Availability of antidotes in Moroccan hospitals: a national survey

Abstract

Aim

The lack of availability of antidotes is a challenge for hospitals all over the world. The objective of our study was to investigate the availability of antidotes in Moroccan hospitals.

Methods

A cross-sectional, questionnaire-based study was conducted from November 2018 to April 2019. The questionnaire was sent to 25 hospitals in order to investigate the availability of 42 selected antidotes based on the International Programme on Chemical Safety list.

Results

The survey response rate was 68%. Of the 42 selected antidotes, 38 (90.5%) were available depending on the hospitals included in the study. We found a strong correlation between the availability of antidotes and hospital bed capacity, and logistic regression analysis revealed that bed capacity is the only factor strongly associated with higher antidote stock levels. Some essential antidotes such as digoxin-specific antibody, protamine sulfate, flumazenil and glucagon were unavailable in many of the small- and medium-sized hospitals, and methylene blue, sodium nitroprussiate, Prussian blue and anti-snake venom were absent in all of the hospitals.

Conclusion

Despite the great efforts that have been made to improve the availability of antidotes in Morocco, some of these vital products are still lacking in Moroccan hospitals.

Introduction

The management of poisoning cases generally involves a comprehensive and multidisciplinary approach. In most cases, this approach consists of eliminating or evacuating the poison and also normalising the organism's function by symptomatic treatment. However, sometimes resorting to specific treatment with an antidote is essential and represents the best way of achieving a better poisoning outcome.

An antidote is defined as a ‘therapeutic substance used to counteract the toxic action of a specific xenobiotic’.¹ Antidotes are the treatment of choice for many poisoning episodes and are sometimes the only life-saving therapy available. Antidotes should be administered as soon as possible depending on the nature of the poisoning as delayed administration can negatively influence the prognosis of intoxication.

The International Programme on Chemical Safety (IPCS) and the World Health Organization (WHO)² proposed a classification comprising four groups of antidotes according to their effectiveness in clinical practice and urgency of need:

• Group 1: Antidotes considered useful in the treatment of poisoning

• Group 2: Agents used to prevent the absorption of poisons, to enhance their elimination or to provide supportive treatment

• Group 3: Therapeutic agents useful in the management of poisonings

• Group 4: Antidotes and related agents considered to be obsolete.

Antidotes are also subdivided according to the urgency of availability and their effectiveness. In terms of the urgency of availability, antidotes are classified in three levels, namely Class A: Antidotes should be immediately available (within 30 min); they must be stocked by all hospitals; Class B: Antidotes are required within 2 hours; they can be stocked at certain main hospitals; and Class C: Antidotes are required within 6 hours; they may be stocked at central regional warehouses. According to their effectiveness, antidotes have been classified in three classes, namely 1: Efficacy well documented; 2: Antidote widely used, but requiring further research concerning effectiveness; and 3: The antidote is of questionable usefulness. The combination of classification according to urgency of availability (Class A, B and C) and effectiveness (Class 1, 2 and 3) is the main criteria for the indication of an antidote.

For all categories of antidotes, the quantities stored in hospital facilities must meet usage requirements.

The availability of antidotes is associated with adequate stocking in hospitals. The minimum stocking level of antidotes as recommended by the Royal College of Emergency Medicine and National Poison Information Service Guideline on Antidote Availability in Emergency Departments (United Kingdom, 2017) was estimated based on the treatment of one 70 kg adult patient over the first 24 hours after exposure.³ This recommended quantity of antidotes can be revised upwards for collective poisoning. The maximum quantity is determined based on local poisoning data.^{3 4} However, it is important to distinguish between availability and accessibility of antidote. If the availability depends on adequate stocking, the accessibility depends on several other factors, the most important of which are marketing authorisations and local supplier procurement. This remains a major problem in developing countries.

The lack of adequate and readily available antidotes in healthcare settings is a global problem and has been documented in a number of studies.^5–23 The intensity of the unavailability of antidotes varies by country and region, and it is more significant in developing countries. Several reasons have been put forward to explain this finding such as antidotes’ infrequent use, cost and short shelf life.²⁴

In 2007 we published an article that demonstrated the significant lack of availability of antidotes in several Moroccan hospitals.¹⁴ Since then, several actions have been carried out to improve the availability of antidotes in Moroccan hospitals. Therefore, the purpose of this study was to assess whether antidote stocking has improved since 2007. We have widened our sample of healthcare settings compared with our earlier work.

Methods

This investigation was a cross-sectional survey carried out by means of a questionnaire to evaluate the availability of antidotes in Morocco. Data collection was conducted from November 2018 to April 2019. The questionnaire followed a similar design to that used in our previously published study¹⁴ with some modifications. The questionnaire comprised 26 questions organised in several parts which made it possible to collect general information concerning the nature of participating hospitals, including the number of operational beds, the absence or presence of an emergency department, and the organisation of the pharmaceutical department. The questionnaire included 42 antidotes based on the IPCS list.² In order to be available, the stored quantity of antidote must be sufficient to commence treatment and continue it for a further 24 hours.³ The study was approved by the local Ethical Committee of the Faculty of Medicine and Pharmacy in Rabat, Morocco.

The questionnaire also concerned toxicological information as regards the number of poisoning episodes per year and the availability of antidotes and their management. Pharmacists were asked to indicate whether or not these antidotes were available at their pharmacies and the reason for their unavailability. The questionnaire was sent by email and via Google Forms with the possibility of completing and returning the questionnaire in the same manner.

The questionnaire was sent to the 25 main hospitals in Morocco; these hospitals cover 11 (of 12) administrative regions and therefore the majority of the national territory. Public and military hospitals were included in the study; however, private hospitals were excluded. Non-responders were reminded twice by e-mail addressed to the pharmacy director. Any questionnaire with less than 60% of the total number of questions completed was excluded from the study.

The results were presented as absolute numbers and percentages for categorical variables and as medians and ranges for quantitative variables. Comparisons between groups were done using Chi square or Fisher's exact tests. Pearson’s correlation coefficient was calculated to assess the degree of association between the hospital bed capacity and antidote availability. Binary logistic regression was used to assess and identify the influence of variables on antidote availability; odds ratios with 95% confidence intervals were calculated. All analyses were performed using SPSS 21.0 for Windows (SPSS, Inc., Chicago, IL, USA). P values less than 0.05 were considered to be statistically significant.

Results

A total of 17 (68%) hospitals completed the questionnaire. The bed capacity exceeded 900 for three hospitals (these being the most important university hospitals in Morocco with teaching functions), while six hospitals had a capacity of between 300 and 900 beds and eight hospitals had fewer than 300 beds. All participating hospitals reported that they offered emergency care. The permanent presence of a pharmacist was guaranteed in nine hospitals and only two hospitals offered toxicology testing.

Nine hospitals declared that they received fewer than 10 000 poisoning cases per year; the other hospitals declared that they did not have data on poisoning cases. Nine of the 17 participating hospitals reported having a list of drugs identified as antidotes but they did not know how this list wasgenerated, while the others claimed to have established their lists through regulatory texts, based on a review of the literature or by consulting local experts and hospital drugs committees. The IPCS recommendations were recognised by only two pharmacists.

The majority (13/17) of hospitals included in the study confirmed that they obtain antidotes from the health ministry, and eight of them receive antidotes from the Poison Control Centre of Morocco. Two military hospitals purchase their antidotes directly from foreign suppliers (since their purchasing procedure allows this), while the two hospital and university centres obtain antidotes by open government contracts.

Of the 42 selected antidotes, 38 (90.5%) were available depending on the hospitals included in the study. table 1 summarises the availability of antidotes considered useful in the treatment of poisoning (Group 1, IPCS) while table 2 shows the availability of antidotes used to prevent the absorption of poisons, to enhance their elimination or to provide supportive treatment (IPCS, Group 2). Group 2 antidotes appear to be more available in hospitals than Group 1 antidotes (p<0.001). As regards all classes of antidotes combined, the availability of antidotes appears be better in hospitals with a large bed capacity (table 3) and we found a strong correlation between the availability of antidotes and hospital bed capacity (r=0.83, p<0.001, n=17). Logistic regression analysis revealed that the only factor strongly associated with higher antidote stock levels was bed capacity. Hospitals with a larger bed capacity stocked more antidotes (table 4). However, none of the hospitals provided data on their stocking capacity. Methylene blue, sodium nitroprussiate, Prussian blue and anti-snake venom were absent in all of the hospitals, and some essential antidotes that must be used within 30 min of the poisoning episode such as digoxin-specific antibody had low availability.

Table 1.

Availability of antidotes considered useful in the treatment of poisoning (International Programme on Chemical Safety (IPCS), Group 1)

Antidote	Poisoning indication	Status*	Availability (n (%)) (n=17)
Amylnitrite	Cyanide	A2	3 (17.7)
Atropine	Organophosphorus or carbamate	A1	14 (82.4)
Calcium gluconate	Hydrofluoric acid	A1	14 (82.4)
Dantrolene	Neuroleptic malignant syndrome	A2	3 (17.7)
Dicobalt edetate/hydroxocobalamin (Cyanokit)	Cyanide	A1	2 (11.8)
Diazepam	Organophosphorus	A2	12 (70.6)
Digoxin-specific antibody	Digoxin and related glycosides	A1	4 (23.6)
Ethanol (intravenous or per os)	Methanol, ethylene glycol	A1	4 (23.6)
Fomepizole	Methanol, ethylene glycol	A1	2 (11.8)
Glucagon	Beta-blockers	A1	6 (35.3)
Isoprenaline	Beta-blockers	A1	2 (11.8)
Methylene blue	Methemoglobinaemia	A1	0 (0)
Naloxone	Opioids	A1	10 (58.8)
Phentolamine	MAOI interaction, cocaine, epinephrine and ergot alkaloid	A1	3 (17.7)
Physostigmine	Anticholinergic syndrome	A1	6 (35.3)
Propranolol	Beta-adrenergic agonists	A1	7 (41.2)
Protamine sulfate	Heparin	A1	5 (29.4)
Pyridoxine	Isoniazid	A2	5 (29.4)
Sodium thiosulfate	Cyanide, nitroprusside	A1	4 (23.6)
Sodium nitrite	Intoxication with cyanides	A1	3 (17.7)
Sodium nitroprussiate	Ergotism	A1	0 (0)
Acetylcysteine	Acetaminophen (paracetamol)	B1	5 (29.4)
Anti-snake venom	Venomous snake	B2	0 (0)
Desferroxamine	Iron poisoning	B1	4 (23.6)
Dimercaprol	Arsenic poisoning	B1	3 (17.7)
Flumazenil	Benzodiazepines	B2	4 (23.6)
Folinic acid	Methotrexate Methanol	B1 B2	3 (17.7)
Methionine	Acetaminophen (paracetamol)	B1	3 (17.7)
Neostigmine	Neuromuscular block (curare type) and peripheral anticholinergic effects	B1	12 (70.6)
Pralidoxime	Organophosphate	B2	4 (23.6)
Prussian blue	Thallium	B2	0 (0)
Silibinin	Amatoxin-containing mushrooms	B2	2 (11.8)
Calcium disodium EDTA	Lead	C2	2 (11.8)
Phytomenadione (vitamin K1)	Vitamin K-dependent anticoagulants	C1	9 (52.9)
Succimer	Lead, mercury, arsenic	C3	2 (11.8)
Trientine (triethylene tetramine)	Copper (Wilson’s disease)	C2	3 (17.7)
Antidote availability (median of % (range))			20.7 (0–82.4)

*Status according to the IPCS classification: urgency of availability (Class A, B or C) and the degree of proven effectiveness (Class 1, 2 or 3).²

IPCS, International Programme on Chemical Safety; MAOI, monoamine oxidase inhibitors.

Table 2.

Availability of antidotes used to prevent the absorption of poisons, to enhance their elimination or to provide supportive treatment (International Programme on Chemical Safety (IPCS), Group 2)

Antidote	Toxic agent	Status*	Availability (n (%)) (n=17)
Activated charcoal	Agents to prevent absorption of toxic substances by the gastrointestinal tract	A1	10 (58.8)
Dimethicone	Anti-foaming agent	A1	2 (11.8)
Sodium bicarbonate	Agents to alkalinise urine or blood	A1	15 (88.2)
Magnesium citrate, sulfate, hydroxide	Whole gut lavage	B3	8 (47.1)
Polyethylene glycol	Whole gut lavage	B2	3 (17.6)
Sodium bicarbonate	Drug with membrane stabilising effects	A1	15 (88.2)
Antidote availability (median of % (range))			53.0 (11.8–88.2)

*Status according to the IPCS classification: urgency of availability (Class A, B or C) and the degree of proven effectiveness (Class 1, 2 or 3).²

IPCS, International Programme on Chemical Safety

Table 3.

Availability of different classes of antidotes according to hospital bed capacity

Hospital bed capacity (n)	Class A antidotes (n (%)) (n=23)	Class B antidotes (n (%)) (n=11)	Class C antidotes (n (%)) (n=4)	P value
Large >900 (n=3)	19 (82.6)	10 (90.9)	2 (50.0)	<0.001*
Medium 300–900 (n=6)	15 (65.2)	6 (54.6)	1 (25.0)	<0.001*
Small <300 (n=8)	6 (26.1)	1 (9.1)	0 (0)	<0.001*

*P value <0.05 considered significant

Table 4.

Hospital bed capacity associated with antidote availability

Hospital bed capacity (n)	OR	95% CI	P value*
<300	1		Reference
300–900	2.81	1.61 to 5.30	<0.001*
>900	4.08	2.15 to 12.82	<0.001*

*P value <0.05 considered significant

In response to the question regarding supply difficulties, all hospitals declared that budgetary constraints, short shelf-life and the absence of national recommendations constituted a major handicap to the supply of antidotes.

Discussion

The usual and effective management of most poisoning episodes is based mainly on the maintenance of vital functions, decontamination, increased elimination as well as symptomatic treatment. Although the use of specific antidotes is rarely considered, it can sometimes be decisive in the outcome of certain intoxications. However, antidote stocking represents a major challenge to hospitals all over the world; and despite expert consensus guidelines, several previously published studies have shown insufficient stocking of antidotes in hospitals.^5–23 This study aimed to evaluate antidote availability in public hospitals in Morocco.

In 2007, a survey of antidote availability in eight Moroccan hospitals demonstrated an important lack of adequate and readily available antidotes and only 18/43 (41.9%) of the selected antidotes were available. None of the eight hospitals stocked methylene blue, digoxin-specific antibody, succimer, fomepizole, acetylcysteine, pyridoxine, glucagon and activated charcoal.³ Our study found that in 2019, the availability of these antidotes had increased considerably; only methylene blue was not available compared with the 2007 study and 38/42 (90.5%) of the selected antidotes were available depending on the hospital. This improvement could be due to the great efforts made by the Ministry of Health in Morocco and greater awareness among healthcare professionals of the need for proper stocking of antidotes. Indeed, since 2007, the Moroccan Ministry of Health has created an antidote stockpile managed by the Poison Control Centre of Morocco, with the objective being to ensure the availability of essential antidotes, and to promote the rationalisation of their use. Following this decision, several antidotes became available with rational distribution depending on the regional epidemiology of poisoning cases.²⁴ Moreover, we observed a definite improvement in the availability of antidotes in the two military hospitals, this being mainly due to a better awareness among healthcare professionals since the hospitals' purchasing procedures had not changed since our previous study. These hospitals can purchase antidotes and other drugs directly either from foreign or national pharmaceutical markets.

The availability of antidotes can vary greatly from one hospital to another depending mainly on the size of the facility. Antidotes are, in general, adequately stocked in the larger hospitals; and in agreement with a previous study, the number of visits to the emergency department and the consumption of antidotes can be used as indicators for stocking adequate antidotes in the hospital or pharmacy.⁸ In our present study we found a strong correlation between the availability of antidotes and hospital bed capacity, and the logistic regression analysis model revealed that the number of hospital beds was associated with a high rate of antidote availability stocking. All groups of antidotes were more available in large, compared to medium and small, hospitals. This highlights a gap in the supply of important medicines to some hospitals in Morocco. This result is consistent with previous studies,5 7 9–11 13 15 25 which report that larger teaching hospitals tended to stock more antidotes than smaller and non-teaching hospitals, where antidotes could be seen as relatively exotic products and thus may be excluded from the hospitals’ routine purchase list. Conversely, the large hospitals in Morocco are those that have hospital pharmacists with pharmaceutical permanence and databases dedicated to poisoning cases. In this context, hospital pharmacists can improve the availability of antidotes by establishing a nomenclature specific to these products with dedicated budget lines and optimisation of use. These factors may contribute to better availability of antidotes in these hospitals.

We noticed that none of the 42 selected antidotes were available in all hospitals. Some essential antidotes such as digoxin-specific antibody, protamine sulfate, flumazenil and glucagon were unavailable in many small- and medium-sized hospitals; this can be explained by the limited use of these antidotes and their high cost. For example, digoxin-specific antibody is unquestionably effective in cases of severe digoxin poisoning²⁶ and yet only four of the surveyed hospitals stock it. This applies also to cyanide antidotes which were available in very few hospitals and yet they must be used urgently (ie, within 30 min). This contradicts the WHO guidelines for Poison Control Centre recommendations, which recommends that all immediate antidotes should be available at the hospital site at all times.¹ In these situations, interhospital transfer of expensive and rarely used antidotes may be effective for treating acute poisoning episodes. It is important, however, to clarify that anti-snake venom, which was not available in any of the hospitals, is stored in the antidote stockpile of the Poison Control Centre and distributed as needed. Some reasons for not stocking antidotes, as reported in previous studies, included budget constraints, high cost, short shelf-life and national unavailability.^{14 15 27} This is in accordance with our findings, but there coud be other reasons such as the absence of requests from physicians, the fact that antidotes can be obtained expeditiously from neighbouring facilities in cases of urgent need, and the lack of comprehensive guidelines regarding antidotes in Morocco. The unavailability of some antidotes through normal commercial channels may also contribute to insufficient antidote stocking in Morocco.

In contrast, other antidotes such as atropine, diazepam and neostigmine were available in most hospitals; these medicines are in high demand within Moroccan hospitals. This finding has been reported by other studies, which noted that antidotes uncommonly used and/or used to treat conditions other than poisonings were more frequently stocked.⁵

The widespread unavailability of antidotes has been documented in several studies. This unavailability affects both developed and developing countries. Inadequate stocking of antidotes has been reported in Canada,6 9 10 13 USA,²⁸ Norway,⁸ Denmark,¹² UK,¹⁹ Czech Republic,¹¹ Greece,⁷ Austria,¹⁵ New Zealand,^{17 21} Brazil,^{18 22} Taiwan,⁵ Malaysia,¹⁶ Korea²⁰ and in some Arabic countries.14 23 25 29 30 In developed countries the unavailability affects only rarely required and expensive antidotes,12 13 19 28 whereas in developing countries the problem is more serious and often involves essential antidotes.^{14 18 23} This difference could be mainly due to the lack of guidelines, financial resources and the non-marketing of antidotes by local suppliers in some countries. This problem could be ameliorated by international guidelines, reducing excessive stock of expensive antidotes and facilitating the trade of antidotes between different countries.

The present study gave us a clear vision about antidote availability in Morocco since the 17 hospitals that responded favourably to our survey represent the most important healthcare facilities in our country. While great efforts have been made to improve antidote availability in Morocco, some of these vital products are still lacking in Moroccan hospitals. Raising awareness about the importance of antidotes by education, appropriate legislation, and regular review of antidote storage with distribution plans might ultimately provide solutions to this problem.

This study has a number of limitations. First, our objective was only to document the availability of antidotes in Moroccan hospitals without studying the other factors that determine the appropriateness of antidote stocking. The stored amounts and their variability during different periods of the year must also be investigated. In addition, the recommended quantities of various antidotes is revised upwards for collective poisoning such as amanita intoxication for which large amounts of silibinin, or rather betalactams, are necessary for the management of intoxicated patients. Preparations for disasters, including terrorist attacks, must be a reason to increase antidote stocking. Second, some regions did not participate in our survey such as the extreme south and the eastern zone which are distant from major cities. Finally, this study relied on self-reported data and neither direct observations nor site visits were conducted. Self-reported responses have specific disadvantages; they can be exaggerated, respondents may not reveal personal details, and various biases may affect the results.

Conclusions

Great efforts have been made to improve the availability of antidotes in Morocco in recent years. However, this availability varies according to the size of the hospitals and many life-saving antidotes are still lacking in some hospitals. Interhospital transfer and redistribution of resources in some healthcare settings could improve these deficiencies at no additional cost. Finally, the competent authorities have to take more concrete actions to facilitate access to antidotes by developing expert consensus guidelines to assist hospitals in reducing costs and improving patient care by adequately stocking essential antidotes.

What this paper adds.

What is already known on this subject?

• Antidote stocking represents a major challenge to hospitals worldwide which negatively affects the management of poisoning cases. This finding has been confirmed by several studies.

• A survey showed significant lack of availability of antidotes in several Moroccan hospitals in 2007. Since then, several actions have been carried out to improve the availability of antidotes in Moroccan hospitals.

What this study adds?

• This study aimed to assess whether antidote stocking has improved since 2007 in Morocco by surveying the most important healthcare settings in the country.

• The study's findings suggest that availability of antidotes varies greatly depending on the size of the hospital.

• Despite an improvement compared with a previous study, some antidotes are still insufficiently stocked in Moroccan hospitals, despite the great efforts that have been made to improve antidote availability in Morocco.

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information. Not applicable.

Ethics statements

Patient consent for publication

Not required.

Ethics approval

The study was approved by the local Ethical Committee of the Faculty of Medicine and Pharmacy in Rabat, Morocco.