Definition and classification for adverse events following spinal and peripheral joint manipulation and mobilization: A scoping review

Martha Funabashi; Lindsay M. Gorrell; Katherine A. Pohlman; Andrea Bergna; Nicola R. Heneghan

doi:10.1371/journal.pone.0270671

Table 2

Studies providing direct adverse event definition and classification system (n = 30).

Author, year, citation Study Design Definition Classification system
Powell et al. 1993 [8] Case Report / series The definition of "complication" is broadened to include indirect injury in which treatment postpones the appropriate diagnosis or continues in spite of progressive symptoms or signs, then the incidence may be higher. Severe: if the treatments were unsuccessful, resulted in major disability or death.

Senstad et al. 1996a [36] Survey Some type of unpleasant side effect after the previous treatment Adequate reactions: does not influence the working ability with spontaneous remission completed, at the latest, 2 days after the manipulation
Exceeding reactions: objective worsening of the pre-existing state, with decreased work capacity, and spontaneous remission exceeding 2 days
Authors used:
On a scale from 1 to 4:
Minor = 1
Unbearable = 4

Leboeuf-Yde et al. 1997 [37] Survey Any additional discomfort after the previous treatment Common/Normal reactions: early onset, mild-to-moderate severity and gone within 48 hours
Self-reported unpleasant reactions Light or moderate reactions: little or no effect on normal daily activities

Thiel et al. 2006 [38] Survey A patient safety incident can be defined by: Low Harm: Incident required extra observation or minor treatment (additional therapy or medication over short period of time, does not include admission to hospital or attending as an outpatient on repeated occasions)
Moderate Harm: Incident resulted in a moderate increase in additional treatment (admission to hospital or attending as an outpatient on repeated occasions, or requiring surgery or prolonged episodes of care) and caused significant but not permanent harm
‘‘That was a threat to my patient’s well-being, and I don’t want it to happen again” Severe Harm: Incident resulted in permanent harm (harm or disability directly related to incident and leading to permanent lessening of bodily functions, or sensory, motor, physiologic or intellectual deficit)
Death: Incident directly resulted in death
Near Miss: No harm occurred—Incident had potential to cause harm but was prevented either by chance or deliberate action

Rubinstein et al. 2007 [9] Observational Study A new related complaint that was not present at baseline or a worsening of the presenting complaint or an existing complaint by >30% compared with baseline Intense AE: any AE fulfilling our definition of an adverse event and that also scored ≥8 in intensity on the 11-point NRS.
Serious AE: events resulting in death, life-threatening situations, the
need for admittance to a hospital, or temporary or permanent disability.

Rubinstein et al. 2008 [39] Observational Study A new related complaint that was not present at baseline, or a worsening of the neck pain or any other existing complaint by >30% compared to baseline. Intense AE: any AE fulfilling our definition of an adverse event, and which also scored ≥8 in intensity on the 11-point NRS.
Serious AE: events resulting in death, life-threatening situations, the need for admittance to a hospital, or temporary or permanent disability.

Rubinstein et al. 2008 [40] Observational Study Either a new complaint or the worsening of an existing complaint by more than 30% compared to baseline (more than MCID on 11-point NRS) Intense AE: any AE fulfilling the definition, and which also scored 8 or higher in intensity on the 11-point NRS.
Serious AE: events resulting in death, life-threatening situations, the need for admittance to a hospital, or temporary or permanent disability.

O’Shaughnessy et al. 2010 [35] Case Report / series Side-effects of a benign nature included increased pain and/or stiffness of short duration Mild to moderate: little or no influence on daily activities, brief, with spontaneous recovery and lasting no more than a few days.
Major complications: irreversible

Wangler et al. 2011 [41] Consensus An adverse event is an injury related to medical management, in contrast to a complication of disease. Preventable or Non-preventable.
Adverse drug reaction is a complication that occurs when the medication is used as directed and in the usual dosage.
Preventable AE: An adverse event caused by an error or other type of systems or equipment failure.
An adverse event is the result of a care delivery problem related to chiropractic management, in contrast to complications of disease.

Eriksen et al. 2011 [42] Trial Symptomatic Reaction: a new related complaint that was not present at baseline or a worsening of the presenting complaint by >30% compared with baseline occurring <24 hours following care Intense symptomatic reaction: any complaint fulfilling our definition of a SR that also scored ≥8 in intensity on the 11-point NRS
Any discomfort or unpleasant reaction that they felt was related to their chiropractic care Serious AE: events resulting in death, life-threatening situations, need for admittance to a hospital, or temporary or permanent disability

Puentedura et al. 2011 [43] Trial Sequelae medium- to long-term in duration, with moderate to severe symptoms that were serious, distressing, and unacceptable to the patient and required further treatment Minor side effects: short term, mild in nature, nonserious, transient, were reversible consequences of the treatment and disappear within 24 to 48 hours

Rubinstein et al. 2011 [44] Review Transient increase in pain; exacerbations of symptoms; aggravation of condition, worsening of pain Serious AE: defined as an event leading to hospitalisation or death within one week of treatment

Dagenais et al. 2012 [45] Survey Harm is any negative health outcome observed in a clinical trial, regardless of whether it was definitively related to the intervention. This is true even when the harm does not become apparent until the treatment has been used by many patients for extended periods. This term, therefore, incorporates concepts related to adverse events, adverse reactions, side effects, and safety, and favors disclosure regardless of causation. Benign: mild to moderate intensity, and resolve spontaneously
Minor: short term, mild intensity and do not require treatment; gets better on their own in a few days
Moderate: medium to long term and of moderate intensity
Major: medium to long term, require treatment and are of moderate to severe intensity
Serious: result in death, hospitalization, or permanent injury

Nee et al. 2012 [46] Trial Aggravation of existing symptoms or provocation of other unpleasant sensations after each neural tissue management treatment session Mild: do not require additional treatment, usually last <24 hours, have minimal impact on daily activities, and do not reduce a participant’s chance of improving with neural tissue management

Walker et al. 2013 [47] Trial From protocol: On 0–10 NRS score:
Mild = 1 to 3
Adverse events are undesirable reactions to treatment.
Moderate = 4 to 6
Any new unwelcome symptoms OR an increase of your presenting symptoms during the first 48 hours (two days) after treatment Severe = 7 to 10

Pohlman et al. 2014 [22] Consensus Any unfavorable sign, symptom, or disease temporally associated with the treatment, whether or not caused by the treatment. Mild: Asymptomatic or mild symptoms, self-care only (e.g., ice/heat, over-the-counter analgesic);
Moderate: Limiting age-appropriate activities of daily living (e.g., work, school) OR sought care from a medical doctor;
Severe: Medically significant but not immediately life-threatening; temporarily limits self-care (e.g., bathing, dressing, eating); OR urgent or emergency room assessment sought;
Serious: Results in death OR a life-threatening adverse event OR an AE resulting in inpatient hospitalization or prolongation of existing hospitalization for more than 24 hours; a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; a congenital anomaly/birth defect

Paanalahti et al. 2014 [19] Trial Events that had occurred within 24 hours following the treatment. Definitions based on duration and/or severity of the reaction:
Short minor: NRS ≤3 and <24 hours of duration
Long minor: NRS ≤3 and ≥24 hours of duration
Short moderate: NRS >3 and <24 hours of duration
Long moderate: NRS >3 and ≥24 hours of duration
Serious adverse event: the patient had a loss of bowel/bladder function, stroke, fracture or where hospitalized

Dougherty et al. 2014 [20] Trial Any undesirable medical event with new onset or significant exacerbation during the course of the study, regardless of whether or not it was considered to be related to study treatment Serious: any AE occurring during the study or within 30 days of conclusion of study participation resulting in any one of the following outcomes: death, life threatening persistent or significant disability/incapacity, hospitalization (when the result of an AE occurring during the study; note, hospitalization for an elective procedure or for treatment of a pre-existing condition not worsened during the study was not considered an serious AE; admission to the emergency room for 23 hours or less was not considered a hospitalization), congenital anomaly, important medical event (i.e., an event that in the opinion of the investigator may jeopardize the participant and may require medical or surgical intervention to prevent one of the outcomes listed above)

Han et al. 2015 [48] Protocol Any new unwelcome symptoms or an increase of presenting symptoms during the first 48 hours (two days) after treatment; Mild AE: 1-3/10 on an 11-point NRS
Moderate AE: Original pain increased regionally or/and radically after the intervention, with its intensity rated below 8/10 on an 11-point NRS (From questionnaire [additional file 1] = 4-6/10 on 11-point NRS)
Any additional problems or increasing difficulties with the activities of daily living after spinal manipulation Severe AE: the radicular pain intensity is rated above 8/10 on an 11-point NRS, ankle-foot sensorimotor function is suddenly absent, or defecation dysfunction and saddle anesthesia occur (From questionnaire [additional file 1] = 7-10/10 on 11-point NRS)

Woodfield et al. 2015 [49] Review An increase in baseline pain or a new complaint within 24 hours Mild symptomatic reactions of short-duration (<24 hours) and only “little” effect on daily activities, similar to the short-term effect of exercise.

Kim et al. 2016 [50] Protocol Any unexpected signs or symptoms during the treatment Spilker classification:
Mild: not needing additional intervention, nor significantly inhibiting to the normal lifestyle (function) of the participant
Moderate: significantly inhibiting to the normal lifestyle (function) of the participant, and may need additional intervention, recovering afterwards
Severe: severe AE requiring intensive intervention, and leaving sequelae

Thoomes-de Graaf et al. 2017 [51] Survey Reference to any untoward medical occurrence and the lack of a causal relationship Minor adverse events: short term and mild, nonserious, transient and easily reversible, requiring no further treatment or alteration of management strategy as the consequences are short term and contained.
Moderate adverse effects were defined identically, but being only moderate in severity.
Major adverse effects were defined as lasting medium to long term, being moderate to severe, unacceptable, serious and distressing and normally requiring further treatment.

Nielsen et al. 2017 [21] Review Any untoward occurrence that may present during treatment Serious AEs are conditions requiring hospital admission (or mortality)

Swait et al. 2017 [11] Review Untoward, undesirable or detrimental, have an impact on the patient and are caused by a healthcare process rather than the natural process of disease Mild or benign events: short-term, non-serious, the patient’s function remains intact, and they are transient/reversible; no treatment alterations are required because the consequences are short-term and contained.
Moderate AEs: as major adverse events but moderate in severity.
Major AEs: medium to long-term, moderate to severe and unacceptable; they normally require further treatment and are serious and distressing.
Authors used:
Benign: mild to moderate, transient adverse events
Serious: moderate to major, long-term adverse events

Shin et al. 2017 [52] Protocol Any unexpected or unintended patient reaction Spilker classification:
Mild: not needing additional intervention, nor significantly inhibiting to the normal lifestyle (function) of the participant
Moderate: significantly inhibiting to the normal lifestyle (function) of the participant, and may need additional intervention, recovering afterwards
Severe: severe AE requiring intensive intervention, and leaving sequelae

Degenhardt et al. 2018 [10] Observational Study Any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medical treatment or procedure that may or may not be considered related to the medical treatment or procedure. Serious AE: result in death or hospitalization, or caused permanent disability.
Authors used:
Responses of worse or much worse were considered to indicate that an adverse event had occurred
Exacerbation of the patients’ chief complaints or a new symptom.

Do et al. 2018 [53] Protocol Undesirable and unintentional signs (i.e., abnormal laboratory test results), symptoms, or disease occurring after treatment, which does not have to have a causal relationship with the treatment Mild: no need for additional procedures and no great interference with the subject’s everyday life (function)
Moderate: significant interference of the subject’s everyday life (function), probable need for additional procedures but followed by resolution after the procedure
Severe: calling for advanced procedure, and leaving sequelae will be applied for evaluation.

Tabell et al. 2019 [54] Observational Study Pain and loss of function with impact on daily living or work On a 0–10 NRS scale:
No AE = <1
Mild AE = 1–3
Moderate/Major AE = ≥4

Lim et al. 2019 [55] Trial From protocol: From protocol:
Spilker classification:
Mild: not needing additional intervention, nor significantly inhibiting to the normal lifestyle (function) of the participant
Moderate: significantly inhibiting to the normal lifestyle (function) of the participant, and may need additional intervention, recovering afterwards
Any unexpected or unintended patient reaction
Severe: severe AE requiring intensive intervention, and leaving sequelae

Pohlman et al. 2020 [56] Survey Any unfavorable sign, symptom, or disease temporarily associated with the treatment, whether or not caused by the treatment, specifically any worsened or new symptom. Mild: Mild symptoms, self-care only (e.g., ice/heat, over-the-counter analgesic).
Moderate: Limiting age-appropriate activities of daily living (e.g., work, school) OR sought care from a medical doctor.
Worsened and new symptoms
Severe: Medically significant but not immediately life-threatening; temporarily limits self-care (e.g., bathing, dressing, eating) (for 5 years of age and older); OR urgent or emergency room assessment sought.
A new AE: a symptom that was not noted pre-treatment but was reported post-treatment.
A worsening AE: a symptom noted pre-treatment with increased severity post-treatment Serious: Results in death OR a life-threatening AE OR an adverse event resulting in inpatient hospitalization or prolongation of existing hospitalization for more than 24 hour; a persistent or significant incapacity or substantial disruption of the ability.

NRS: numeric rating scale;
MCID: minimal clinically important difference;
AE: adverse event.

Author, year, citation	Study Design	Definition	Classification system
Powell et al. 1993 [8]	Case Report / series	The definition of "complication" is broadened to include indirect injury in which treatment postpones the appropriate diagnosis or continues in spite of progressive symptoms or signs, then the incidence may be higher.	Severe: if the treatments were unsuccessful, resulted in major disability or death.

Senstad et al. 1996a [36]	Survey	Some type of unpleasant side effect after the previous treatment	Adequate reactions: does not influence the working ability with spontaneous remission completed, at the latest, 2 days after the manipulation
			Exceeding reactions: objective worsening of the pre-existing state, with decreased work capacity, and spontaneous remission exceeding 2 days
			Authors used:
			On a scale from 1 to 4:
			Minor = 1
			Unbearable = 4

Leboeuf-Yde et al. 1997 [37]	Survey	Any additional discomfort after the previous treatment	Common/Normal reactions: early onset, mild-to-moderate severity and gone within 48 hours
Leboeuf-Yde et al. 1997 [37]	Survey	Self-reported unpleasant reactions	Light or moderate reactions: little or no effect on normal daily activities

Thiel et al. 2006 [38]	Survey	A patient safety incident can be defined by:	Low Harm: Incident required extra observation or minor treatment (additional therapy or medication over short period of time, does not include admission to hospital or attending as an outpatient on repeated occasions)
		A patient safety incident can be defined by:	Moderate Harm: Incident resulted in a moderate increase in additional treatment (admission to hospital or attending as an outpatient on repeated occasions, or requiring surgery or prolonged episodes of care) and caused significant but not permanent harm
		‘‘That was a threat to my patient’s well-being, and I don’t want it to happen again”	Severe Harm: Incident resulted in permanent harm (harm or disability directly related to incident and leading to permanent lessening of bodily functions, or sensory, motor, physiologic or intellectual deficit)
			Death: Incident directly resulted in death
			Near Miss: No harm occurred—Incident had potential to cause harm but was prevented either by chance or deliberate action

Rubinstein et al. 2007 [9]	Observational Study	A new related complaint that was not present at baseline or a worsening of the presenting complaint or an existing complaint by >30% compared with baseline	Intense AE: any AE fulfilling our definition of an adverse event and that also scored ≥8 in intensity on the 11-point NRS.
			Serious AE: events resulting in death, life-threatening situations, the
			need for admittance to a hospital, or temporary or permanent disability.

Rubinstein et al. 2008 [39]	Observational Study	A new related complaint that was not present at baseline, or a worsening of the neck pain or any other existing complaint by >30% compared to baseline.	Intense AE: any AE fulfilling our definition of an adverse event, and which also scored ≥8 in intensity on the 11-point NRS.
Rubinstein et al. 2008 [39]	Observational Study		Serious AE: events resulting in death, life-threatening situations, the need for admittance to a hospital, or temporary or permanent disability.

Rubinstein et al. 2008 [40]	Observational Study	Either a new complaint or the worsening of an existing complaint by more than 30% compared to baseline (more than MCID on 11-point NRS)	Intense AE: any AE fulfilling the definition, and which also scored 8 or higher in intensity on the 11-point NRS.
Rubinstein et al. 2008 [40]	Observational Study		Serious AE: events resulting in death, life-threatening situations, the need for admittance to a hospital, or temporary or permanent disability.

O’Shaughnessy et al. 2010 [35]	Case Report / series	Side-effects of a benign nature included increased pain and/or stiffness of short duration	Mild to moderate: little or no influence on daily activities, brief, with spontaneous recovery and lasting no more than a few days.
O’Shaughnessy et al. 2010 [35]	Case Report / series		Major complications: irreversible

Wangler et al. 2011 [41]	Consensus	An adverse event is an injury related to medical management, in contrast to a complication of disease.	Preventable or Non-preventable.
		Adverse drug reaction is a complication that occurs when the medication is used as directed and in the usual dosage.	Preventable or Non-preventable.
			Preventable AE: An adverse event caused by an error or other type of systems or equipment failure.
		An adverse event is the result of a care delivery problem related to chiropractic management, in contrast to complications of disease.

Eriksen et al. 2011 [42]	Trial	Symptomatic Reaction: a new related complaint that was not present at baseline or a worsening of the presenting complaint by >30% compared with baseline occurring <24 hours following care	Intense symptomatic reaction: any complaint fulfilling our definition of a SR that also scored ≥8 in intensity on the 11-point NRS
Eriksen et al. 2011 [42]	Trial	Any discomfort or unpleasant reaction that they felt was related to their chiropractic care	Serious AE: events resulting in death, life-threatening situations, need for admittance to a hospital, or temporary or permanent disability

Puentedura et al. 2011 [43]	Trial	Sequelae medium- to long-term in duration, with moderate to severe symptoms that were serious, distressing, and unacceptable to the patient and required further treatment	Minor side effects: short term, mild in nature, nonserious, transient, were reversible consequences of the treatment and disappear within 24 to 48 hours

Rubinstein et al. 2011 [44]	Review	Transient increase in pain; exacerbations of symptoms; aggravation of condition, worsening of pain	Serious AE: defined as an event leading to hospitalisation or death within one week of treatment

Dagenais et al. 2012 [45]	Survey	Harm is any negative health outcome observed in a clinical trial, regardless of whether it was definitively related to the intervention. This is true even when the harm does not become apparent until the treatment has been used by many patients for extended periods. This term, therefore, incorporates concepts related to adverse events, adverse reactions, side effects, and safety, and favors disclosure regardless of causation.	Benign: mild to moderate intensity, and resolve spontaneously
			Minor: short term, mild intensity and do not require treatment; gets better on their own in a few days
			Moderate: medium to long term and of moderate intensity
			Major: medium to long term, require treatment and are of moderate to severe intensity
			Serious: result in death, hospitalization, or permanent injury

Nee et al. 2012 [46]	Trial	Aggravation of existing symptoms or provocation of other unpleasant sensations after each neural tissue management treatment session	Mild: do not require additional treatment, usually last <24 hours, have minimal impact on daily activities, and do not reduce a participant’s chance of improving with neural tissue management

Walker et al. 2013 [47]	Trial	From protocol:	On 0–10 NRS score:
		From protocol:	Mild = 1 to 3
		Adverse events are undesirable reactions to treatment.	Mild = 1 to 3
		Adverse events are undesirable reactions to treatment.	Moderate = 4 to 6
		Any new unwelcome symptoms OR an increase of your presenting symptoms during the first 48 hours (two days) after treatment	Severe = 7 to 10

Pohlman et al. 2014 [22]	Consensus	Any unfavorable sign, symptom, or disease temporally associated with the treatment, whether or not caused by the treatment.	Mild: Asymptomatic or mild symptoms, self-care only (e.g., ice/heat, over-the-counter analgesic);
			Moderate: Limiting age-appropriate activities of daily living (e.g., work, school) OR sought care from a medical doctor;
			Severe: Medically significant but not immediately life-threatening; temporarily limits self-care (e.g., bathing, dressing, eating); OR urgent or emergency room assessment sought;
			Serious: Results in death OR a life-threatening adverse event OR an AE resulting in inpatient hospitalization or prolongation of existing hospitalization for more than 24 hours; a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; a congenital anomaly/birth defect

Paanalahti et al. 2014 [19]	Trial	Events that had occurred within 24 hours following the treatment.	Definitions based on duration and/or severity of the reaction:
			Short minor: NRS ≤3 and <24 hours of duration
			Long minor: NRS ≤3 and ≥24 hours of duration
			Short moderate: NRS >3 and <24 hours of duration
			Long moderate: NRS >3 and ≥24 hours of duration
			Serious adverse event: the patient had a loss of bowel/bladder function, stroke, fracture or where hospitalized

Dougherty et al. 2014 [20]	Trial	Any undesirable medical event with new onset or significant exacerbation during the course of the study, regardless of whether or not it was considered to be related to study treatment	Serious: any AE occurring during the study or within 30 days of conclusion of study participation resulting in any one of the following outcomes: death, life threatening persistent or significant disability/incapacity, hospitalization (when the result of an AE occurring during the study; note, hospitalization for an elective procedure or for treatment of a pre-existing condition not worsened during the study was not considered an serious AE; admission to the emergency room for 23 hours or less was not considered a hospitalization), congenital anomaly, important medical event (i.e., an event that in the opinion of the investigator may jeopardize the participant and may require medical or surgical intervention to prevent one of the outcomes listed above)

Han et al. 2015 [48]	Protocol	Any new unwelcome symptoms or an increase of presenting symptoms during the first 48 hours (two days) after treatment;	Mild AE: 1-3/10 on an 11-point NRS
			Moderate AE: Original pain increased regionally or/and radically after the intervention, with its intensity rated below 8/10 on an 11-point NRS (From questionnaire [additional file 1] = 4-6/10 on 11-point NRS)
		Any additional problems or increasing difficulties with the activities of daily living after spinal manipulation	Severe AE: the radicular pain intensity is rated above 8/10 on an 11-point NRS, ankle-foot sensorimotor function is suddenly absent, or defecation dysfunction and saddle anesthesia occur (From questionnaire [additional file 1] = 7-10/10 on 11-point NRS)

Woodfield et al. 2015 [49]	Review	An increase in baseline pain or a new complaint within 24 hours	Mild symptomatic reactions of short-duration (<24 hours) and only “little” effect on daily activities, similar to the short-term effect of exercise.

Kim et al. 2016 [50]	Protocol	Any unexpected signs or symptoms during the treatment	Spilker classification:
			Mild: not needing additional intervention, nor significantly inhibiting to the normal lifestyle (function) of the participant
			Moderate: significantly inhibiting to the normal lifestyle (function) of the participant, and may need additional intervention, recovering afterwards
			Severe: severe AE requiring intensive intervention, and leaving sequelae

Thoomes-de Graaf et al. 2017 [51]	Survey	Reference to any untoward medical occurrence and the lack of a causal relationship	Minor adverse events: short term and mild, nonserious, transient and easily reversible, requiring no further treatment or alteration of management strategy as the consequences are short term and contained.
			Moderate adverse effects were defined identically, but being only moderate in severity.
			Major adverse effects were defined as lasting medium to long term, being moderate to severe, unacceptable, serious and distressing and normally requiring further treatment.

Nielsen et al. 2017 [21]	Review	Any untoward occurrence that may present during treatment	Serious AEs are conditions requiring hospital admission (or mortality)

Swait et al. 2017 [11]	Review	Untoward, undesirable or detrimental, have an impact on the patient and are caused by a healthcare process rather than the natural process of disease	Mild or benign events: short-term, non-serious, the patient’s function remains intact, and they are transient/reversible; no treatment alterations are required because the consequences are short-term and contained.
			Moderate AEs: as major adverse events but moderate in severity.
			Major AEs: medium to long-term, moderate to severe and unacceptable; they normally require further treatment and are serious and distressing.
			Authors used:
			Benign: mild to moderate, transient adverse events
			Serious: moderate to major, long-term adverse events

Shin et al. 2017 [52]	Protocol	Any unexpected or unintended patient reaction	Spilker classification:
			Mild: not needing additional intervention, nor significantly inhibiting to the normal lifestyle (function) of the participant
			Moderate: significantly inhibiting to the normal lifestyle (function) of the participant, and may need additional intervention, recovering afterwards
			Severe: severe AE requiring intensive intervention, and leaving sequelae

Degenhardt et al. 2018 [10]	Observational Study	Any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medical treatment or procedure that may or may not be considered related to the medical treatment or procedure.	Serious AE: result in death or hospitalization, or caused permanent disability.
		Authors used:
		Responses of worse or much worse were considered to indicate that an adverse event had occurred
		Exacerbation of the patients’ chief complaints or a new symptom.

Do et al. 2018 [53]	Protocol	Undesirable and unintentional signs (i.e., abnormal laboratory test results), symptoms, or disease occurring after treatment, which does not have to have a causal relationship with the treatment	Mild: no need for additional procedures and no great interference with the subject’s everyday life (function)
			Moderate: significant interference of the subject’s everyday life (function), probable need for additional procedures but followed by resolution after the procedure
			Severe: calling for advanced procedure, and leaving sequelae will be applied for evaluation.

Tabell et al. 2019 [54]	Observational Study	Pain and loss of function with impact on daily living or work	On a 0–10 NRS scale:
			No AE = <1
			Mild AE = 1–3
			Moderate/Major AE = ≥4

Lim et al. 2019 [55]	Trial	From protocol:	From protocol:
			Spilker classification:
			Mild: not needing additional intervention, nor significantly inhibiting to the normal lifestyle (function) of the participant
			Moderate: significantly inhibiting to the normal lifestyle (function) of the participant, and may need additional intervention, recovering afterwards
		Any unexpected or unintended patient reaction
		Any unexpected or unintended patient reaction	Severe: severe AE requiring intensive intervention, and leaving sequelae

Pohlman et al. 2020 [56]	Survey	Any unfavorable sign, symptom, or disease temporarily associated with the treatment, whether or not caused by the treatment, specifically any worsened or new symptom.	Mild: Mild symptoms, self-care only (e.g., ice/heat, over-the-counter analgesic).
			Moderate: Limiting age-appropriate activities of daily living (e.g., work, school) OR sought care from a medical doctor.
		Worsened and new symptoms
		Worsened and new symptoms	Severe: Medically significant but not immediately life-threatening; temporarily limits self-care (e.g., bathing, dressing, eating) (for 5 years of age and older); OR urgent or emergency room assessment sought.
		A new AE: a symptom that was not noted pre-treatment but was reported post-treatment.
		A worsening AE: a symptom noted pre-treatment with increased severity post-treatment	Serious: Results in death OR a life-threatening AE OR an adverse event resulting in inpatient hospitalization or prolongation of existing hospitalization for more than 24 hour; a persistent or significant incapacity or substantial disruption of the ability.