug events (ADEs). Consequently, physicians are expected to be precise while prescribing to them. However, only one-third of physicians in our study gave correct responses to the question about dose calculation in children and adults. These findings are contrary to the result of a previous study from Australia that reported a high percentage of medical students were well aware of the dose calculation methods (Harries and Botha, 2013). Our survey revealed that the age, level of education, working experience, and hospital type are related to better HAMs administration scores among physicians. These findings are in line with a recent study reported from KPK Province, Pakistan, where age and working experience of the medical doctors are associated with better drug safety knowledge (Sharif et al., 2021). In our previous study conducted among nurses, no associations though were observed between HAMs administration awareness with age, experience, and level of education (Salman et al., 2020). We are not sure of the reasons why; however, this may relate to greater learning curves among physicians as they gain experience. We also found that physicians currently serving in tertiary care/teaching hospitals possessed better HAMs awareness compared with primary and secondary hospital physicians, similar to the previous study conducted among nurses from tertiary care hospitals that found they also had better HAMs knowledge (Salman et al., 2020). This may reflect a greater complexity of cases in tertiary hospitals and the need to be more vigilant regarding HAMs.

HAMs typically require special precautions during their prescription, administration, and storage in the wards. Consequently, special regulations are typically needed to avoid any harm due to their inappropriate use. Using inconsistent abbreviations while prescribing HAMs carries an even greater risk of MEs, so prescribers need to be careful while prescribing them. The use of only “U” instead of “units” needs to be avoided as an appropriate strategy for the prescriber, as discussed in the previous study (Zyoud et al., 2019). Insulin is a refrigerated medicine (2–8°C), whereas heparin should be stored at room temperature under lock and key (Riley and Meyers, 2016). Regarding atracurium regulation, it should be refrigerated at 2–8°C to preserve potency, and it should be used within 14 days, even if re-refrigerated. This is a concern as an earlier study by Engels et al. revealed that 6% of HAMs-related errors were associated with their inappropriate storage (Engels and Ciarkowski, 2015). Again, some physicians in our study were not familiar with these regulations on HAMs. This is different from our findings among registered nurses where the majority of study participants were familiar with HAM related regulations (Salman et al., 2020). This may be because nurses typically administer heparin and consequently are expected to know more about storage requirements.

Verbal orders about medication are associated with MEs due to poor audition, understanding, and wrong word heard; thus, verbal orders about HAMs should not be delivered by the physicians (Moghaddasi et al., 2017). For the safety of patients, there is a recommended place in the patient's medical record for the prescription of HAMs in order that all members of the health care provision team can easily identify it and be attentive while dealing with that drug. After prescribing, physicians must instruct the nursing staff to use a “double-check policy” (Hewitt et al., 2016) to confirm the patient's name, drug name, dose, frequency, and route of administration before initiation of medication administration. Encouragingly, most of our study physicians followed good practices including prescribing HAMs with complete instructions, stressing double-check policies, and following standard operating procedures developed to reduce HAM-related errors as all these strategies have been devised to reduce errors related to HAMs.

The current survey showed that most of the Pakistani physicians possessed average knowledge about the administration and regulation of HAMs. Similar trends were observed about their practices related to HAM during their routine work. Consequently, policy makers and others need to instigate future measures to enhance patient safety during routine health care provision. All concerned authorities should take appropriate steps to revise the current curriculum in medical institutions to ensure key subjects about patient's safety, in particular, HAMs, are included. All hospital settings should also ensure continuous trainings/workshops for the physicians with a special focus on HAMs and patient safety. Standard operating procedures related to HAMS administration and regulations should also be introduced and monitored at the institutional level. Moreover, hospitals should seek to establish multidisciplinary health care provision teams, if not already implemented, through engaging board-certified clinical pharmacists and specialized nurses to develop guidelines and standard operating procedures to minimize future harms related to the medication use process, and continually monitor activities.