Adverse Drug Reactions and Anaesthesia: A Narrative Review
Correspondence Address :
Dr. Ramyavel Thangavelu,
Associate Professor, Department of Anaesthesiology, Pondicherry Institute of Medical Sciences, Kalathumettupathai, Ganapathichettikulam, Village No. 20,
Kalapet-605014, Puducherry, India.
E-mail: ramyavel1988@gmail.com
Adverse drug reactions are defined as the effects created by drugs producing unintended or noxious response in doses normally used for prophylaxis, diagnosis or therapy of diseases. Adverse drug reactions under anaesthesia occur by a number of mechanisms and several risk factors are often involved. The overall incidence of adverse drug reactions to anaesthetic drugs ranges between 1 in 10,000 and 1 in 20,000. Electronic databases were searched to obtain the relevant literature with keywords related to adverse drug reactions and anaesthesia. Total 110 articles were reviewed, bibliography cross-checked and relevant literature was included. This article discusses about the adverse drug reactions to various anaesthetic as well as non anaesthetic drugs used intraoperatively. Anaphylaxis under anaesthesia, its pathophysiology, clinical and laboratory diagnosis, management and prevention has also been discussed in detail. Allergic drug reactions and anaphylaxis in the operating room often presents unique diagnostic concerns as the early signs of anaphylaxis are often masked under general anaesthesia. The use of surgical drapes and use of multiple potential allergen drugs under anaesthesia also make the diagnostic process difficult. Thus, an adequate knowledge, understanding, vigilance and proper documentation with reporting in case of an event is warranted by the attending anaesthesiologist for a good perioperative outcome with decreased morbidity and mortality.
Allergen drugs, Allergic reactions, Drug events, Operating room
Anaesthetists are the medical specialists more likely to witness Adverse Drug Reactions (ADRs) in their practice. This is due, in part to the nature of the perioperative period, in which patients are exposed to a large variety of potential allergens including anaesthetic drugs as well as other miscellaneous agents like antiseptics, dyes, contrast, latex and antibiotics. The incidence of adverse drug reactions to anaesthetic drugs ranges between 1 in 10,000 to 1 in 20,000 with mortality in the order of around 10% (1),(2). Hence, it is essential that, anaesthesiologists, as perioperative specialists remain vigilant to the possibility of ADRs and be well informed about their recognition, immediate treatment and follow-up.
LITERATURE SEARCH
A literature search was undertaken using several electronic databases, (PubMed, Cochrane databases and specific journals), which pertain to adverse drug reactions in medicine and anaesthesia. The searches were conducted by the first author. The evidence and data cited consists of findings from either individual studies/case reports/series/meta-analysis or narrative/clinical reviews related to the topic. The aim of this article is to provide a comprehensive review on the adverse drug reactions in the field of anaesthesia. The review has also dealt in detail with anaphylaxis, pathophysiology, its diagnosis, management and reporting.
DEFINITIONS AND CLASSIFICATIONS
Adverse drug reaction is defined as any drug response that is not of prophylactic, diagnostic or therapeutic benefit to the patient. It can range from mild skin rashes to severe clinical presentation which accounts to about 10% and result in 0.02-0.04% of morbidity and mortality (3).
Classification of ADR: They can be classified as:
• Type A (Augmented): About 85-90% reaction which are relatively common and related to the main pharmacological effects of the drug. They are dose temporal and associated withdrug administration such as medication overdose, exaggeration of drug’s normal pharmacological actions, interactions with other drugs (4).
• Type B (Bizzare): About 10-15% reaction occurs due to some sort of genetic predisposition. They are called true allergy and are immunologically mediated. The event of sensitisation is followed by generation of specific antibodies. Upon renewed exposure, specific T-cells and/or Abs may mediate allergic reactions (Type 1-4 reactions according to Gell and Coombs) (Table/Fig 1) (5).
ADVERSE DRUG REACTIONS UNDER ANAESTHESIA
Adverse drug reactions under anaesthesia occur by a number of mechanisms and several risk factors are often involved (6). Though, a majority of reactions occur during induction and are non fatal, 9% of them can be fatal and represent a significant cause of morbidity and mortality (2).
In 60-80% cases, the observed manifestation of ADRs during General Anaesthesia (GA) is cardiovascular collapse, a relatively late event (7). The early manifestations are masked during GA. Adverse drug reactions that happen during general anaesthesia can be due to drug overdose, secondary adverse effects, idiosyncratic reactions, drug intolerance, drug interactions and allergic reactions/hypersensitivity or anaphylaxis (immunological) (8).
ADR to Intravenous Induction Agents
The reactions to intravenous induction agents can vary from mild induction complications {excitatory phenomenon, respiratory depression, Cardiovascular System (CVS) changes} to severe hypersensitivity or idiosyncratic reactions (immune mediated/anaphylaxis) (9).
The (Table/Fig 2) summarises the various system wise adverse drug reaction of intravenous induction agents based on various reports and reviews from the literature. Though, a majority of adverse reactions to induction agents are mild/transient and might not require active intervention in normal subjects, a constant vigilant anaesthesiologist is warranted to diagnose or manage severe life threatening reactions in those who are intolerant to the drug and thus might have exaggerated responses (10),(11),(12),(13),(14),(15),(16).
ADR to Opioids and Benzodiazepines
Though, benzodiazepines are considered to be cardiostable with transient side effects, cases of cardiac arrest have been reported in the literature following rapid intravenous injection of diazepam or midazolam (17). There has also been a recent shift towards non opioid based anaesthesia practice in view of adverse effects of opioids mainly on the respiratory system (Table/Fig 3) (18),(19),(20),(21),(22).
ADR to Muscle Relaxants
Evidence states Neuromuscular Blocking Agents (NMBA) to be the first cause of perioperative reactions during general anaesthesia (23). Though, administration of muscle relaxant may cause immunologically mediated Type 1 hypersensitivity response and/or complement activation, it is more commonly due to the release of histamine from tissue mast cells that causes clinical manifestations (Table/Fig 4) (24),(25),(26),(27).
ADR to Inhalational Agents
The most common adverse effect of inhaled anaesthetic agents is Postoperative Nausea and Vomiting (PONV) (28). A few inhalation agents are known to irritate the airways of patients with severe asthma and induce bronchospasm due to the pungent smell on induction, primarily with desflurane and isoflurane. Sevoflurane, desflurane and isoflurane decrease systemic vascular resistance leading to a drop in systemic blood pressure. These changes are transient and mild in normal subjects, however, are more profound in hypovolemic patients. Malignant Hyperthermia (MH) is also an adverse effect that can occur with the administration of inhaled anaesthetics, most commonly seen with the inhaled gas halothane. Patients susceptible to this adverse effect have heritable alterations between their proteins and muscular cytosolic concentrations of Ca2+ (29). Nitrous oxide can cause diffusion hypoxia quickly following discontinuation of the agent. It is recommended that 100% FiO2 be used to counteract the rapid dilution of O2 in the alveoli (Table/Fig 5) (30),(31),(32),(33).
ADR to Local Anaesthetics
Systemic and localised adverse effects of local anaesthetic drugs usually occur because of excessive dosage, rapid absorption or inadvertent intravenous injection. The incidence of true allergy is not known, but has been widely quoted that <1% of all reactions to local anaesthetics are allergic in nature (Table/Fig 6) (34),(35),(36),(37).
ADR to Neuraxial/Regional Anaesthesia
The adverse complications of regional anaesthesia range from bothersome to crippling and life threatening complications (38). The adverse effects can be classified as that resulting from physiological excessive side-effects, placement of the needle (or catheter) and drug toxicity (Table/Fig 7).
The incidence of neurologic Central Neuraxial Blockade (CNB) complications is estimated to be between 1/1000 and 1/1,000,000 (39). A very large survey of regional anaesthesia from France showed relatively low incidence of serious complications from regional anaesthesia (40). The incidence of complications were higher with spinal than with epidural anaesthesia. Though fatal cardiac arrest events were encountered, they could not be directly attributed to spinal anaesthesia. About 80% of patients with neurological deficits had complete recovery within three months.
NON ANAESTHESIA DRUG RELATED ADVERSE REACTIONS
Non anaesthesia drugs causing adverse drug reactions (Latex, antibiotics, plasma volume expanders, blood) have been studied extensively (41),(42),(43).
Latex Allergy
There is evidence that about 20% of perioperative anaphylaxis is attributed to latex and it is the second cause of adverse reactions during the perioperative period (44). Patients undergoing multiple surgical procedure or patients who need chronic bladder care (urogenital malformations, spinal cord trauma), professional exposure in healthcare workers (41). Obstetric population are associated with an increased frequency of latex allergy. Sensitised individuals may develop urticaria, angioedema, allergic rhinitis, asthma or anaphylaxis (45). Prevention can be done by either avoidance of sensitisation in high risk population or by establishing a latex free environment in Operation Theatre (OT) and recovery rooms.
Antibiotic Allergy
About 15% of anaesthesia related anaphylaxis perioperatively are due to antibiotics (46). Anaphylaxis to antibiotics are more common with penicillins and cephalosporins constituting to 70% of perioperative anaphylactic reactions induced by antibiotics (42).
Beta lactam antibiotics, vancomycin and quinolones are also frequently implicated. Vancomycin, is typically associated with “red man syndrome” characterised by flushing, pruritis and an erythematous rash of the head and upper torso and arterial hypotension (47).
Colloids
Adverse drug reaction to colloids have been discussed widely in the literature (48). Anaphylactic reactions to gelofusine and other gelatine based plasma volume expanders carries an incidence of 0.07-0.15% (43). They are three times more likely to cause anaphylaxis than crystalloids and albumin (49). There has also been higher incidence of allergic reaction to first and second generation starches.
These reactions are normally type 1, IgE mediated anaphylaxis reaction, though rarely anaphylactoid reactions have also been reported. Cutaneous signs followed by hypotension is the most common presenting sign perioperatively, with reactions most commonly occurring within ten minutes of starting the infusion (50).
Chlorhexidine
The incidence of anaphylaxis to chlorhexidine is about 0.78 per 1,00,000 exposures (51). Patients may often become sensitised to chlorhexidine before a surgical procedure as it is widely used all over the world as a common skin disinfectant in minor skin scratches and as a mouth wash (52). Reported symptoms in the literature vary from mild cutaneous reactions to severe life threatening anaphylaxis (53). Povidone Iodine (betadine), another commonly used topical antiseptic solution has been found to be associated with allergic contact dermatitis.
Non Steroidal Anti-inflammatory Drugs (NSAIDS)
Multiple studies have identified aspirin and NSAIDS as one of the commonest causes of drug induced anaphylaxis (54),(55). Inhibition of Prostaglandin E2 (PGE 2) pathway (cyclooxygenase) leads to excessive leukotriene production and subsequent mediator release. The route of administration is usually oral, rectal or intravenous with onset of reaction upto 10 minutes, 15-30 minutes and upto 60 minutes after the administration.
Blood and Blood Products
There is consensus that blood transfusion has been associated with both acute non immune mediated and acute immune mediated reaction with a reported incidence of 3% (56). Multiple studies have identified allergic reactions like urticaria with erythema and pruritis, that occur within seconds or minutes of the start of transfusion or may take several hours to develop (57).
Anaphylaxis is a more severe form of an allergic reaction with an incidence of 1:20000 to 1:50000 transfusions (58). Though, it is easy to identify adverse transfusion reactions in awake patients, it often becomes difficult to identify adverse transfusion reaction under anaesthesia. In these situations, signs like arrhythmias, tachycardia, localised or cutaneous reactions, hypotension or increased airway resistance due to laryngo or bronchospasm may serve as an indicator of underlying adverse transfusion reaction [56,58]. In one of the case reports by Rudingwa P et al., the presence of acute intraoperative hematuria was the only clue that led to the suspicion of mismatch transfusion and thereby initiated further evaluation and treatment (59). It is mandatory to record the type of transfusion reaction suspected, length of time of reaction after starting, volume, type and pack numbers of blood products transfused in the patient’s notes (56).
OTHER MISCELLANEOUS AGENTS
Many other non specific agents used during anaesthesia may be associated with anaphylaxis, including apoprotinin, protamine, ondansetron, radiological contrast dyes, oxytocin [60-62]. When a trigger is not identified following standard investigation with routine suspected agents, the possibility of other less common or “hidden” allergens should be considered.
ANAPHYLAXIS UNDER ANAESTHESIA
Incidence: The incidence of anaphylaxis is estimated between 1 in 4,000 and 1 in 20,000 anaesthetic procedures, as reported by Mali S, in a review article (63). However, anaphylactic reactions (immune IgE mediated) cannot be clinically distinguished from non immune mediated mast cell reactions (account for 30-40% of hypersensitivity reactions) (44). In one of the recent studies on anaphylaxis during general anaesthesia, an IgE mediated cause was identified in 64% of cases with NMBA constituting the leading cause of anaphylaxis (38%).
Aetiological factors: Multiple studies in the literature have identified neuromuscular blocking agents to represent the first cause of perioperative anaphylaxis followed by latex (12.1%), antibiotics (8%), induction agents (3.7%), opioids (1.4%), colloids (2.7%) and others like dyes and antiseptics (2.9%) (64),(65).
Pathophysiology: The clinical features in anaphylaxis are due to ongoing release of mediators from mast cells and basophils, mediated by Type E immunoglobulins (66).
The mechanism involves production of IgE antibodies on initial exposure to an allergen in susceptible individuals (67). On re-exposure, multicentric allergen cross links two specific IgE receptors which then induce a signal transduction cascade releasing systemically preformed mediators (histamine, tryptase and chymase) and proteoglycans from cells within tissues and blood. The involved target organs include skin, mucus membrane, cardiovascular, respiratory and gastrointestinal systems (66).
Recognition of anaphylaxis under anaesthesia: In event of an anaphylactic reaction, numerous factors make assessment and establishing a temporal relationship difficult. As with anaesthesia practice, several medications are usually administered and in quick succession, there may be difficulty in distinguishing the haemodynamic effects of anaesthetic drugs from anaphylaxis (63). Cutaneous features of anaphylaxis may go undetected in a fully draped patient, the clinical features may be delayed or confused with other causes of hypotension like myocardial infarction, cardiac arrhythmias, drug overdose or pulmonary embolus (68),(69).
Clinical feature: A survey of anaphylaxis as reported in the National Audit Project (NAPS 6), during anaesthesia demonstrated that CVS symptoms (73.6%), cutaneous symptoms (69.9%) and bronchospasm (44.2%) were the most common clinical features (70).
Ring and Messmer described a severity grading in clinical diagnosis of anaphylaxis, where, grades I and II reactions are not life-threatening and are more likely to be non allergic, although they may still be IgE-mediated. Grades III and IV are life-threatening conditions, also called ‘anaphylaxis’, which are usually IgE-mediated (Table/Fig 8) (71).
Diagnosis
The aetiological diagnosis of an immediate reaction occurring under anaesthesia depends on a triad including clinical, biological and allergologic evidence (Table/Fig 9) (72).
1) Clinical diagnosis: The first line of evidence for the diagnosis of anaphylaxis includes the features and severity of clinical signs. According to Ring and Messemer, grade III or IV symptoms are reported to be associated with severe anaphylaxis reaction. The symptoms often include bronchospasm, cutaneous mucus signs, pulmonary edema, desaturation and difficult lung inflation due to severe bronchospasm (42). Cardiovascular symptoms often progress to arrhythmias and cardiovascular collapse. Acute coronary events associated with hypersensitivity reaction are referred to as Kounis syndrome (allergic angina) (71).
A number of factors have been explored in the literature, and it is found that patient’s sensitivity level, allergen concentration and the route of administration are important in determining the onset and severity of symptoms (42).
2) Biological assessment: In-vitro and in-vivo biochemical tests such as an increase in serum histamine concentration and tryptase measurements are recommended for the diagnosis of immediate reaction (72). Other in-vitro tools have been proposed like specific IgE assays for various drugs (thiopentone, propofol, antibiotics) (73).
3) Allergologic/skin tests: Multiple studies have been conducted and concluded skin tests to be the gold standard for detection of IgE mediated reaction. It is performed by exposing the mast cells of the skin to the suspected allergen in patients having experienced anaphylaxis (74). The test help to identify the causative agent to definitely avoid it.
Treatment of Anaphylaxis
A number of protocols and management algorithms have been described in the literature for acute recognition and management of anaphylaxis (75),(76).
1) Restoration of CVS haemostasis: Expansion of intravascular volume status with administration of iv epinephrine is the first priority (75).
Fluid therapy: Upto 73% of blood volume may extravasate into the interstitial space within 15 minutes after the onset of event. Recent consensus of the International Suspected Perioperative Allergic Reaction (ISPAR) group recommends that crystalloid boluses upto 20 mL/kg, repeated where the clinical response is inadequate and further choice tailored to the severity of anaphylaxis.
Adrenaline: Early administration of intravenous adrenaline is warranted (77). Grade 3 may require titrated intravenous (i.v) bolus administration (100-200 μ) followed by continuous infusion (1-4 ug/min). Grade 4: Cardiac arrest requires CPR and high doses of epinephrine 1-3 mg i.v over three minutes followed by continuous infusion (4-10 μg/min) (78).
2) Restoration of airway and management of bronchospasm: If the event has occurred after administration of NMBAs, airway should be promptly secured if not done already. If during RA such as due to antibiotics, oxygen by face mask should suffice, followed by further management accordingly (78).
Bronchospasm is treated with inhaled beta 2 agonists via a nebulizer (salbutamol or albuterol). In case of persistent bronchospasm, iv injection of beta 2 agonist is recommended and a continuous infusion (5-25 μg/min) is considered. Intravenous glucocorticoids (like methylprednisolone) remain a key component of management, as their potential anti inflammatory effects decrease airway inflammation.
3) Other miscellaneous agents
a) A systemic review and meta analysis of 30 clinical trials, has stated corticosteroids and/or H1 receptor antagonists (anti histamines) to be of proven benefit especially for angioedema (79).
b) Sugammadex should be administered, in the setting of rocuronium related anaphylaxis.
4) Anaphylactic shock refractory to adrenaline:
Adrenaline sometimes fail to restore the profound disturbances of CVS haemostasis. This singular entity is called anaphylactic shock refractory to catecholamines (3-5%). It occurs because of (80):
• Failure to discontinue the culprit agent or lower the anaesthetic depth.
• Underdosing or overdosing of adrenaline (leading to desensitisation)
• Delayed adrenaline administration
• Inadequate fluids
Arginine Vasopressin (AVP) may be used as an alternative rescue therapy in such scenarios, in a dose of 1-2 IU; followed by infusion at 2 IU/hr.
Nor adrenaline, metaraminol, glucagon.A review of case reports recommended the use of nor adrenaline, metaraminol and glucagon in this setting especially for patients on beta blocker therapy (80).
Extracorporeal Life Support (ECLS) has been successfully used in a few cases of refractory anaphylaxis.
Prevention of Anaphylaxis
1) In case of history of anaphylaxis to a particular drug, it should be avoided with planning of safe alternatives for the same.
2) When specific agent was not identified, it should be considered to replace all drugs administered before the onset of reaction with alternatives.
3) In case of susceptible individuals/history of atopy, it is advisable to avoid triggers like Latex, use alternatives to NMBAs like LA and inhalational agents if possible, and slow administration of histamine releasing drugs (81).
4) Premedication with steroids and/or anti histamines have been found to be useful, though controversial reports exists (82).
REPORTING OF ADR UNDER ANAESTHESIA
Critical incident reporting is the key component of patient safety (83). This involves introduction of Incident Reporting Systems (IRS) which have been organised at variety of levels: within individual departments of anaesthesia, within individual hospitals at regional level and national level (84). While immediate analysis and feedback are essential at local level, wide dissemination of safety lessons can improve patient care on a larger scale.
There are four basic steps in a successful critical incident reporting and analysis (85),(86).
a) Data input: Should be independent and non punitive.
b) The data: The actual data reporting should have the freedom to narrate what actually happened.
c) Analysis: A good quality report should tend itself for detailed analysis of the chain of events that lead to the incident.
d) Feedback: To learn from mistakes and to ensure systems are improved for better patient safety in future and to encourage further reporting.
The main reasons for under reporting includes fear of punitive action, legal ramifications, lack of understanding as to what should be reported and lack of awareness as to how reported incidents will be analysed.
The nature of anaesthetic practice is such that exposure to risk is inordinately high. Adequate knowledge and experience, proper perioperative assessment of the patient, labelling of syringes, checking of lines and cannulas, slow administration of drugs are necessary to decrease the incidence of ADRs in anaesthesia. Anaphylaxis is the most serious ADR and can be life threatening. Prevention, management, documenatation, appropriate labelling of the patient and critical incident reporting should be encouraged in anaesthesia practice to improve patient safety and decrease morbidity and mortality.
DOI: 10.7860/JCDR/2022/55703.16567
Date of Submission: Feb 15, 2022
Date of Peer Review: Apr 05, 2022
Date of Acceptance: Apr 18, 2022
Date of Publishing: Jul 01, 2022
AUTHOR DECLARATION:
• Financial or Other Competing Interests: None
• Was informed consent obtained from the subjects involved in the study? No
• For any images presented appropriate consent has been obtained from the subjects. No
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