The antivenoms (AVs) are biological drugs defined by World Health Organization (WHO) as the purified fraction of immunoglobulins (Ig) or immunoglobulin fragments fractionated —Fab or F(ab’) ₂— from the plasma of animals that have been immunized against one or more venoms; hence, their suitable use can prevent or reverse most of the negative effects of envenoming after the administration of an intravenous infusion of the AV.¹ However, bites or stings from venomous animals (BSVA) may happen in remote areas, quite far from a specialized hospital (i.e., in rural areas) or urban areas (i.e., by occupational exposure to venomous animals). Accordingly, primary attention will be provided, at best, on small health centers which not necessarily have AVs available for an emergency case. Therefore, the patients are referred to another specialized hospital depending mainly on its facilities and on the local health system.^2,3

These circumstances should be considered because medical attention timing is a very important prognosis factor to ensure efficacy and safety of the treatment. If the hospitals had biological therapies (BT) in emergency or intensive care units (ICU), there would be a problem: they often do not have a suitable pharmacovigilance (PV) process to guarantee the effectiveness, safety and rational BT use. Thus, it is necessary to establish a PV method inside hospitals in order to support the prognosis of a critical patient during the medical intervention and follow-up.

However, AVs may not have the same importance for health programs like other diseases and BT. Unfortunately, in emerging regions such as Latin America and Africa, there are not sufficient reimbursement programs to encourage the clinical research to develop new treatments. Accordingly, lack of access to AVs is common because it is considered a low-prevalence disease in many countries.

Therefore, the role of academies of medicine, toxicology, pharmacology, pharmacy, as well as the civil society must support the establishment of a unified knowledge, national registry, better clinical trials, continuous medical update, diffusion of training programs, access, and governmental awareness about envenoming by BSVA for the benefit of patient safety. WHO has recommended to establish public health strategies as an urgent measure to ensure the availability of safe, effective, and affordable AVs, especially for developing countries (i.e. in Mexico), as well as to improve the regulatory control over the manufacture, import and sale.1 Therefore, a complementary tool to achieve this objective is PV.

PV is defined by the WHO as “the science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or any other drug-related problem”.⁴

Currently, 194 countries are part of WHO and 131 countries are members of Program for International Drug Monitoring (PIDM) coordinated by the Uppsala Monitoring Center (UMC). Mexico is part of PIDM since 1999, represented by the PV National Center of the Federal Commission for the Protection against Sanitary Risk in the Health Ministry (COFEPRIS). Mexican PV is regulated by Mexican Official Standard NOM-220-SSA1-2016⁵, which is consistent with the guidelines from the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use, specifically, ICHE2E.⁶ Although technical requirements for drug registration are recommended here, they are mainly focused on compliance of regulatory authorities and pharmaceutical industry. Thus, AVs have limited clinical data because the local guidelines are focused on the compliance of reports (i.e. coming from clinical trials), but they do not make a reference on the attention of critical patient where the PV application is different from others medical areas, especially in the attention of vulnerable groups such as geriatric and pediatric patients.^4,7,8 Therefore, it is necessary the implementation of PV in the emergency unit and ICU for cases of envenoming by BSVA to distinguish the adequately effectiveness and safety profile of AVs.

The aim of this paper is outlining an overview about the clinical setting of envenoming, the current treatment and its relationship with the PV as a complementary activity to improve the quality, effectiveness, safety of AVs, through a perspective of experts in Mexico.

Envenoming by BSVA is a process whereby the venom is injected in a patient through the bite or sting of a venomous animal or ingestion of toxins produced by animals or plants.⁹ This perspective article will be focused on three envenoming of medical importance: 1) scorpion sting, 2) spider bites, and 3) snake bite.

Epidemiology

Cases of envenoming by endemic species have been reported in tropical regions of countries such as Mexico, United States, Brazil, Colombia, Costa Rica, Ecuador, Venezuela, Argentina, Australia and specifically in Trinidad and Tobago, Turkey, Sri Lanka, and Nigeria. Global epidemiology data has been suggested around 3 million cases per year with more than 150,000 deaths by BSVA.^10,11

Besides being not easily available, these data could be underestimated because not all patients receive quick attention at the hospital, mainly due to other causes such as cultural belief, lack of infrastructure/national registries, non-updated/incomplete data or inaccessibility to treatment.¹ Because of its apparent low prevalence, envenoming by BSVA could be classified as orphan disease only if it meets some regulatory requirements.¹² More epidemiological data are needed for national prevention programs and registry of cases in order to improve the health attention, especially in vulnerable population.

In particular, the Epidemiology General Direction from Mexico reported 336 268 (100%) new cases of BSVA in 2017 mainly due to scorpion stings, 295 321 (87.8%) of them were confirmed cases. Likewise, there were 37 213 (11%) accidents including spider species bites and 3 734 (1.1%) cases of snake bites.

Apparently, BSVA with major prevalence in Mexico were scorpion species stings. They ranked number 13 as primary cause of disease at national level in 2015 (rate of 0.03% per 100 000 inhabitants), and the third place on national mortality over children between 1-4 years old with a mortality rate of 0.2% per 100 000 inhabitants (national mortality by subjected causes to epidemiological surveillance). They were only preceded by deaths due to acute respiratory infection and acute diarrheal disease.

The Mexican states with major number of reported cases are Jalisco, Guanajuato, Guerrero, Morelos, Michoacán, Nayarit, Puebla, Colima, Estado de México, Durango, Sinaloa, Sonora and Zacatecas. The more affected populations were adults, young, and children.¹³

Scorpion stings

More than 1.2 million of cases per year, leading to 3 250 deaths worldwide, have been estimated due to scorpion stings. Dangerous scorpion genus/species for human have been described in Latin America such as Centruroides sp (i.e. Bark scorpion —Centruroides sculpturatus—) and Tityus sp (i. e. Brazilian yellow scorpion —Tytus serrulatus—), among others.^14,15

Spider bites

Unfortunately, there is not a global appraisal and reports are confusing because of methodological deficiencies and a lack of differential diagnosis.

Most spider species are not considered dangerous; however, Toxic Exposure Surveillance System from American Association of Poison Control Centers reported a total 48 411 cases in 2016. Only 15 480 cases were treated into Health Care Facility which they confirmed 7 deaths. Likewise, between 2001 and 2010, an estimated of 169 010 cases were attended in the emergency unit by bite and sting from insects or arachnids in United States. Arachnids were responsible for 20.8% of cases, the spider species were responsible for 2/3 of all cases, but only the 2.2% resulted in envenoming cases by spider bite.^16,17

Spider genus / species dangerous for human have been described in Latin America such as Latrodectus sp (i.e. black widow —Latrodectus mactans—) and Loxocele sp (i.e. violinist, brown or recluse spider —Loxosceles laeta—), among others.^18,19

Snake bites

This type kills >100 000 people and maims >400 000 people every year. Snake genus/species have been described in Latin America such as Crotalus sp (i.e. Mexican west coast rattlesnake —Crotalus basiliscus—) and Micrurus sp (i. e. aquatic coral snake —Micrurus surinamensis—), among others.^20,21

Summary of signs and symptoms

Venom is composed by a complex mixture of non-protein and protein substances (i.e. metallic ions, lipids, glycosides, free amino acids), but especially hydrolytic and proteolytic enzymes as well as peptide toxins or non-toxic peptides (depending on species).^22,23

Table 1 shows a comparison between several signs and symptoms from human life-threatening envenoming animals.

Hence, the clinical manifestations are heterogeneous and they will depend on the animal type, bite or sting type, amount of injected venom, place of depot, attacked body surface, age of patients and their health condition.²⁹ Understanding of natural history of disease will support the challenges from addressing for diagnosis, severity, treatment and prognosis. BSVA may cause other potentially serious complications for the patient, such as infections, amputations, compartmental syndrome, recurrences, scar deformations, and psychological traumas. The likelihood of death must be low if there is an available treatment in the hospital and if clinical approach is suitable.^10,30 Therefore, attention for envenoming must be comprehensive and multidisciplinary.

Systemic response to venom

Immune response to snake and scorpion venoms has been described previously.^31-33 The patients could develop similar signs and symptoms of allergy before administration of AV. Currently, anaphylaxis rare cases (≤1%) by snake bites have been documented, but the differential diagnosis is not clear yet.³⁴

Health professionals must consider that not only the specific antibodies against the venom are produced as immune response after envenoming (i.e. IgE or IgG), but also they could induce the production of others mediator types such as Na⁺, Ca⁺2, K⁺, adrenaline, aldosterone, nitric oxide, angiotensin converting enzyme, and angiotensin II. They may trigger several additional clinical manifestations to envenoming.³⁵

Compartment syndrome

It is an uncommon neuromuscular complication after a BSVA. It is the result of an edema (i.e. by snake bite) causing an increase in pressure within one or more fascial compartments, hypoxia and acidosis, which further increases capillary permeability and interstitial liquid extravasation.²⁴ This may impair blood flow and irreversibly damage the muscle and nerve with a potential loss of functionality. Early diagnosis during admission is crucial to reduce this secondary complication.³⁶

Diagnosis and severity

Consensus over envenoming diagnosis by BSVA is limited because the diversity of venomous animals is very wide; thus, the clinical manifestations and severity classification will depend on complex variables both entomology/herpetology (as public health system) and clinical practice in each region. Then, defining a unique criteria for the envenoming approach is a challenge. However, there are evidence-based recommendations which may support the diagnosis and prognosis. Table 2 shows a summary of recommendations over diagnosis, classification, and laboratory tests to surveillance from envenoming evolution by BSVA. Unfortunately, there is not a consensus about the approach for spider bites. Conversely, the local guidelines and medical reviews for a better understanding about diagnosis and treatment should be noted.^29,37-41

Starting treatment

Before starting treatment, the differential diagnosis must be based on physical examination and on clinical record. Due to specific circumstances in clinical setting, it will not always be possible to identify the venomous specie regarding all entomology/herpetology criteria. Accordingly, the criteria for starting treatment will be based on human life-threatening signs and symptoms, taking into consideration that not all BSVA induce envenoming. For instance, 20-25% patients suffer “dry bite” of snake, that is to say, venom is not released on damaged site, but if patients develop any or minimum evidence of envenomation they should be given antivenom.⁴⁶

Types of AV

AVs are neutralizing proteins with or without changes over chemical structure for improving their affinity-avidity, pharmacokinetics (PK) or pharmacodynamics (PD) properties. They are biochemically called glycoproteins or immunoglobulins G (IgG) obtained by purification from hyperimmunized serum of animals (i. e. horses).⁴⁷

Nowadays, three types of AV have been developed: 1) polyvalent IgG, 2) polyvalent fragments of IgG —F(ab’)₂—, and 3) polyvalent fragments of IgG —Fab—. The two last ones were structurally modified by enzymatic digestion on key binding sites with the purpose of eliminating Fc portion of IgG associated with effector mechanisms such as activation of complement (i. e. C1q), proinflammatory cells (i. e. mast cells) or ADR (type 1 hypersensitivity), among others.^48,49

Dosage

Doses scheme is still used empirically due to the lack of robust clinical trials. There are not comprehensive studies of posology, but the potency may determine the doses of AV required to neutralize the toxins. Greater therapeutic effect could be exerted with AVs of high potency and specificity. Nevertheless, there are not sufficient clinical trials “head-to-head” comparing the low potency AVs against high potency AVs. The non-envenomation should not be treated with AV (see Table 2).

Moderate (grade II) or severe cases (grade III) should be treated starting with escalating doses under manufacturer-indicated protocol (low→ high) until decreasing signs and symptoms of envenoming and preserving permanent surveillance during hospitalization. Table 2 also shows a summary of the experts’ recommendations over treatment with AVs. Apparently, the doses for risk groups such as children, pregnant women, and elderly are not different from the conventional scheme. Unfortunately, there are not comprehensive clinical trials to confirm it.

Recommendations by Mexican authorities

Clinical practice guidelines (with evidence-based methods) for diagnosis and treatment in Mexico recommended the next start doses: 1) scorpion sting, 1-6 vials 2) spider bite, one vial (possibly more vials will be used depending on clinical response), and 3) snake bite, 4-25 vials. The patient will be observed and if there is no clinical improvement, another dose will be administered equal or in accordance with the recommendations of the clinical practice guide.^50-52

Clinical pharmacology

AVs are therapeutic proteins administered by intravenous (i.v) or other parenteral route. They are also distinguished by means of its pharmacological activity, measured as potency (Effective doses —ED₅₀—) or mass units (mg) associated with the affinity-avidity ratio.⁵³

Pharmacodynamics (PD) is similar to monoclonal antibodies (MAbs), that is to say, they have neutralizing activity against specific antigens over conformational or lineal epitopes. However, several AVs are polyclonal; thus, the selectivity and specificity is minor than MAbs. This may be necessary because the protein composition of venom is heterogeneous and the antigens (or epitopes) would be not unique by species, only related to them. Therefore, PD mechanism of the AVs is neutralizing over the binding site(s) from antigen(s) also called epitope(s) and it (they) would be composed of continuous or discontinuous amino acid sequences.^54-56

AVs as well as MAbs have an Ig-based structure, but cannot induce active immunity or cells B-mediated immunological memory against the venom.^57,58 Likewise, long time ago, some researchers indicated a mechanism of “artificial passive immunity” as acting manner of the AVs but only when they contain the IgG (antiserum) with the complete structure. Consequently, some regulatory agencies worldwide may classify them as vaccines or essential biologicals.⁵⁹

Currently, the fragments from F(ab’)₂ and Fab would not necessarily meet this rule due to the previous changes on its chemical structure and advances over the manufacturing.⁶⁰ Then, on the one hand, it would a regulatory re-classification of AVs be suitable due to the current technologies.

It is important to highlight that the pharmacology of AV is different from conventional drugs (i. e. acetaminophen) in terms of absorption, distribution, metabolism, elimination and excretion, adverse drug reactions, immunogenicity, serum sickness, and dosage.

Absorption

Predominantly, AVs will be administered intravenously with infusion velocity recommended by manufacturer of the AV; hence, the bioavailability may theoretically achieve up to 100%. On the other hand, the absorption mechanism after subcutaneous and intramuscular administration is not completely understood and some evidence shows a contradictory therapeutic effect with this route, may be because of differences over the bioavailability.^60-63

Distribution

AVs as Ig-based therapeutic proteins do not bind to plasma proteins and they are strictly dependent on their limited capacity to diffuse through cell membranes because the IgG have a high molecular weight. Therefore, the volume of distribution (Vd) is expected to be relatively small or approximately equal to volume of plasma, regardless of dose used.⁶⁴ Additionally, Fc portion of the IgG plays a crucial role both in half-life time and in the crossover to the placenta barrier because all subclasses of IgG are transported through them by the neonatal receptor FcRn expressed into several tissues. It is expected certain traces of AV in fetus.⁶⁵ It is worth saying, the fragments F(ab’)₂ and Fab have a less molecular weight than cIgG because the Fc portion was previously digested by industrial processes. Theoretically, the IgG fragments would have a better penetration at damaged tissue and absent of crossover toward fetus. Notwithstanding, it has been not tested on comprehensive preclinical models.

Metabolism, elimination and excretion

AVs are neutralizing protein mixtures with a long-half life time dependent on molecular weight. They will not be metabolized by the classical via of cytochrome P450 (phase I) or conjugation (phase II). Metabolism of AV will be chiefly activated by unspecific catabolic proteases. This results in a higher half life time with cIgG than the Fab and F(ab’)₂ fragments.

When AVs are formed by cIgG (molecular weight ≥150 kDa), a minimal glomerular filtration rate is expected; therefore, only small amounts could be detected in the urine. Some fragments of ≤ 60 kDa (i.e. Fab or F(ab’)₂) will be filtered and excreted by the kidney, with an elimination rate approximately equal to the rate of glomerular filtration. However, the elimination of IgG is often a saturable and slow process; so, the clearance of AVs would decrease with dose. It will depend of the expression of therapeutic target. Hence, the clearance of Fab and F(ab’)₂ fragments would be higher than cIgG, i.e., the time inside the body will be higher on cIgG than Fab and F(ab’)₂ fragments.^66,67

Adverse drug reactions

Adverse Drug Reactions (ADR) have been reported during the infusion protocol up to >50%, especially during the first 20 min, 2 h, 4 h, 8 h, and 24 h after administration. Syndrome of release of cytokines and hypersensitivity reactions are rare (<5%) and all these include symptoms such as rash, bronchospasm, nausea, vomiting, headache and fever or well, severe symptoms as anaphylaxis, hypotension and altered level of consciousness, among others.^68-70 However, the signs and symptoms often may be misinterpreted with those related to the natural history of envenoming because there is not a complementary tool or sufficient clinical insight to distinguish them. Likewise, temporary cessation of AV will solve some mild reactions. In case of severe anaphylaxis, the World Allergy Organization recommends an initial administration of intramuscular adrenaline into the lateral thigh, 0.01 mg/kg to maximum of 0.3 mg. To unresponsive patients, they recommend an adrenaline infusion (0.5 ml/Kg/h, of 1 mg in 100 ml) and titration according to response. Monitoring, nebulized salbutamol for bronchospasm, and intravenous atropine for severe bradycardia are recommended. Premedication to decrease the potential ADR is controversial because the limited clinical trials are not concluding.

The type of ADR among AVs apparently do not differ, but their frequency/severity have been reported and may depend on the quality or purity of AV.^71,72 The physiopathology mechanism of acute reactions is uncertain, but it may be the result of type I hypersensitivity or a combination of non-immunes, immunes mechanisms, although ADR may occur in those patients without previous exposure to animal proteins, i.e. coming from equines.⁷³

Immunogenicity

The development of an immune response against AVs may negatively impact its pharmacokinetics. For instance, it may increase the clearance, modify the binding site to epitopes or alter the safety and efficacy profile. Human antibodies against AVs may be neutralizing or non-neutralizing depending on its effect over the pharmacological activity. If the AVs came from horse, then, the human antibodies “anti-antivenom” or “anti-drug” may be also called human “anti-horse” antibodies, which would be different from the human “anti-toxin” antibodies addressed against the protein composition of venom from venomous animals.

Immunogenicity of BT is an issue poorly understood; however, several researches indicate a crucial role of some trigger factors such as the molecular weight, BT type, drug target, glycosylation profile, pharmaceutical excipients, purity grade, treatment time, doses frequency, via of administration, dosage, concomitant drugs, age, comorbidities, genetic profile, among others.^74,75 Unfortunately, it has been not comprehensively assessed with AV.

Serum sickness

It is rarely (<5% of cases) the result of an excess of foreign antigens that form circulating immune complex with different molecular weight for a certain period of time (i.e. until 20 days) after administration of AV coming from heterologous serum.

Immune system cannot recognize them and induces the delayed production of other human antibodies “anti-immunocomplex” which are deposited over organs (i.e., the kidney) and tissues raising a long-term damage. Signs and symptoms of serum sickness are confusing but could be defined as lethargy, headache, muscle/joint aches, and fever or similar to allergy, and infections until tissue damage.⁷⁶

It occurs with the AVs formed by cIgG (anti-serum), but the risk of immunocomplex formation should be lower with the fragments Fab and F(ab’)₂ because the time into body is lower than cIgG and the Fc portion has been deleted, which is associated to secondary binding site and pro-inflammatory mechanisms.⁷⁷ However, there are not robust clinical trials assessing it.

Recurrent signs

They are signs of envenomation occurring after stabilization of laboratory parameters, even with medication. They may happen during 24 hours or up to 2 weeks after the critical stage of envenoming. This phenomenon has been documented in the coagulopathy by snake bites⁷⁸ but not with scorpion stings or spider bites.

Recurrent mechanism by snake bite is unclear, but it has been previously hypothesized that depots of non-neutralized venom may continue being released into the blood flow after antivenoms levels fall, which causes recurrent coagulopathy.⁷⁹ Another proposed mechanism is the dissociation of AV-venom complexes, intensifying coagulopathy. If it recurs, retreatment with AV should be considered to prevent important bleeding.⁸⁰ More knowledge about PK-PD parameters of AVs may support the understanding of this phenomenon.

WHO has recommended to establish public health strategies as an urgent measure to ensure the availability of AVs both safe, effective and affordable, especially for developing countries as well as to improve the regulatory control over the manufacture, import and sale^.1 Therefore, it is necessary the implementation of PV in the emergency unit and ICU for achieve this objective.

Due to limited clinical information of the therapy with AVs, complementary tools of surveillance applied by hospital PV unit (HPU) are needed to ensure its quality, effectiveness, and safety post-marketing because they will have a crucial role since admission, during the intervention, transfer emergency to ICU, until discharge and post-ambulatory surveillance. Crisis setting within emergencies as well as in ICU exposes the patient to numerous medications, procedures and health care providers; therefore, an accurate and multidisciplinary intervention is necessary because there is a high risk of experiencing ADR, other drug-related problems, and making medication errors.^81,82

The reported benefits of the intervention of HPU inside emergencies and in ICU result on improvements over safety culture, identification and classification of ADR, frequencies, decrease of costs related to ADR, among others.^83-85

Since these areas are critical, HPU will provide support by means of tools and strategies to ensure quality of medication with the purpose of assessing the efficacy and safety of AVs in real practice.

Methods for the traceability before infusion

The technologies for traceability of a drug may ensure an infusion free from manufacturing errors.⁸⁶ Indeed, the problem of counterfeit and substandard drugs is worrying.

In particular, WHO defines “substandard drugs” to those genuine medicines (with sanitary registry or good manufacturing practices) which have failed to pass the quality measurements and standards set for them.⁸⁷ They are also known as “out of specification” and are often manufactured into emerging countries by unqualified personnel⁸⁸ and the AVs could contain unknown impurities and bacteria (it release pyrogens).

Nonetheless, substandard AVs may be difficult to detect in the clinical practice because they seem identical to the previously approved product by regulatory agency and could not cause an ADR. However, they often would fail to properly treat the disease or condition they were intended to, and may lead to serious health consequences, including death. Fortunately, some technological innovations have been introduced in the manufacturing process for improving AVs quality,⁸⁹ onsite PV systems, and product authentication systems.⁹⁰

Monitoring during infusion protocol

ADR have been reported during the infusion protocol, especially during the first hours after administration. Syndrome of release of cytokines, hypersensitivity reactions, immunogenicity and delayed reactions may be present during the infusion.^68-70

Hence, every hospital previously must set the guidelines for preparation of sterile and non-sterile mixtures. For example, Mexico has an Official Standard called NOM-249-SSA1-2010 about preparations (Sterile mixtures: nutritional, medicinal, infrastructure for their preparation) and current supplementary guidelines of pharmacopoeia for the good practices over the preparation of sterile and non-sterile mixtures.⁹¹ Moreover, the legal framework is based both on articles 198 (fraction IV), 258, 259, 261, 368, 369, 370 and 371 from Health General Law in Mexico,⁹² on articles 8, 99, 100, 109, 112 and 163 from Regulation of Health Products.⁹³ The purpose of the guidelines is ensuring the identity, purity, concentration, potency, harmlessness, and safety of intravenous drugs, such as AVs.

Interestingly, it has been reported the use of transfer summaries “emergencies →ICU” as an effective tool to increase ADR detection and medication errors as complementary methods to the existing pharmaceutical services (i.e. medication prescription reviewed for appropriateness and its reconciliation).^94-98 It may be useful for PV of AVs during and after infusion protocol.

Pharmacovigilance in toxicological emergencies

Emergency unit is aimed to receive patients in critical situations, with or without imminent risk of death. Unfortunately, there is not published data about the specific patterns of suspected ADR or other drug-related problems. However, indirect data has been reported a total of 6-10% of admissions by suspected ADR in emergencies.⁸¹ Therefore, an appropriate pharmaceutical intervention is absolutely need because the medication protocols are most complex compared to others medical areas. For example, a study reported the high prevalence (61%) of potential drug-drug interactions in patients admitted to emergency unit from a tertiary care hospital in Mexico.⁹⁹

Similarly, a current study shows the effectiveness of a pharmaceutical intervention and it is addressed to physicians working in emergency and coordinated by a pharmacist in a Mexican pediatric hospital of tertiary care on the ADR identification and reporting. Here, >97% of ADR were correctly identified before and after the intervention, but only <7-42% of ADR were reported before and after the inter vention, respectively. The researchers conclude that emergency physicians identify a suspected ADR, but fail to report them. However, this study reported a significant increase over the number of reports of suspected ADR.¹⁰⁰ This is an opportunity to add a PV system particularly in toxicological emergencies as a strategy to additionally guarantee the welfare of patient.

On the other hand, if patients have a life-threatening medical condition they will require constant monitoring of vital signs and other medical parameters in ICU. Here, the hospital attention is different from the emergency unit and a transfer to another ward is required. This moment is critical for a suitable PV of AVs. Notwithstanding, the clinical setting of the PV in ICU is different from emergencies. For example, an observational study reported a low incidence of ADR related to drug-drug interactions (DDI) in ICU due to strict control of this medical area.¹⁰¹ Likewise, there is a higher incidence of suspected ADR in ambulatory patients compared with the hospitalized patients;⁸³ while a total of 7-15% of suspected ADR cases contributes significantly to ICU admissions.^82,101 Thus, this evidence would support, at least, the hypothesis of a higher risk of ADR of AVs in the emergency units, mainly due to several complex circumstances of medical admission.

Notification of suspected ADR and causality assessment

The suspected ADR must be notified and subsequently evaluated for the causality assignment through algorithms. Indeed, the algorithms in PV are used to assess the causality of suspected ADR through flowcharts or assessment questions.

Currently, there is not a universally accepted method for assessing them, but according to the causality assessment, provided by WHO and UMC,¹⁰² there are probabilistic categories called —Certain, Probable/Likely, Possible, Unlikely, Conditional/Unclassified, Non-assessable/Unclassifiable—. Hence, there are several algorithms, but the best known is Naranjo’s algorithm. Table 3 shows the comparison among them, highlighting the advantages and limitations in real practice.

On other hand, the similarity among the three algorithms (Naranjo, Jones and Begaud) has been assessed in the diagnosis of drug hypersensitivity; the ADR most frequent with the treatment of AV. The authors indicated dissimilarity between the algorithms, but they agree with Jones’ and Naranjo’s methods.¹⁰⁴ In addition, the results were similar when evaluating ADR in the ICU using Naranjo’s, Kramer’s and Jones’ algorithms. Authors suggested an instrument selection with any of the three instruments will be reasonable but there is lower variability with the Kramer method; however, it is a very long appraisal which will be little practical both at the clinical setting and at toxicological emergencies.¹⁰³

Proposal for a modified Naranjo’s algorithm

A modification of the Naranjo’s algorithm is proposed here because it would be a fast and feasible algorithm used for cases of suspected ADR with AVs. Moreover, the modification is necessary because 1) the effectiveness and safety profile between the AVs worldwide has not been widely shown; 2) there is a complex setting between the admission and transfer of a patient; 3) frequency and type of suspected ADR with AVs, and especially 4) because the signs and symptoms of the suspected ADR often may be confused with those related to the natural history from envenoming or the ADR of the other conventional drugs used of infusion therapy (i.e. prazosin). Thus, a modified Naranjo’s algorithm may help to increase the clinical acuity for distinguish them.

Although Naranjo’s algorithm does not provide high sensitivity and specificity by itself over particular cases, it is possible that a change may be useful to a “quicker check list” in toxicological emergencies or an initial appraisal of suspected ADR.

The modification consists of replacing questions 6 and 7 because they would not be related to clinical setting of AVs and they may be confusing factors. These replaced questions are related to the clinical investigation and therapeutic monitoring by laboratory but not to the real clinical practice of treatment.

Frequently, when the causality of a suspected ADR is researched in the PV practice with AVs, these questions (6 and 7) are answered as “unknown”. This would affect the scale as well as the sensitivity and specificity of causality grade by high likelihood to be classified as “possible”. In order to decrease it, this proposal consist of replacing these questions for others related to clinical questions at issue of AVs for decision making in toxicological emergencies. It will not modify the scale because they have the same logic. Therewith, it would be possible an increase in the sensitivity and specificity about causality grade of suspected ADR.

Table 4 shows the modified Naranjo’s algorithm proposed here. Notwithstanding, a clinical study will be need to confirm the validity of this proposal as future perspectives.

Quality of PV report

It is widely dependent on the quality of the clinical file; thus, anecdotal great efforts have been established for improving both of them. According to the Mexican Official Standard NOM 220-SSA1-2016 dealing with PV, there is certain information grade based on the data received in the notifications as follows: 1) Grade 0, it includes an identifiable patient, at least one ADR or some other safety problems related to the use of medications and vaccines, suspect medication or vaccine and data from the notifier; 2) Grade 1, idem + it includes start dates of the ADR, date of beginning of treatment and date of treatment end (day, month and year); 3) Grade 2, idem + it includes generic denomination, distinctive name, dosage, route of administration, reason for prescription, consequence of the event, important data of the clinical records, batch number, and manufacturer’s name; 4) Grade 3, idem + it includes the result of the re-administration of the medication or vaccine.

The goal will be reported to the sanitary authority, as well as the ADR associated to AV with a high grade of information (between 2-3) and the higher causality (understanding previously the clinical setting of AV treatment) to support the decision making and avoidability. Since the PV report quality would be influenced by indirect and direct factors of medical attention, it is necessary to know the envenoming setting as a whole. Graphic 1 shows the interrelation with those factors.

Follow-up after discharge

The PV in the envenoming ambulatory care is a challenge because the patients with favorable prognosis and subsequent discharge have, at least, a sequel or signs or symptoms of serum sickness (until 5-15 days ago), but they do not often return to the hospital. Thus, it is recommended that HPU gathers data from patients and asks for the informed consent to be subsequently contacted by a health professional with the purpose of carrying out the follow-up after a successfully solved the envenoming crisis. Besides, several studies described the electronic and mobile resources for medication safety and PV to enhance patient safety in the ambulatory care setting;¹⁰⁵ thus, they may be implemented by HPU with a few respective modifications.

There are other AV-related factors which indirectly may affect the effectiveness and safety of the treatment; for instance, tourniquets are generally not recommended for snakebites due to high risk of fatality. Likewise, traditional manipulations like local incision and suction are not recommended.¹⁵ If the patient arrived with a tourniquet already placed by a family member or rescuer before being admitted to emergencies, do not to remove (as some experts have recommended) the pressure until prepared to manage acute toxicity.^106,107

Commonly, the patients living in rural areas go to the local healer —Curandero— before going to the first contact physician. Then, the patients are submitted to unknown procedures such as consuming herbal remedies which could interact with other drugs both in emergencies and ICU.^108,109 Moreover, a long delay because of a slow transportation and a lack of available transport are some factors limiting the timely access to AV, and accordingly, to a favorable prognosis.^2,37 Physicians and HPU must record these variables in the medical record because they are associated to therapeutic fail and other complications (see Graphic 1).