Thesis Submitted in Partial Fulfillment of the Requirements for the Degree of
Master of Science Under the supervision of
Lina Jankauskaite
Department of Pediatrics Medical Academy
Of the Lithuanian University of Health Sciences
Midazolam usage in the
Pediatric emergency department
Of Lithuanian University of Health Sciences
Hospital Kauno Klinikos
by
ALBORS DAEMI
©Albors Daemi 2019
Lithuanian University of Health Sciences May 2019
TABLE OF CONTENTS
TABLE OF CONTENTS ... 2 SUMMARY ... 3 CONFLICT OF INTEREST ... 3 ACKNOWLEDGMENTS ... 4 ABBREVIATION LIST ... 4AIMS AND OBJECTIVES ... 4
INTRODUCTION ... 5 LITERATURE REVIEW ... 6 Pharmacological issues ... 6 Cognitive effects ... 7 Side effects ... 8 Dosage ... 10 METHODS ... 11 Patient selection ... 11
Sedation criteria and administration ... 11
The procedure ... 11
Outcome measures ... 12
Statistical data analysis ... 13
RESULTS ... 14
DISCUSSION ... 20
Limitations of study ... 21
SUMMARY
Authors name: Albors DaemiTitle: Midazolam usage in the pediatric emergency department of the hospital of the LSMU clinics Background: Children often present to the emergency department with agitation and anxiety. Midazolam is one of the most used agents to provide anxiolysis in this case. We sought to evaluate the efficacy and safety of this treatment in an emergency setting.
Aim and objectives: To characterize effectiveness and complications in children receiving oral or intranasal midazolam, as well as to develop guidelines for its administration in the pediatric emergency department of Kaunas Clinics Hospital LSMU. To evaluate the prescribed dosage of midazolam and its possible associations with the adverse reactions
Material and Methods: All pediatric patients under the age of 18, that presented to the pediatric emergency department and required a single dose of midazolam before the procedure were included in this study. Every child was observed and monitored for 20 minutes after the procedure. The primary outcome was the detection and evaluation of side effects.
Results: Of the 31 children included in this study, minor side effects were recorded in 21 cases (65%). Severe side effects were not recorded. The median age was 4.5±3.6 years. The most common side effect was paradoxical reactions (25%). We recorded 85% of all side effects when the applicated dosage was less than 0.3mg/kg (OR 1.8, 95% 0.22-14.8; p=0.58). The most common procedure was laceration repair. We found a significant correlation between the occurrence of side effects and this procedure type (relative risk: 2.34, 95% CI 1.3-4.57; p=0.0057). In addition, there was a significant correlation between an administered dosage lower than 0.26mg/kg and the occurrence of either diminished heart rate, blood pressure, respiratory rate or oxygen saturation.
Conclusion: Midazolam is an important sedation agent in the pediatric emergency department. Nevertheless, should the administration route as well as the dosage carefully be evaluated beforehand. Additionally, due to the possible occurrence of non-detectable side effects, it is obligatory to implement a follow-up monitoring after the procedure was accomplished.
Recommendations: It is recommended to establish strict dosage guidelines for intranasal, as well as oral administrations of midazolam. We also advise increasing the maximal dosage, so older and heavier patients can still benefit from an adequate sedation.
CONFLICT OF INTEREST
The author reports no conflict of interest.ACKNOWLEDGMENTS
The author expresses uppermost appreciation to Lina Jankauskaite for the introduction to the fascinating world of scientific research as well as educative support along the process of researching. Moreover, the author would like to thank Goda Mickeviciute, Egle Zelbiene, Milda Seskute and Mantas Simutis for their outstanding help and support during the initial phase of the study. Partial gratitude is expressed to Ignas Sutkevicius, for aiding the statistical analysis. Lastly, the author would like to gratefully acknowledge the help and support of the entire staff of the pediatric emergency department of LSMU clinics for providing an uppermost child appropriate and empathetic environment.
ABBREVIATION LIST
ADR Adverse reactions mmHg Millimeters of mercury
BP Blood pressure N Number
CA Catheterization NV Nausea and vomiting
CI Confidence interval OR Odds ratio
CYP3A4 Cytochrome P450 3A4 PO Per oral
ED Emergency department PR Paradoxical reactions
GA General anesthesia PS Procedural sedation
GABA gamma-aminobutyric acid RC Repositioning casting
HR Heart rate RR Respiratory rate
IN Intranasal Rr Relative risk
IV Intravenous SaO2 Oxygen saturation
KG Kilogram SD Standard deviation
LR Laceration repair SE Side effects
LSMU KK Lithuanian University of Health Sciences Kauno Klinikos
US Ultrasonography
MG Milligram NV Nausea and vomiting
INTRODUCTION
When children present to the emergency department (ED), they are often subjected to painful procedures, such as venipuncture, immunization, urine catheterization, wound suturing or immobilization. While the diagnostic procedure or treatment methods are necessary and can be lifesaving, the procedural pain, agitation and anxiety children experience are unnecessary and can aggravate the process of the procedure, lead to refusal, increase anxiety and fear of a child and contribute to distress of the parents or caregivers [1]. Depending on the level of anxiety and agitation, some patients are unwilling to cooperate during their procedure under local anesthesia alone; they often have to undergo general anesthesia (GA) as a last resort. Even though some complex procedures are considered to be safer and more successful under GA [2], procedural sedation (PS) is thought to be superior to GA for many other procedures [3]. PS involves the administration of a sedative or dissociative medication, potentially with an analgesic, with the purpose of maintaining spontaneous respiratory and cardiovascular functions, whilst undergoing an agonizing and painful procedure [4]. Therefore, the use of PS has been widely adopted in the field of pediatric anesthesia and it has become an important humanistic aspect of child care as well as a standard practice in pediatric pain medicine worldwide [5-7]. Since physicians have to choose amongst an armamentarium of pharmacological agents, that have different mechanisms of action, the general consensus about the agent, as well as dosage and route of administration is debated amongst policymaking entities within medical specialties and regulatory agencies [8, 9]. Much of the current literature focusses on the use of medication combinations, or the comparison to a single agent [7, 10, 11]. In the study at hand, we have conducted a prospective research analyzing the use of midazolam, which is amongst the most widely discussed topics in pediatric anesthesia [12]; while some administer it as a standard medication, others only see benefits in the pharmacological alternatives and have dismissed it from their hospitals practice [1, 12]. In clinical reality, however, pro and contra debates fail to generate general consent, since not everything is considered black or white. The multivariate impact of factors influencing the decision, have to be carefully considered and analyzed. Another challenging problem is, the lack of standardization of reporting of the outcomes by the original studies [7].
We believe that children should be successfully induced with the lowest possible agitation, anxiousness and pain. This study was therefore conducted to analyze the usage of midazolam in the pediatric ED of the Lithuanian University of Health Sciences Hospital Kauno Klinikos (LSMU KK), and to investigate whether the adverse drug reactions (ADR) outweigh its positive effects.
The lack of a regulated dosage, route of administration and indication regiment in the pediatric ED of LSMU KK, and the fact that, to our knowledge, no other studies have yielded a regulatory guideline for the application of midazolam, have instigated this research.
LITERATURE REVIEW
In order to acquire a sufficient knowledge foundation about the topic at hand, an extensive amount of research was reviewed. In the following literature review, related publications were critically evaluated and classified to allow a brief synopsis, with the intention of pointing out inadequacies, as well as benefits of it.
Midazolam is a gamma-aminobutyric acid (GABA) receptor agonist and has proven to be safe and effective for use in children to provide anxiolysis and preanesthetic sedation [13-15]. It acts by enhancing the affinity of GABA for its receptor site on the receptor complex. The pharmacodynamic consequences include anxiolysis, sedation, anterograde amnesia and reduction of seizure activity. The action intensity depends on the degree of receptor occupancy [16, 17]. In addition to the previously mentioned properties, midazolam is a short acting benzodiazepine and benefits from a wide range of administration routes, such as per oral (PO), intranasal (IN), intravenous (IV) or rectal [18]. These valuable attributes grant Midazolam an advantage amongst the contenders for the gold standard of pediatric preprocedural sedation. However, the controversies about its usage persist [7, 18-20].
Pharmacological issues
Regarding the duration of action, midazolam is considered to be a short acting anesthetic agent [21-23]. While comparing it to diazepam, it is indeed a shorter acting drug, because of its only metabolite (1-OH midazolam), but the elimination half-life still ranges between 1-2h in toddlers and is considerably longer in small infants, children and adults [24-28]. In order for the plasma levels to be reduced below a concentration of 40ng/ml, which is associated with clinical effects, it will take more than one elimination half-life time [28, 29]. Additionally, two studies that compared the plasma concentration before and after surgery in adults and children, discovered a number of patients having higher plasma midazolam levels than before the procedure [30, 31]. Steiner et al. concluded that the elimination half-life of perorally used midazolam leads to increased plasma levels at the end of a short procedure compared to those at induction of anesthesia [31].Therefore, when comparing it to other short acting agents, such as remifentanil and propofol, midazolam does not qualify as a short-acting drug [27, 28, 32-34].
route, they hypothesized, that it could be due to the large variations of rectal pH and its effect on absorption of the drug [38-41]. Midazolam has a unique chemical structure; depending on the pH, it can either produce highly water soluble salts, or exist in benzodiazepine ring-closed form [42]. As a result, the pH and consequently the composition of the generic formulation have an impact on its absorption and thus on its bioavailability in the system [41]. Additional studies showed a low and highly variably bioavailability in rectal and oral routes [43, 44]. A study conducted by Reed et al. described a range of bioavailability from 9% to 71% [45]. Secondly, the bitter taste of midazolam that is difficult to mask, as well as the pH related intense burning sensation associated with the IN administration, both contribute to an overall poor acceptance in a pediatric setting [46, 47]. In addition, the admixture of agents to cover its taste, will have an effect on the pH, and thus impact absorption and bioavailability [41, 48]. We believe there could be a correlation between the pharmacological formulations along with the patient’s diverse biological factors, and the occurrence of ADR. A new approach of systematic and theoretic analysis is required for qualified understanding.
Cognitive effects
The ability of midazolam to produce anterograde amnesia is considered to be one of its main advantages for its use in the pediatric emergency setting [49, 50]. It is thought, that its effect prevents the occurrence of intraprocedural awareness and postprocedural maladaptive behavior [28]. As an instance, a research conducted by Kain et al. has provided evidence for less maladaptive behavior due to the amnestic effect of midazolam [51]. In contrast to this finding, a more recent study conducted by Cox et al. that reviewed relevant literature from 1990 until 2006, failed to detect a difference in post-operative behavior after the premedication with midazolam [21]. A closer look at the amnestic effects, however, reveals significant shortcomings. Anterograde amnesia is the impairment of for explicit acquired information [28], and placebo-controlled studies have shown that midazolam impairs explicit memory [52]. While explicit memory is formed by conscious recollection of events, implicit memory requires no conscious recollection of information and can be displayed by a change of a person’s behavior or performance [53-55]. Behavioral outcomes, howsoever, are related to the expression of implicit and explicit memory [28].
In the light of reported studies on the effect of midazolam on implicit as well as explicit memory, it is conceivable that, midazolam impairs explicit memory while leaving implicit memory intact [56, 57]. Furthermore, Stewart, et al. hypothesized, that this finding could provide a potential explanation for the paradoxical findings of increased post-surgical anxiety in children, that were premedicated with midazolam [56]. These unexpected findings signal the need for additional studies to understand more about the effect of midazolam on memory in a pediatric emergency setting.
A different subject matter requiring additional studies is the anesthetics induced apoptotic neurodegeneration in infants. A study by Jevtovic et al. which was conducted on infant rats, showed that
a combination of anesthetic agents (midazolam, nitric oxide and isoflurane) commonly used in pediatric anesthesia, causes widespread apoptotic neurodegeneration, deficits in hippocampal synaptic function, and persistent memory/learning impairments [58]. These findings signal the need for additional studies to understand more about the role of midazolam on induced apoptotic neurodegeneration. It is imperative determine if similar effects could be relevant to the application in humans.
Side effects
Many drugs evoke ADR that may be related to administration route, dosage, age of patient inter alia [59]. Midazolam is not to be exempted from that list. The side effects may vary from commonly observed minor effects, which may require little or no intervention, to more severe but rare effects [18]. Concerning the safety along with the occurrence of ADR, dental research findings assures relative safety and rare occurrence of side effects [18, 60]. A closer look to the literature, however, reveals certain shortcomings. None of the studies included in the reviews at hand, only analyzed vital parameters such as blood pressure (BP) and respiratory rate (RR). Consequently, apparent minor ADR, such as diminished RR or low BP could have gone unnoticed. Research regarding a pediatric ED setting has been limited. It solely focusses on theeffectiveness of midazolam, by assessing pain via the visual analog scale (VAS) or by comparing completion rates, rather than the occurrence and classification of ADR [36, 61]. Most side effects are present in the Table 1. Nonetheless, many researchers have detected a great variety of paradoxical reactions (PR) (Table 2) [62-64]. The research conducted by Shin et al. discovered an age and dosage related correlation to the occurrence of PR [64]. After the IV administration of either 0.1 or 0.05mg/kg to children divided into age groups of 1-3 or 3-5 years, they concluded that lower age and higher dosage had higher occurrence of PR (29.3%, 12.2%, 7.3%, 2.4% respectively). At the same time, PR still present with difficulties, since it is not clear, if it is due to insufficient dosage, or it might be a true PR [48].
Table 1. Side effects of midazolam adapted from British national formulary (BNF) [65]
Abb. IN: intranasal
Table 2. Paradoxical reactions [62, 66]
Cardiovascula r system Respiratory system Neurological system Gastrointestinal System Miscellaneous -Cardiac arrest -Heart rate changes -Hypotension -Thrombosis -Laryngospasm -Bronchospasm -Respiratory depression -Respiratory arrest -Drowsiness -Confusion -Ataxia -Amnesia -Euphoria -Hallucinations -Dizziness -Vertigo -Urinary retention -Incontinence -Visual disturbances -Hiccups -Increased appetite Jaundice -Loss of appetite -Skin reactions -Salivation changes -Burning sensation with IN application -Muscle weakness -Anaphylaxis -Dry mouth
Psychological reactions Physical reactions -Hallucinations
-Disorientation -Dysphoria -Other psychological
phenomena
-Intense frightened state -Inconsolable Crying -Restlessness -Agitation -Combativeness -Violent / aggressive behavior -Act of self-harm -Physical assault
Dosage
There are a lot of discrepancies amongst researchers regarding the dosage of oral administration. A small number of authors have recognized a low dosage to be successful, like Silver, et al. who stated a better success rate of 0.3mg/kg than 0.5mg/kg (75% and 60% respectively) [67, 68]. Yet, a considerable body of literature exists on favoring a higher dosage to be more effective [41, 46, 61, 69]. The majority of these favor a dosage of 0.5mg/kg to be effective. Peretz et al. even concluded that 0.75mg/kg might be superior to 0.5 mg/kg [69].
The administration of IN midazolam shows some advantages over the PO due to its rapid absorption via the nasal mucosa, since it is not subject to an extensive first-pass hepatic effect [70]. These studies compared an identical dose of IN and IV midazolam, 0.1mg/kg and 0.2mg/kg respectively, and concluded similar effects [70, 71]. Concerning the IN-dosage guidelines, research coincides to a range between 0.3 and 0.5mg/kg [36, 68, 72]. This range gains more support by a 1994 study stating that a dosage of 0.2mg/kg is linked to only 2/3 satisfactory results [67]. Another important study conducted by Silver et al. concluded, that a 0.5mg/kg dosage is superior to a 0.3mg/kg [73]. An ongoing study by Gomes et al. is comparing the efficacy of IN midazolam dosages ranging from 0.2 -0.5mg/kg, in correlation to behavior and side effects et alia [37].
Over time, an extensive amount of literature has developed, albeit, to our knowledge, no prior studies have examined the correlation between dosage and incidence of ADR. This paper addresses the correlation between dosage and ADR, so far lacking in the scientific literature.
In conclusion, a more systematic and theoretical analysis of the pharmacological factors, together with the integration of more ADR related research, are needed for a full comprehension of the given topic. The literature demonstrates the lack of guidelines besides the incomprehension of PR.
METHODS
This was a prospective observational study conducted in LSMU KK pediatric ED. The study protocol was approved by the local institutional ethics committee and performed in accordance with Declaration of Helsinki and good clinical practice guidelines.
Patient selection
All children who visited the pediatric ED during the period of December 1, 2018 and February 28, 2018 and required procedural sedation with midazolam were recruited to the study. We included all patients under the age of 18. Patients with chronic diseases, disabilities, patients whose parents refused participation and patients that needed general anesthesia were excluded. After obtaining the consent of the legal guardians, demographic data (gender, age, diagnosis), procedure and patient vitals such as BP, RR, heart rate (HR) and oxygen saturation (SaO2) were documented. Patients vitals were followed up post procedurally in 5-minute intervals (max. 20min). No names were included in the research.
Sedation criteria and administration
The decision to administer midazolam, its route and dosage were determined by a senior pediatrician, or a fellow emergency doctor on duty. Briefly, the conclusion to administer midazolam was made when the patient was very agitated during the first inspection in the examination rooms or he/she was to undergo a minor painful procedure or patient’s history stated a previous painful experience. After the decision was made, the nurse on duty administered (PO or IN) a 5mg/ml midazolam for IV preparation by the company “Braun”, according the physician’s prescription and the patient was asked to sit in the lobby until the procedure. Depending on the procedure, the patient was prepared accordingly. An independent observer was present to evaluate compliance of the child during the procedure.
The procedure
Before the start of the procedure, the patient was either separated from (laceration repair (LR) and imaging), or accompanied by their parents (catheterization, bone repositioning and casting, wound dressing and suture removal). Extra emphasis was placed on patient contact to optimize a pediatric friendly atmosphere throughout all the procedures. Children that were to undergo a procedure involving a needle puncture were treated with a topical analgesic. Prior to a LR, the patients were administered local anesthetics. When patient presented increased movement during the procedure, nurses or parents were asked to perform gentle restrain. After the procedures, the patient was accompanied to the observation room. HR, BP, RR and SaO2 were monitored in 5 minutes intervals for 20-30 minutes after
the procedure. With the objective to determine possible side effects, a visual field test, as well as anaphylactic symptoms were evaluated.
Outcome measures
The main outcome measure was occurrence of side effects. The documented vitals, as well as the observed procedural compliance were further discussed with the senior pediatrician. The vital parameters were analyzed according to the correct age values (Table 3, 4).
Abb. HR: heart rate; BP: blood pressure Abbr. RR: respiratory rate; min: minute
Min: minute; mmHg: millimeters of mercury LSMU: Lithuanian university of health
sciences
Readings were divided into the following: within range, mild deviations and moderate deviations (Table 5). Two mildly deviated or one moderately deviated reading were classified as minor ADR; whereas, one or more moderate deviated readings were grouped as major ADR. Other side effects, such as PR, visual disturbances (VD) and other (dystaxia and dysarthria) were evaluated clinically in
Table 3. HR and BP according to age adapted from
Nelson Textbook of pediatrics 19th edition[74] Table 4. Respiratory rate vs. age LSMU pediatric textbook 2014
Age HR (beats/min) BP (mmHg) Age (breaths/min) RR
0-3 months 100-150 65-85/45-55 Neonates 60-80 3-6 months 90-120 70-90/50-65 < 2 months 50-60 06-12 months 80-120 80-100/55-65 2-12 months 40-50 1-3 years 70-110 90-105/55-70 1-5 years 30-35 3-6 years 65-110 95-110/60-75 5-10 years 25 6-12 years 60-95 100-120/60-75 10-18 years 20 >12 years 55-85 110-135/65-85 >18 years 14-18
Abb. SaO2: oxygen saturation; RR: respiratory rate; BP: blood pressure; HR: heart rate
Statistical data analysis
Descriptive statistics were used to describe the study population and expressed in terms of frequency, percentage, mean and standard deviation (SD). Statistical analysis was conducted using Microsoft excel and Google sheets. A pivot table was constructed as well as a multivariate regression was used to examine for possible confounders. The following variables were tested: midazolam dosage per weight, procedure type, age, gender and route of administration. P<0.05 was considered as statistically significant.
Table 5. Deviation criteria
Vital measurement Mild deviation Moderate deviation
SaO2 (%) <94% <92%
RR (breaths/min) <10 >10
BP (mmHg) <15 >15
RESULTS
During the study period, 34 children received midazolam before a procedure in the pediatric ED. Two cases were missed because of incomplete documentation. PO midazolam was used in 20 cases, IN in 11 cases. As shown in Table 6, midazolam was used in 6 different types of emergency situations as following: the most common were LR (53.1%), catheterization (CA, 15.6%) and bone repositioning and casting (BRC, 12.5%).
Table 6. Baseline characteristics
N, n: number; kg: kilograms; mg: milligrams; SD: Standard deviation; US: ultra-sonography.
Demographics N
Age, years (mean ±SD) 4.5±3.6 Weight, kg (mean ±SD) 20.4±13.1 Gender, n (%) n (%) Male 17 (53.1) Female 15 (46.9) Procedure, n (%) n (%) Laceration repair 17 (53.1%) Catheterization 5 (15.6%) Repositioning and casting 4 (12.5%) Imaging (X-Ray, US) 3 (9.4%) Applying dressing to burns 2 (6.2%)
Suture removal 1 (3.1%) Dosage, n (%) n (%) Less than 0.2mg/kg 7 (21.8%) 0.2 - 0.3mg/kg 17 (53.1%) 0.3 0.4mg/kg 3 (9.4%) More than 0.4mg/kg 1 (3.1%) Route of administration, n (%) n (%) Oral 20 (62.5%) Intra nasal 11 (43.4%)
received <0.2mg/kg and 4 received >0.3mg/kg (Table 6). Minor side effects were reported in 21 (65.6%) of the cases. The most common side effect was paradoxical reaction (PR). We recorded 8 cases (25%), in which the child displayed highly agitated behavior during the procedure. The second most common was diminished RR (n=6, 18.6%), followed by lower BP (n=5, 15.6%). Other side effects included low SaO2 (12.5%), VD and nausea or vomiting (NV) which attributed 9.4% and 6.5% of the cases respectively, motor problems such as dystaxia and slurred speech were present in 6.5% of the cases (Table 7).
Table 7. Characteristics in relation to Side effects
Number and percentage of side effects compared to baseline characteristics of entire study population. N: number; mg: milligrams; kg: kilograms;
Male patients were more likely to be affected than female patients (Rr 1.17, 95% CI 0.7-1.97, p=0.54). The route of administration suggests to have an impact on the prevalence of side effects: 70 % of all PO, and 54.5 % of all IN midazolam administrations presented with side effects (Table 7).
Criteria Side effects
Age (months) n (%) 5-24 4 (50%) 25-44 5 (55.6%) 45-64 6 (85.7%) 65-84 3 (100%) 85-104 1 (50%) >105 2 (66.7%) Dosage, n (%) Less than 0.26mg/kg 14 (66.7%) 0.26mg/kg to less than 0.36mg/kg 6 (28.6%) 0.36mg/kg to less than 0.46mg/kg 1 (4.7%) More than 0.46mg/kg 0 (0%) Gender Male 12 (70.6%) Female 9 (60%) Route of administration Oral 14 (70%) Intranasal 6 (54.5%)
Most of the patients which displayed side effects were under 5 years of age (71.1%) and 90 % of all patients between the age of 3.7 and 7 years of age presented with at least one or more side effects (Figure 1).
Figure 1. Side effects in relation to age
Number (n) of patients that presented with side effects in correlation to age in months.
According to our study, the highest number of side effects was recorded in a range between 0.16 – 0.26 mg/kg (Figure 2) and 78.1% of all procedures had a dosage lower than 0.3mg/kg. We observed that 85% of side effects occurred at that range. A dosage under 0.26mg/kg was linked to a lower blood pressure (80%), lower respiratory rate (100%), as well as lower O2 saturation; 75% of all readings occurred with a dosage lower than 0.26mg/kg.
Figure 2. Side effects in relation to dosage 0 1 2 3 4 5 6 7 5-24 25 - 44 45 - 64 65 - 84 85 - 105 > 105 S ide e ff ec t ( n) Age in months 2 4 6 8 10 12 Side ef fects (n)
Additionally, all cases with nausea or vomiting, as well as all visual disturbances were noted with a dosage lower than 0.26mg/kg (Figure 3 and 4).
Figure 3. Side effect types in relation to dosage
Number (n) of respective side effect compared to the dosage concentration in milligram per kilogram. RR: respiratory rate; BP: mean arterial blood pressure; SaO2: oxygen saturation; VD: visual disturbances, NV: nausea and/or vomiting.
Figure 4. Side effect percentage in relation to dosage
Percentage of respective side effect compared to the dosage concentration in milligram per kilogram of bodyweight. Color coding abbreviations as in Figure 3.
Another finding was that, 7 readings of either low BP, RR or SaO2, occurred without any other side effect. This result casts new light on the importance of follow-up recording, considering that these were to go unnoticed. 1 1 0 0 0 1 2 0 0 0 1 2 1 0 0 2 2 1 0 0 2 4 0 0 0.06 - 0.16 0.16 - 0.26 0.26 - 0.36 0.36 - 0.46 0.46 - 0.5 Side ef fects (n) Dosage concentration RR BP SaO2 VD NV -10 0 10 20 30 40 50 60 < 0.16 0.16 - 0.26 0.26 - 0.36 0.36 - 0.46 0.46 - 0.5 Side ef fect % Dosage concentration
Another strong factor linked to occurrence of side effects was the type of procedure and LR and CA procedures showed to have a higher occurrence of side effects (Figure 5).
Figure 5. Procedure type and side effect occurrence
Number of patients that presented with side effects in relation to the procedure type. CA: catheterization; IM: imaging; LR: laceration repair; RC: bone repositioning and casting; SR: suture removal.
The results of univariate and multivariate regression predictors of side effects in foresaid table, show a significant correlation between LR and the occurrence of side effects (Rr 2.43, 95% CI 1.3-4.57; p=0.0057). As well as a strong connection of a lower dose than 0.26mg/kg and the occurrence of diminished BP, RR or SaO2 (Rr 3.85, 95% CI 1.06-13.93; p=0.039).
Table 8. Results of univariate and multivariate regression of predictors of side effects (n=32)
Abbreviations: n: number; OR: odds ratio; CI: confidence interval; Rr: relative risk; SE: side effect; BP: low blood pressure; RR: respiratory rate; SaO2: oxygen saturation; LR: laceration repair; mg: milligrams; kg: kilograms.
3 2 12 2 1 0 5 10 15 CA IM LR RC SR Side ef fects (n) Procedure type
Predictor OR (95% CI) p-value Rr (95% CI) p-value
Per oral - SE 2.33 (0.49-11.17) 0.29 1.34 (0.74-3.47) 0.33
<0.26mg/kg - BP 2.55 (0.24-25.68) 0.44 2.2 (0.28-17.33) 0.45
<0.26mg/kg – BP, RR, SaO2 10.5 (1.73-63.91) 0.011 3.85 (1.06-13.93) 0.039
LR – SE 5.87 (1.6-21.53) 0.0076 2.43 (1.3-4.57) 0.0057
Figure 6. Procedure type in relation to type of side effect
Number of patients that presented with specific side effects in correlation to type of procedure. N: number; BD: Burn wound dressing; CA: catheterization; IM: imaging; LR: laceration repair; BRC: bone repositioning and casting; SR: suture removal; BP: low blood pressure; RR: low respiratory rate.
Also, the pattern of results showed that females were twice as likely to present with paradoxical reactions (33.3% of females and 17.6% males), whereas males were linked to have lower BP (36.5% males and 16.7% females) and RR readings (38.5% and 12.5% respectively). The route of administration showed no correlation for low BP, RR, SaO2 and PR, but NV and motor problems were only recorded if midazolam was given orally. The continuous monitoring of vital parameters, did not show any patterns with a certain increase or decrease over time. The time between the administration and the beginning of procedure didn’t have an impact on the occurrence of side effects.
0 0 1 1 0 0 0 0 0 2 0 0 0 0 0 2 1 0 0 2 0 3 1 0 0 2 0 3 0 0 0 0 0 4 0 0 BD CA IM LR BRC SR Side ef fects (n) Procedure type
DISCUSSION
The aim of this prospective observational study was to establish safety and efficacy of midazolam, when used as PS in a pediatric emergency setting, as well as the development of guidelines for its use, along with the objectives of understanding the indications of its use and the factors influencing occurrence of reported side effects of it in the pediatric ED.
The indications were well distributed, as it was used in a wide variety of stressful procedures (Table 6).
In our study we found out, that 85% of all side effects occurred if the dosage was less than 0.3mg/kg. However, it was not statistically significant (OR 1.8, 95% 0.22-14.8; p=0.58). But, when looking at the occurrence of either diminished RR, BP or SaO2 with a lower dose than 0.26mg/kg, we found a statistically significant correlation between them (Rr 3.85, 95% CI 1.06-13.93; p=0.039). Unfortunately, there are no previous studies that compare the occurrence of side effects to lower administration dosages. One of the few studies, which looked at lower dosages by Silver et al. concluded in their 1994 study, that a dosage of 0.2mg/kg was linked to less satisfactory results [67]. As previously mentioned in the literature review, the general consensus favors a dosage of 0.5mg/kg to be effective [41, 46, 61, 69].
The main limitation of the study at hand is the lack of patients that received a higher dose of midazolam. These findings should allow pensive reconsideration of the maximal dosage of midazolam, because if the patient is older and weighs more, the minimal effective dose might not be reached without exceeding the maximal dose of 7mg.
A study conducted in 2016 compared oral to intranasal preanesthetic sedation in pediatric patients and showed a better response to drug administration when given orally [46]. Pediatric patients received a 0.2mg/kg dosage intranasally or a 0.5mg/kg dosage orally. The results showed good acceptance as well as a better response of the oral medication, due to nasal irritations when administered intranasally [46]. In a study conducted by Gentz et al. in 2016, the safety and efficacy of midazolam sedation regimes were compared. The authors concluded that oral midazolam is better than intranasally administered. These findings are based on the rates of treatment completion, positive/negative behavior scores and the effectiveness assessed by an operator [22]. In contrary to these findings, we recorded a slight increase in rate of side effects in oral administration (Table 7). We hypothesize, that this might be due to differences in pharmacokinetics and bioavailability. IN medications are absorbed via nasal
leads to a facilitated excretion [77]. Because of this hepatic metabolism, a PO dose should be higher than the IN. The previously mentioned study used 0.5mg/kg when given intranasally and 1mg/kg orally. In the study at hand, the average of oral administration was 0.23±0.096 mg/kg and 0.25±0.06 mg/kg in intranasal administration. It is important to note, that the present evidence relies on a similar administration dose and therefore explain our findings.
Specific side effects related to age were not consistent, except that higher age (>65months) seemed to have an influence on lower RR readings (100%). At this stage of understanding, it remains unclear why a higher age of understanding would have an influence on the respiratory rate depression. Alternatively, it could simply be due to the classification via age ranges and the individual variability amongst foresaid ranges. Previous studies have discussed the probable age restrictions when administrating intravenous or PO midazolam [78, 79] and one study even set the lower age limit to 12 years in pediatric dentistry [80], but we didn’t find any evidence that supports that data.
The research on how the type of procedure influences the efficacy or safety is limited. We found one other study which took the type of procedure into account [61]. It showed, that laceration repair and IV catheterization were associated with an increased risk of failure to complete a procedure (AOR 2.26, 95% CI 0.99-5.11; p<0.025 for laceration repair and AOR 1.63, 95% CI 0.68-3.85; p<0.16 for IV catheterization respectively). When we compared the occurrence of side effects with the LR and CA, however, we found that they were not statistically significant; OR 1.6, 95% CI 0.37-6.9; p=0.53 for laceration repairs and OR 1.67, 95% CI 0.15-6.9; p=0.68 for IV catherization.
All of our procedures started after the onset of midazolam’s maximal anxiolytic effect. According to a study conducted in 2000, the anxiolytic effect of midazolam starts after 14 ± 5 min, when administered via oral route; and as early as 5 min, when administered intranasally [13, 17]. Other researchers found that the maximum sedation anxiolysis starts after 20 min (IN) and 30 min (PO) [68]. However, when analyzing our data, we observed that there was no correlation (OR 1.14, 95% CI 0.18-7.3; p=0.89 for oral administration; and OR 2.0, 95% CI 0.13-31.98; p=0.62).
Limitations of study
The first limitation of the study is that it is a single-center study with a small sample size. To overcome this limitation, a longer duration multi-center study could be performed. Moreover, it was done by one observer which can contribute to a somewhat biased result. To overcome this limitation, a study should be performed by at least two individual independent observers.
The main aim of the study did not focus on the pain evaluation and reduction and no pain severity measurement of any kind was included in our study. The severity of pain before/during or after procedure can have some impact on vital signs of the patient, thus, it can lead to some bias results. Furthermore, an apparent limitation of our study comes with the difficulty of categorization of side effects, especially in regards to paradoxical reactions, such as, agitation, vocalization, body movement, crying and being
tearful. Some of these effects may have been a sign of under- or over sedation rather than a true paradoxical reaction.
Last but not least, a major source of limitation is due to non-compliance while taking vital parameters (BP, RR, HR and SaO2) post procedurally. Many patients were still distressed by the procedure and didn’t allow the measurement of vitals. Moreover, as mentioned above, many physicians tried to administer the lowest dose possible, which resulted in a very low number of patients, that were treated with a higher dose than 0.3mg/kg. This limits the present study, as there is not enough data to calculate a meaningful odds ratio.
Despite these limitations, our study clearly manifests the importance of follow up examination of patients after the application of midazolam. We also put emphasis on the highly variable bioavailability of midazolam after PO administration. We speculate, that this might be due to the pharmacological properties of midazolam. The findings of our study should contribute toward the quest to minimize the pain and distress that children experience because of investigations in the ED.
CONCLUSION
In summary, our results showed a higher incidents of side effects when administering a low dosage (<0.26mg/kg) of midazolam. This is an essential finding in the understanding of the importance of the sufficient dosage observation for ensuring successful anxiolysis and sedation. Importantly, our results provide evidence for the occurrence of side effects, that are undetectable without follow-up monitoring of vital parameters. This validates the importance of follow up monitoring, as to assess the physiological well-being of the child and detecting possible side effects ahead of time. Furthermore, the importance of factors influencing pharmacokinetics, bioavailability and absorption of oral midazolam cannot be neglected. Ideally these findings should be replicated in a study where a majority of factors is defined and unfluctuating. As also recommended above, future work is certainly required to disentangle these complexities in factors influencing the biological and pharmacological relationship.
Midazolam surely is not the ideal preprocedural sedative and its effect on implicit and explicit memory as well as the variance in bioavailability after PO administration, should preferably be subject to more specified research. Nevertheless, the number of drugs, which can compete with midazolam are still limited and while the scientific attempts to find alternatives are ongoing, we must not overlook the
PRACTICAL RECOMMENDATIONS
The study has shown the occurrence of side effects when administering a dosage lower than 0.26mg/kg. To prevent the latter, it is therefore recommended to establish clear dosage guidelines midazolam usage in the pediatric ED. In this regard, it is also considered to modify the maximal dosage recommendation above 7mg, to ensure a sufficient amount of midazolam concentration in older and heavier pediatric patients.
Furthermore, on account of midazolam’s unique pharmacological properties, it is additionally advised to develop administration route specific guidelines for its application, as well as reconsidering the addition of other substances to the oral formulation, for example to cover its bitter taste.
One more aspect of the research suggest that non-detectable side effects can occur without the knowledge of the treating physician. Thus, we recommend an obligatory observation period after the procedure, where all vital parameters (BP, HR, RR, SaO2) are measured.
We believe, premedication with intranasal midazolam second to an intranasal application of a local anesthetic spray, in order to reduce the nasal irritations, is awarded superiority, due to its rapid onset, stable bioavailability and low anticipated reluctance as well as lower dosage. This assumption is advised to be addressed in the future studies.
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Patient number: Age:
Weight: Gender:
Pain score before: ________
TIME OF PROCEDURE: ___________ Pain score after: _______
Reason for Midazolam administration:
Did the patient complain about any adverse drug reactions? YES NO Diagnosis: Concomitant Dx: Procedure: Route of administration: Dosage: Dosage per Kg:
Observation 0min 5min 10min 15min
Heart Rate Res. Rate SaO2 BP
ADR Properties Time of occurrence
Allergic reaction: Seizures: Agitation: Uncontrolled movement or behavior: Shaking: Low BP: Shallow breathing:
