Translational Biomedicine

Keywords

Pediatric population; Surgery; Anesthesiologists

Introduction

Factors that evoke anxiety in children

In 1975 Visintainer and Wolfer [1] described five dimensions of surgical experiences that evoke anxiety to the children. Later in 1995 Squires [2] further elaborated the factors in relation to stress and anxiety in hospital admitted children. In general, in the operating room, the child is exposed to new surroundings with new people in command and in the fear of repeated painful physical stimuli, the exaggerated sense of helplessness crawls over the child’s mind. Parental absence, anxiety or reduced control over the situation further demoralise the child and fear and anxiety overshadows the soothing effort of the healthcare providers. Researchers have found several factors which contribute to the preoperative anxiety in children which includes:

a) Fear of physical harm or bodily injury in the form of pain, mutilation, or even death [1,2];

b) Separation from parents and absence of trusted adults, especially for preschool children1; witnessing of parental anxiety [2]

c) Unknown and unfamiliar place, persons and routines [1,2] hospital food, clothing, and play;

d) Uncertainty about "acceptable" and normative behaviour in a hospital setting [1];

e) Loss of control, autonomy, and competence [1]

f) Exposure and touching of "private parts" by strangers [2]; Shame

g) Medical jargon [2];

In the preoperative period there are also certain time points when the anxiety reaches the maximum. These periods or the ‘stress points’, if not appropriately taken care of, the children try to put maximum resistance to the caregivers. The stress points includes,

• Separation from the parents and/ or trusted adults

• Entry to operating room

• Placement of the child on O.T. table

• Visualisation of syringes

• Attachment of monitors

• Placement of intravenous cannula

• Placement of mask... etc

Factors determining level of anxiety

The level of preoperative anxiety depends on several factors including child related, parent related and the operating room environment related factors (Table 1). Age is considered as one of the most important factors and different presentations of anxiety are noted in children before and after six years of age. Shy or introvert children often demonstrates more anxiety than their extrovert counterpart.

Child Factor		Parental factor		Environment factor
Age	Present as early as 9 months and peaks at 1 year. Highest risk at 1 to 5 years of age [3,4]	Anxious parents	Parental anxiety depends on, personality trait, socioeconomic condition, education, gender of the parent (mothers are more anxious), parents of infants, of children who have been through repeated hospitalizations and baseline temperament of the child [5,6]	More anxiety found in, Increased number of people in the room at induction of anesthesia [8], Longer waiting time between admission at the hospital and induction of anesthesia [8] Negative memories of previous hospital experiences [8], Having a mother who does not practice a religion [8] IV induction Untrained personnel [6] Intensity of light Noisy operating room
Personality	Shy or inhibited children,  High IQ with poor social adaptive abilities [4]	Separated or divorced parents [6]
Previous medical encounter	Previous negative hospital experiences, pediatrician or dentist visits [4]	Quality of parent child relationship	Poorly attended infant may develop poor coping skills in new settings [7]
Education	Not attended pre-school	Number of siblings,	No siblings

Table 1: Factors determining increased anxiety in preoperative period.

Psychological effect of surgery

In 1934 Forsyth [9] first described postoperative psychological response in children. He noted a feeling of betrayal by the family members and a fear towards doctors as well as persons in everyday life in the children after surgery. In 2003 Leroy and colleagues [10] stressed upon the fact that surgical stress can produce physiological, emotional, cognitive, behavioural, and interpersonal changes in children and these changes can persist beyond the immediate postoperative period. In 1996 Kaine and co-workers [3] found, negative behavioural response in 54% children (2 to 10 years) after 2 weeks, 20% after six months and 7.3% after one year of surgery.

In addition to behavioural response preoperative anxiety also activates the endocrine, metabolic and humoral response [5,10- 14]. Stress increases the secretion of corticotropin-releasing hormone and activates the locus ceruleus-norepinephrine/ autonomic systems and their peripheral effectors, the hypothalamic pituitary-adrenal axis and the limbs of the autonomic system resulting in increased level of stress markers in blood namely glucocorticoids, epinephrine, cytokines (IL-6and others) etc [15,16]. There is increased natural killer cell activity as well as alteration in the immunological barrier in children [17]. All these factors culminate in hemodynamic, metabolic (Hyperglycemia, electrolyte disturbances, acid base disorder) adversary in the intraoperative and immediate postoperative period. Lately the children may suffer from, delayed wound healing, negative nitrogen balance, immunosupression and postoperative infections and chronic ill health.

Parental presence

Presence of either or both the parents in the operating room during induction or recovery is a fairly common practice and used as a good alternative to sedative premedications. In spite of a fact that parental presence brings about a sense of security and wellbeing in a child, there are controversies regarding this practice. Behavioural patterns in parents, psychological impact of surgery and medicolegal issues has put this strategy to a big dilemma to the clinicians.

Effect on the children

In 1967 Schulman and associates [18] found presence of mother during anesthesia induction might reduce preoperative anxiety in children. Later in 1983 Hanallah and Rosales [19] observed for some preschool children, allowing the parents to support an anxious child during anaesthesia induction could be very effective in relieving anxiety and could minimizes the need for premedication. These studies, however were nonrandomized, did not control for confounding variables and lacked an appropriate anxiety measurement tool for children. Later several wellstructured studies had been done on this respect and most of the researchers concluded, parental presence does not result in reduced anxiety in children [20-23]. Kain and co-workers [23] in 1998 found oral midazolam is more effective than either parental presence or no intervention for managing a child's and parent's anxiety during the preoperative period. Research in this field further elaborated that presence of an anxious parent during induction of anesthesia may aggravate anxiety in the child [23-26]. In 2006 Kain and co-workers [24] found the presence of a calm parent does benefit an anxious child during induction of anesthesia and the presence of an overly anxious parent has no benefit. Caldwell-Andrews and co-workers [25] observed that mothers who have a high desire to be present in the operating room are very anxious and that their children are likely to exhibit high anxiety levels during induction of anesthesia. This finding was supported by Wang and associates [26] who found, auricular acupuncture significantly decreased maternal anxiety during the preoperative period and children of mothers who underwent acupuncture intervention benefitted from the reduction of maternal anxiety during the induction of anesthesia. Kita and associates [27] found parental presence during induction of anesthesia (PPIA) is not much wanted in children above 10 years of age. In 2009, Chundamala and associates [28] evaluated 14 studies with level II or II evidence and concluded against effectiveness of PPIA in alleviating parents’ or children’s anxiety. They opined in favour of premedication with midazolam or other anxiety-reducing solutions, such as distracting children with video games as a viable alternative. Recently in 2015, Manyande and associates in a Cochrane database systematic review, examined 28 trials including 2681 children and found no significant benefit in terms of reduction of anxiety in PPIA model [29].

Effect on the parents

Parental presence during induction of anesthesia (PPIA) has several psychological as well as physiological impacts on the parents too. Kita and Yamamoto found an acceptance rate of 90% for PPIA in parents and more satisfaction among parents with this technique [27]. A number of surveys have indicated that most parents prefer to be present during induction and believe it to be helpful for the child and the anaesthesiologist [30,31].

The physiological responses of the parents vary with stages of anesthesia and surgery. Kain and co-workers [32] in 2003 recorded hemodynamic responses in parents and observed significantly increased heart rate and skin conductance level in parents in PPIA group especially when the child entered the room and when the child was induced. However, examination of holter data revealed no signs of ischemia or rhythm disturbance during this period.

Effect on the operating room (OR) team

The presence of a person not accustomed to the operating room environment may create disruption of mobility and functioning of the OR personnel. Researchers have reported concern of increased stress on the OR team, reduced efficiency, distraction from the care of patient and teaching of trainees, liability for the parental injury [6]. If the parents are not properly trained, there are possibilities of interference with management of emergency situations which may arise during induction. In case of communication gap between the parents and operating room personnel, functioning of OR may be severely hampered.

Medicolegal Issues

Medicolegal problems may arise due to presence of parents during induction of anesthesia. There is no clear legal literature regarding the role of anaesthesiologist in case of any adverse effect in the parents during PPIA. In case the parents are invited to the OR rather than allowed, the hospital owes a legal responsibility towards the nonpatient. It is also not clear, in case of any mismanagement arising on behalf of the parents due to their ignorance or lack of medical knowledge, will the parents be held responsible or not. To avoid such disputes it is better to obtain a separate informed written consent from the parents before entering the OR.

Non-Pharmacological Management

Behavioural interventions

The preoperative interview: This is the most important step to build trust and develop rapport with the child and family. Explanation of details of OR, surgery and anesthesia in age and education appropriate terms not only helps to alleviate anxiety of the parents but also develops a sense of self confidence in the child.

Preoperative information programme: The children and the parent should be informed adequately regarding the perioperative incidences beforehand through any or multiple communications appropriate to their age, education and intellect [6,33,34] in preoperative clinic within 2 weeks of surgery [35]. Modes include leaflet [36], children’s book [37,38], pamphlets [39], videos [40], tours of the facility [41] etc.

Researchers have found variable responses to the child and the parent by this method. Fincher et al., [42] observed preoperative preparation to be more effective in parents than children. In children it permitted to reduce pain experience in the postoperative period [42,43]. Tourigny and Chartrand [44] found no significant improvement after preoperative virtual tour. Deyirmenjia et al., [45] found no improvement in terms of preoperative and postoperative anxiety in Lebanese patient and emphasised on assessment of patient’s social and cultural background. Kain and co-workers [46] examined effect of combination of different modes of preoperative information programme and concluded; extensive preoperative preparation is helpful to lower levels of anxiety during the preoperative period, but not during the intraoperative or postoperative periods.

Behavioural education programme: Several behavioural interventions have been used successfully to reduce preoperative anxiety and among them development of coping skill was found to be most effective [6]. Other modes include modeling, therapeutic play [43,47], operating room tour and printed material [6], music therapy, clown nurse or clown doctors therapy [48-55]. Coping therapy may include deep breathing, counting, watching a video or handheld game. Distraction is very effective form of coping for young children [56-58]. A child-life specialist (or play specialist) may have an important role in this respect [6].

Music therapy: Music therapy has been found to be effective in adults as anxiolytic and its effectiveness has also been extended to reduction of requirement of anesthetics and muscle relaxants [59]. Kain and co-workers found interactive music therapy to be effective on separation and entrance to the operating room but less effective during the induction of anesthesia [60].

Behavioural interventions targeting healthcare providers: Behavioural adaptation of the healthcare personnel to a child friendly one had been proved to be significantly important in management of preoperative anxiety in children. Coping promoting behaviour are desired from the parents and health care delivery.

‘Let us play Doctor- Doctor’: The authors practise a method of pretend play which is immensely helpful to relieve preoperative anxiety and very easy to conduct in any set up. Although the authors don’t have any strong statistics or comparative model to support its usefulness, this technique is being employed for a long time and the authors’ found it’s quite helpful to alleviate operating room related anxiety in children. At the weekend, after the end of preoperative clinic session, the children posted for surgery in the next 2 weeks are taken to the preoperative preparation room. Each of them is allotted a role to play (e.g, surgeon, anaesthesiologist, patient, sister, ot assistant etc depending on number of children). The anaesthesiologist guides them by preparation of a script and the parents help them to follow their roles. A bed as an OT table, an unused anesthesia machine, face mask without attached circuit, empty saline bottles, infusion sets, venous cannulas, ecg leads are used to mimic a perioperative situation. The cannula is attached (not introduced) to the child (playing the role of a patient) with adhesive tapes. Fake injections are administered through tubing. The end point of the play is regaining consciousness in recovery room. The primary target of this play is to make the children aware of the perioperative environment and thereby reduction of anxiety at several stress points, such as, separation from the parents and/ or trusted adults, entry to operating room, placement on O.T. table, visualisation of syringes, attachment of monitors, placement of mask and to some extent intravenous cannulation. This period also helps in development of rapport with the child as well as the parents and creates a feel good effect on the child’s mind (Table 2).

Intraoperative and Immediate Postoperative	Psychological andBehavioral [3-6,10,61]	Resistance to healthcare provider Susceptibility to injury. Increase motor tone, Stop playing Crying Restlessness, agitation
	Metabolic andHumoral [5,10-14]	Sympathetic stimulation, Increased stress markers in blood Hemodynamic instability: high heart rate and blood pressure [13]. Hyperventilation [61] Hyperglycemia, electrolyte disturbances, acid base disorder
	Others [61-63]	Emergence delirium [62] Delayed awakening. Involuntary micturition Precipitation of cyanotic spell in tetralogy of Fallot
Early Postoperative	Delayed wound healing, Negative nitrogen balance, Immunosupression Postoperative infections
Delayed Postoperative	Fear of physicians Behavioural changes, Nightmares, Separation anxiety, Eating problems, Increased fear of physicians General anxiety Nighttime crying Temper tantrum Apathy and withdrawal Aggressive behaviour

Table 2: Effects of preoperative anxiety.

Pharmacological Management

Pharmacological measures against preoperative anxiety in children include use of sedative premedication in the preoperative room (Table 3). Oral route is preferred although parenteral route is also used where the child allows a venous access. Painful intramuscular injections are usually avoided. Colourful syrup with a sweet taste and flavour is usually preferred and may be administered by the mother prior to surgery in the preparation room. Ideal drug for this purpose should be effective via the oral route, with immediate onset and short duration, should produce amnesia, should not precipitate respiratory depression, should not delay recovery, should not have any serious adverse effect of its own and should not produce paradoxical agitation. The practice of sedative premedication varies widely among different set ups, age groups, regions as well as the choice of the anaesthesiologists [41].

Drugs	Route	Dose	Onset	Disadvantage	Advantage
Midazolam[64]	Oral	0.25-0.75 mg kg-1 (to a maximum of 20 mg) [38,42]	20 minutes [64,65]	Paradoxical reaction (<1%) [66] Delayed recovery	Rapid and reliable onset, Minimal respiratory depression, Antegrade amnesia, Reduced emergence delirium.
	IV	0.1 mg kg-1		Needs cannulation, painful
	Nasal	0.3 mg kg-1	10 minutes [67]	Nasal irritation [67]
	Rectal	0.5 mg kg-1	10 minutes [67]	Hiccup (22-26%) [68]
	SL	0.3 mg kg-1
Clonidine [64, 69-71]	Oral [64]	4 µg kg-1	45 minutes	Long onset time	Well tolerated, Palatable, Predictive effect, Reduce nausea and vomiting [72] Anesthetic and analgesic sparing property [64,69-77]
	Nasal [73-75]	2-4 µg kg-1	30 minutes	Erratic absorbtion
	Rectal [76, 77]	2.5 µg kg-1	20 minute	Postoperative sedation
Dexmedetomidine	Nasal [78-79]	0.5-1 µg. Kg-1	20-40 minutes	More sedation, Prolonged onset	Acceptable cooperation, Arousable sedation
	IV [80]	0.4 μg/kg diluted in 10 ml			Excellent parent separation, Favourable induction conditions, Lower incidence of postoperative agitation and shivering, Hemodynamic stability, No respiratory depression.
Ketamine [64,67,81-83]	Oral [64,67]	3-6 mg k-1	10-20 minutes	Emergence delirium [83] Agitation Excessive salivation [83] Vomiting [83]	No respiratory depression Analgesic sparing. Combination with midazolam preferred [82].
	Nasal	3-5 mg. Kg-1	<10 minutes
	Rectal	5-6 mg kg-1	20-30 minutes
	IM	4-8 mg kg-1
	IV	1-2 mg kg-1
Fentanyl [67, 84-86]	Oral transmucosal	15-20 µg Kg-1	15-20 minute	Respiratory depression Vomiting Facial pruritus No reduction in apprehension.	Sedation Analgesia

N.B., IV: Intravenous, SL: Sublingual, IM: Intramuscular

Table 3: Drugs to manage preoperative anxiety in pediatric patients.

Future trend in pharmacological management

Future research efforts are directed not only towards discovery of better, safer, more tolerable drugs, but also evaluation of newer modes of drug delivery systems. Melatonin, a drug used to treat sleep onset insomnia and delayed sleep phase syndrome is being evaluated for this purpose [64]. Among newer delivery routes transdermal application of drugs with iontophoresis has gained popularity in the recent period for its painless application, early and predictable onset and is being investigated [66,67].

Conclusion

Control of preoperative anxiety in children is an important challenge to the anesthesiologists and considered as a primary objective in current day anesthesia practice. Sedative premedications, parental presence at induction of anaesthesia and behavioural intervention forms the mainstay of anxiety management. Identification of ‘stress points’ are important and significant improvements are noted if these periods are taken care of appropriately. Parental presence should not be mandatory, rather should be case specific. An informed consent should be obtained from the parents for medicolegal purposes. Preoperative interview, videos, clowns, virtual tour all is effective if practiced appropriately. Distractions in the form of deep breathing, videos or toys are very effective and should be used particularly during the ‘stress points’. The authors strongly recommend use of pretend play, as described in the article, to get better control over the stress points.

References

1. Visintainer MA, Wolfer JA (1975) Psychological preparation for surgery pediatric patients: the effects on children's and parents' stress responses and adjustment. Pediatrics 56: 187-202.
2. Squires VL (1995) Child-focused perioperative education: helping children understand and cope with surgery. SeminPerioperNurs 4: 80-87.
3. Kain ZN, Mayes LC, O'Connor TZ, Cicchetti DV (1996) Preoperative anxiety in children. Predictors and outcomes. Arch PediatrAdolesc Med 150: 1238-1245.
4. McCann ME, Kain ZN (2001) The management of preoperative anxiety in children: an update. AnesthAnalg 93: 98-105.
5. Kain ZN, Maclaren J, Mayes LC (2009) Perioperative Behavior Stress in Children. In: Cote CJ, Lerman J, and ID Todres, Eds. A Practice of Anesthesia for Infants and Children. Philadelphia, PA: Saunders Elsevier 27.
6. Ahmed MI, Farrell MA, Parrish K, Karla A (2011) Preoperative anxiety in children risk factors and non-pharmacological management. Middle East J Anaesthesiol 21: 153-164.
7. Turner JC (2009) Theoretical Foundation of Child Life Practice, in The Handbook of Child Life, a Guide for Pediatric Psychosocial Care. Thompson RH Editor, Springfield, Illinois: Charles Thomas 28.
8. Wollin SR, Plummer JL, Owen H, Hawkins RM, Materazzo F (2003) Predictors of preoperative anxiety in children. Anaesth Intensive Care 31: 69-74.
9. Forsyth D (1934) Psychological effects of bodily illness in children. Lancet 227: 15-18.
10. Wright KD, Stewart SH, Finley GA, Buffett-Jerrott SE (2007) Prevention and intervention strategies to alleviate preoperative anxiety in children: a critical review. BehavModif 31: 52-79.
11. Burkhardt U, Vetter B, Wild L, Olthoff D (1995)Plasma catecholamine level and clinical parameters--quality criteria for premedication in childhood. AnaesthesiolReanim 20: 88-96.
12. Kiefer RT, Weindler J, Ruprecht KW (1998) The endocrine stress response after oral premedication with low-dose midazolam for intraocular surgery in retrobulbar anaesthesia. Eur J Ophthalmol 8: 239-245.
13. Li HC, Lopez V (2006) Assessing children's emotional responses to surgery: a multidimensional approach. J AdvNurs 53: 543-550.
14. Corman HH, Hornick EJ, Kritchman M, Terestman N (1958) Emotional reactions of surgical patients to hospitalization, anesthesia and surgery. Am J Surg 96: 646-653.
15. Fell D, Derbyshire DR, Maile CJ, Larsson IM, Ellis R, et al. (1985) Measurement of plasma catecholamine concentrations. An assessment of anxiety. Br J Anaesth 57: 770-774.
16. Ramsay MA (1972) A survey of pre-operative fear. Anaesthesia 27: 396-402.
17. Tannesen E (1989) Immunological aspects of anaesthesia and surgery--with special reference to NK cells. Dan Med Bull 36: 263-281.
18. Schulman JL, Foley JM, Vernon DT, Allan D (1967) A study of the effect of the mother's presence during anesthesia induction. Pediatrics 39: 111-114.
19. Hannallah RS, Rosales JK (1983) Experience with parents' presence during anaesthesia induction in children. Can AnaesthSoc J 30: 286-289.
20. Hickmott KC, Shaw EA, Goodyer I, Baker RD (1989) Anaesthetic induction in children: the effects of maternal presence on mood and subsequent behaviour. Eur J Anaesthesiol 6: 145-155.
21. Bevan JC, Johnston C, Haig MJ, Tousignant G (1990) Preoperative parental anxiety predicts behavioural and emotional responses to induction of anaesthesia in children. Can J Anaesth 37: 177-182.
22. Kain ZN, Mayes LC, Caramico LA, Silver D (1996) Parental presence during induction of anesthesia. A randomized controlled trial. Anesthesiology 84: 1060-1067.
23. Kain ZN, Mayes LC, Wang SM, Caramico LA, Hofstadter MB (1998) Parental presence during induction of anesthesia versus sedative premedication: which intervention is more effective? Anesthesiology 89: 1147-1156.
24. Kain ZN, Caldwell-Andrews AA, Maranets I, Nelson W, Mayes LC (2006) Predicting which child-parent pair will benefit from parental presence during induction of anesthesia: a decision-making approach. AnesthAnalg 102: 81-84.
25. Caldwell-Andrews AA, Kain ZN, Mayes LC, Kerns RD, Ng D (2005) Motivation and maternal presence during induction of anesthesia. Anesthesiology 103: 478-483.
26. Wang SM, Maranets I, Weinberg ME, Caldwell-Andrews AA, Kain ZN (2004) Parental auricular acupuncture as an adjunct for parental presence during induction of anesthesia. Anesthesiology 100: 1399-1404.
27. Kita T, Yamamoto M (2009) Parental presence is a useful method for smooth induction of anesthesia in children: a postoperative questionnaire survey. Masui 58: 719-723.
28. Chundamala J, Wright JG, Kemp SM (2009) An evidence-based review of parental presence during anesthesia induction and parent/child anxiety. Can J Anaesth 56: 57-70.
29. Manyande A, Cyna AM, Yip P, Chooi C, Middleton P (2015) Non-pharmacological interventions for assisting the induction of anaesthesia in children. Cochrane Database Syst Rev 7:CD006447.
30. Ryder IG, Spargo PM (1991) Parents in the anaesthetic room. A questionnaire survey of parents' reactions. Anaesthesia 46: 977-979.
31. Braude N, Ridley SA, Sumner E (1990) Parents and paediatric anaesthesia: a prospective survey of parental attitudes to their presence at induction. Ann R CollSurgEngl 72: 41-44.
32. Kain ZN, Caldwell-Andrews AA, Mayes LC, Wang SM, Krivutza DM, et al. (2003) Parental presence during induction of anesthesia: physiological effects on parents. Anesthesiology 98: 58-64.
33. Franck LS, Spencer C (2005) Informing parents about anaesthesia for children's surgery: a critical literature review. Patient EducCouns 59: 117-125.
34. Astuto M, Rosano G, Rizzo G, Disma N, Raciti L, et al. (2006) Preoperative parental information and parents' presence at induction of anaesthesia. Minerva Anestesiol 72: 461-465.
35. Spencer C, Franck LS (2005) Giving parents written information about children's anesthesia: are setting and timing important? PaediatrAnaesth 15: 547-553.
36. Bellew M, Atkinson KR, Dixon G, Yates A (2002) The introduction of a paediatric anaesthesia information leaflet: an audit of its impact on parental anxiety and satisfaction. PaediatrAnaesth 12: 124-130.
37. Felder PR, Maksys A, Noestlinger C, Gadner H, Stark H, et al. (2003) Using a children's book to prepare children and parents for elective ENT surgery: results of a randomized clinical trial. Int J PediatrOtorhinolaryngol 67: 35-41.
38. Margolis JO, Ginsberg B, Dear GL, Ross AK, Goral JE, et al. (1998) Paediatric preoperative teaching: effects at induction and postoperatively. PaediatrAnaesth 8: 17-23.
39. Chan CS, Molassiotis A (2002) The effects of an educational programme on the anxiety and satisfaction level of parents having parent present induction and visitation in a postanaesthesia care unit. PaediatrAnaesth 12: 131-139.
40. McEwen A, Moorthy C, Quantock C, Rose H, Kavanagh R (2007) The effect of videotaped preoperative information on parental anxiety during anesthesia induction for elective pediatric procedures. PaediatrAnaesth 17: 534-539.
41. Karimi R, Fadaiy Z, Nikbakht NA, Godarzi Z, Mehran A (2014) Effectiveness of orientation tour on children's anxiety before elective surgeries. Jpn J NursSci 11: 10-15.
42. Fincher W, Shaw J, Ramelet AS (2012) The effectiveness of a standardised preoperative preparation in reducing child and parent anxiety: a single-blind randomised controlled trial. J ClinNurs 21: 946-955.
43. He HG, Zhu L, Li HC, Wang W, Vehviläinen JK, et al. (2014) A randomized controlled trial of the effectiveness of a therapeutic play intervention on outcomes of children undergoing inpatient elective surgery: study protocol. J AdvNurs 70: 431-442.
44. Tourigny J, Chartrand J (2009) Evaluation of a preoperative virtual tour for parents and children. RechSoinsInfirm : 52-57.
45. Deyirmenjian M, Karam N, Salameh P (2006) Preoperative patient education for open-heart patients: a source of anxiety? Patient EducCouns 62: 111-117.
46. Kain ZN, Caramico LA, Mayes LC, Genevro JL, Bornstein MH, et al. (1998) Preoperative preparation programs in children: a comparative examination. AnesthAnalg 87: 1249-1255.
47. Paladino CM, Carvalho Rd, Almeida FdeA (2014) Therapeutic play in preparing for surgery: behavior of preschool children during the perioperative period. Rev Esc Enferm USP 48: 423-429.
48. Yun OB, Kim SJ, Jung D (2015) Effects of a Clown-Nurse Educational Intervention on the Reduction of Postoperative Anxiety and Pain Among Preschool Children and Their Accompanying Parents in South Korea. J PediatrNurs S0882-5963(15)00084-6.
49. Golan G, Tighe P, Dobija N, Perel A, Keidan I (2009) Clowns for the prevention of preoperative anxiety in children: a randomized controlled trial. PaediatrAnaesth 19: 262-266.
50. Meiri N, Ankri A, Hamad SM, Konopnicki M, Pillar G (2015) The effect of medical clowning on reducing pain, crying, and anxiety in children aged 2-10 years old undergoing venous blood drawing-a randomized controlled study. Eur J Pediatr.
51. Messina M, Molinaro F, Meucci D, Angotti R (2014) Preoperative distraction in children: hand-held videogames vs clown therapy. Pediatr Med Chir 36: 98.
52. Wolyniez I, Rimon A, Scolnik D, Gruber A, Tavor O, et al. (2013) The effect of a medical clown on pain during intravenous access in the pediatric emergency department: a randomized prospective pilot study. ClinPediatr (Phila 52: 1168-1172.
53. Agostini F, Monti F, Neri E, Dellabartola S, de Pascalis L, et al. (2014) Parental anxiety and stress before pediatricanesthesia: a pilot study on the effectiveness of preoperative clown intervention. J Health Psychol 19: 587-601.
54. Vagnoli L, Caprilli S, Robiglio A, Messeri A (2005) Clown doctors as a treatment for preoperative anxiety in children: a randomized, prospective study. Pediatrics 116: e563-567.
55. Patel A, Schieble T, Davidson M, Tran MC (2006) Distraction with a hand-held video game reduces pediatric preoperative anxiety. PaediatrAnaesth 16: 1019-1027.
56. Moadad N, Kozman K, Shahine R, Ohanian S, Badr LK (2015) Distraction Using the BUZZY for Children During an IV Insertion. J PediatrNurs S0882-5963(15)00239-0.
57. Trottier ED, Ali S, Le May S, Gravel J (2015) Treating and Reducing Anxiety and Pain in the Paediatric Emergency Department: The TRAPPED survey. Paediatr Child Health 20: 239-244.
58. Goldberger J, Gaynard L (1990) Helping children cope with health care procedures. Contemporary Pediatrics 158.
59. Kar SK, Ganguly T, Roy SS, Goswami A (2015) Effect of Indian Classical Music (Raga Therapy) on Fentanyl, Vecuronium, Propofol Requirements and Cortisol levels in Cardiopulmonary Bypass. J AnesthCrit Care Open Access 2: 00047.
60. Kain ZN, Caldwell-Andrews AA, Krivutza DM, Weinberg ME, Gaal D, et al. (2004) Interactive music therapy as a treatment for preoperative anxiety in children: a randomized controlled trial. AnesthAnalg 98: 1260-1266.
61. Burton L (1984) Anxiety relating to illness and treatment. In V. Verma (Ed.), Anxiety in Children (pp. 151-172). New York: Methuen Croom Helm.
62. LeRoy S, Elixson EM, O'Brien P, Tong E, Turpin S, et al. (2003) American Heart Association Pediatric Nursing Subcommittee of the Council on Cardiovascular Nursing; Council on Cardiovascular Diseases of the Young. Recommendations for preparing children and adolescents for invasive cardiac procedures: a statement from the American Heart Association Pediatric Nursing Subcommittee of the Council on Cardiovascular Nursing in collaboration with the Council on Cardiovascular Diseases of the Young. Circulation 108: 2550-2564.
63. Schwartz BH, Albino JE, Tedesco LA (1983) Effects of psychological preparation on children hospitalized for dental operations. J Pediatr 102: 634-638.
64. O'Sullivan M (2013) Wong GK. Preinduction techniques to relieve anxiety in children undergoing general anaesthesia. ContinEducAnaesthCrit Care Pain 13: 196-199.
65. Suresh S, Cohen IJ, Matuszczak M (1998) Dose ranging, safety, and efficacy of a new oral midazolam syrup in children [abstract]. Anesthesiology89: A1313.
66. Rosenbaum A, Kain ZN, Larsson P, Loniqvist PA, Wolf AR (2009) The place of premedication in pediatric practice. PaediatrAnaesth 19: 817-828.
67. McCann ME, Kain ZN (2001) The management of preoperative anxiety in children: an update. AnesthAnalg 93: 98-105.
68. Marhofer P, Glaser C, Krenn CG, Grabner CM, Semsroth M (1999) Incidence and therapy of midazolam induced hiccups in paediatric anaesthesia. PaediatrAnaesth 9: 295-298.
69. Huber D, Kretz FJ (2005) Efficacy of clonidine in paediatric anaesthesia. AnasthesiolIntensivmedNotfallmedSchmerzther 40: 567-575.
70. Nishina K, Mikawa K, Shiga M, Obara H (1999) Clonidine in paediatric anaesthesia. aediatrAnaesth 9: 187-202.
71. Sahoo S, Kaur M, Tripathy HK, Kumar A, Kohli S, et al. (2013) Comparative evaluation of midazolam and clonidine as pediatric oral premedication. Anesth Essays Res 7: 221-227.
72. Alizadeh R, Mireskandari SM, Azarshahin M, Darabi ME (2012) Oral clonidine premedication reduces nausea and vomiting in children after appendectomy. Iran J Pediatr 22: 399-403.
73. Mitra S, Kazal S, Anand LK (2014)Intranasal clonidine vs. midazolam as premedication in children: a randomized controlled trial. Indian Pediatr 51: 113-118.
74. Larsson P, Eksborg S, Lannqvist PA (2012) Onset time for pharmacologic premedication with clonidine as a nasal aerosol: a double-blind, placebo-controlled, randomized trial. PaediatrAnaesth 22: 877-883.
75. Almenrader N, Larsson P, Passariello M, Haiberger R, Pietropaoli P, et al. (2009) Absorption pharmacokinetics of clonidine nasal drops in children. PaediatrAnaesth 19: 257-261.
76. Bergendahl HT, Lönnqvist PA, Eksborg S, Ruthström E, Nordenberg L, et al. (2004) Clonidine vs. midazolam as premedication in children undergoing adeno-tonsillectomy: a prospective, randomized, controlled clinical trial. ActaAnaesthesiolScand 48: 1292-1300.
77. Lönnqvist PA, Bergendahl HT, Eksborg S (1994) Pharmacokinetics of clonidine after rectal administration in children. Anesthesiology 81: 1097-1101.
78. Talon MD, Woodson LC, Sherwood ER, Aarsland A, McRae L, et al. (2009) Intranasaldexmedetomidine premedication is comparable with midazolam in burn children undergoing reconstructive surgery. J Burn Care Res30: 599-605.
79. Sheta SA, Al-Sarheed MA, Abdelhalim AA (2013) Intranasaldexmedetomidinevs midazolam for premedication in children undergoing complete dental rehabilitation: a double-blinded randomized controlled trial. PaediatrAnaesth 24: 181-189.
80. Bhadla S, Prajapati D, Louis T, Puri G, Panchal S, Bhuva M (2013) Comparison between dexmedetomidine and midazolam premedication in pediatric patients undergoing ophthalmic day-care surgeries. Anesth Essays Res 7: 248-256.
81. Malinovsky JM, Servin F, Cozian A, Lepage JY, Pinaud M (1996) Ketamine and norketamine plasma concentrations after i.v., nasal and rectal administration in children. Br J Anaesth 77: 203-207.
82. Funk W, Jakob W, Riedl T, Taeger K (2000) Oral preanaesthetic medication for children: double-blind randomized study of a combination of midazolam and ketamine vs midazolam or ketamine alone. Br J Anaesth 84: 335-340.
83. Filatov SM, Baer GA, Rorarius MG, Oikkonen M (2000) Efficacy and safety of premedication with oral ketamine for day-case adenoidectomy compared with rectal diazepam/diclofenac and EMLA. ActaAnaesthesiolScand 44: 118-124.
84. Friesen RH, Lockhart CH (1992) Oral transmucosal fentanyl citrate for preanesthetic medication of pediatric day surgery patients with and without droperidol as a prophylactic anti-emetic. Anesthesiology 76: 46-51.
85. Epstein RH, Mendel HG, Witkowski TA, Waters R (1996) The safety and efficacy of oral transmucosal fentanyl citrate for preoperative sedation in young children. AnesthAnalg 83: 1200-1205.
86. Ginsberg B, Dear RB, Margolis JO, Dear GD, Ross AK (1998) Oral transmucosal fentanyl citrate as an anaesthetic premedication when dosed to an opioid effect vs total opioid consumption. PaediatrAnaesth 8: 413-418.

Keywords

Pediatric population; Surgery; Anesthesiologists

Introduction

Factors that evoke anxiety in children

In 1975 Visintainer and Wolfer [1] described five dimensions of surgical experiences that evoke anxiety to the children. Later in 1995 Squires [2] further elaborated the factors in relation to stress and anxiety in hospital admitted children. In general, in the operating room, the child is exposed to new surroundings with new people in command and in the fear of repeated painful physical stimuli, the exaggerated sense of helplessness crawls over the child’s mind. Parental absence, anxiety or reduced control over the situation further demoralise the child and fear and anxiety overshadows the soothing effort of the healthcare providers. Researchers have found several factors which contribute to the preoperative anxiety in children which includes:

a) Fear of physical harm or bodily injury in the form of pain, mutilation, or even death [1,2];

b) Separation from parents and absence of trusted adults, especially for preschool children1; witnessing of parental anxiety [2]

c) Unknown and unfamiliar place, persons and routines [1,2] hospital food, clothing, and play;

d) Uncertainty about "acceptable" and normative behaviour in a hospital setting [1];

e) Loss of control, autonomy, and competence [1]

f) Exposure and touching of "private parts" by strangers [2]; Shame

g) Medical jargon [2];

In the preoperative period there are also certain time points when the anxiety reaches the maximum. These periods or the ‘stress points’, if not appropriately taken care of, the children try to put maximum resistance to the caregivers. The stress points includes,

• Separation from the parents and/ or trusted adults

• Entry to operating room

• Placement of the child on O.T. table

• Visualisation of syringes

• Attachment of monitors

• Placement of intravenous cannula

• Placement of mask... etc

Factors determining level of anxiety

The level of preoperative anxiety depends on several factors including child related, parent related and the operating room environment related factors (Table 1). Age is considered as one of the most important factors and different presentations of anxiety are noted in children before and after six years of age. Shy or introvert children often demonstrates more anxiety than their extrovert counterpart.

Psychological effect of surgery

In 1934 Forsyth [9] first described postoperative psychological response in children. He noted a feeling of betrayal by the family members and a fear towards doctors as well as persons in everyday life in the children after surgery. In 2003 Leroy and colleagues [10] stressed upon the fact that surgical stress can produce physiological, emotional, cognitive, behavioural, and interpersonal changes in children and these changes can persist beyond the immediate postoperative period. In 1996 Kaine and co-workers [3] found, negative behavioural response in 54% children (2 to 10 years) after 2 weeks, 20% after six months and 7.3% after one year of surgery.

In addition to behavioural response preoperative anxiety also activates the endocrine, metabolic and humoral response [5,10- 14]. Stress increases the secretion of corticotropin-releasing hormone and activates the locus ceruleus-norepinephrine/ autonomic systems and their peripheral effectors, the hypothalamic pituitary-adrenal axis and the limbs of the autonomic system resulting in increased level of stress markers in blood namely glucocorticoids, epinephrine, cytokines (IL-6and others) etc [15,16]. There is increased natural killer cell activity as well as alteration in the immunological barrier in children [17]. All these factors culminate in hemodynamic, metabolic (Hyperglycemia, electrolyte disturbances, acid base disorder) adversary in the intraoperative and immediate postoperative period. Lately the children may suffer from, delayed wound healing, negative nitrogen balance, immunosupression and postoperative infections and chronic ill health.

Parental presence

Presence of either or both the parents in the operating room during induction or recovery is a fairly common practice and used as a good alternative to sedative premedications. In spite of a fact that parental presence brings about a sense of security and wellbeing in a child, there are controversies regarding this practice. Behavioural patterns in parents, psychological impact of surgery and medicolegal issues has put this strategy to a big dilemma to the clinicians.

Effect on the children

In 1967 Schulman and associates [18] found presence of mother during anesthesia induction might reduce preoperative anxiety in children. Later in 1983 Hanallah and Rosales [19] observed for some preschool children, allowing the parents to support an anxious child during anaesthesia induction could be very effective in relieving anxiety and could minimizes the need for premedication. These studies, however were nonrandomized, did not control for confounding variables and lacked an appropriate anxiety measurement tool for children. Later several wellstructured studies had been done on this respect and most of the researchers concluded, parental presence does not result in reduced anxiety in children [20-23]. Kain and co-workers [23] in 1998 found oral midazolam is more effective than either parental presence or no intervention for managing a child's and parent's anxiety during the preoperative period. Research in this field further elaborated that presence of an anxious parent during induction of anesthesia may aggravate anxiety in the child [23-26]. In 2006 Kain and co-workers [24] found the presence of a calm parent does benefit an anxious child during induction of anesthesia and the presence of an overly anxious parent has no benefit. Caldwell-Andrews and co-workers [25] observed that mothers who have a high desire to be present in the operating room are very anxious and that their children are likely to exhibit high anxiety levels during induction of anesthesia. This finding was supported by Wang and associates [26] who found, auricular acupuncture significantly decreased maternal anxiety during the preoperative period and children of mothers who underwent acupuncture intervention benefitted from the reduction of maternal anxiety during the induction of anesthesia. Kita and associates [27] found parental presence during induction of anesthesia (PPIA) is not much wanted in children above 10 years of age. In 2009, Chundamala and associates [28] evaluated 14 studies with level II or II evidence and concluded against effectiveness of PPIA in alleviating parents’ or children’s anxiety. They opined in favour of premedication with midazolam or other anxiety-reducing solutions, such as distracting children with video games as a viable alternative. Recently in 2015, Manyande and associates in a Cochrane database systematic review, examined 28 trials including 2681 children and found no significant benefit in terms of reduction of anxiety in PPIA model [29].

Effect on the parents

Parental presence during induction of anesthesia (PPIA) has several psychological as well as physiological impacts on the parents too. Kita and Yamamoto found an acceptance rate of 90% for PPIA in parents and more satisfaction among parents with this technique [27]. A number of surveys have indicated that most parents prefer to be present during induction and believe it to be helpful for the child and the anaesthesiologist [30,31].

The physiological responses of the parents vary with stages of anesthesia and surgery. Kain and co-workers [32] in 2003 recorded hemodynamic responses in parents and observed significantly increased heart rate and skin conductance level in parents in PPIA group especially when the child entered the room and when the child was induced. However, examination of holter data revealed no signs of ischemia or rhythm disturbance during this period.

Effect on the operating room (OR) team

The presence of a person not accustomed to the operating room environment may create disruption of mobility and functioning of the OR personnel. Researchers have reported concern of increased stress on the OR team, reduced efficiency, distraction from the care of patient and teaching of trainees, liability for the parental injury [6]. If the parents are not properly trained, there are possibilities of interference with management of emergency situations which may arise during induction. In case of communication gap between the parents and operating room personnel, functioning of OR may be severely hampered.

Medicolegal Issues

Medicolegal problems may arise due to presence of parents during induction of anesthesia. There is no clear legal literature regarding the role of anaesthesiologist in case of any adverse effect in the parents during PPIA. In case the parents are invited to the OR rather than allowed, the hospital owes a legal responsibility towards the nonpatient. It is also not clear, in case of any mismanagement arising on behalf of the parents due to their ignorance or lack of medical knowledge, will the parents be held responsible or not. To avoid such disputes it is better to obtain a separate informed written consent from the parents before entering the OR.

Non-Pharmacological Management

Behavioural interventions

The preoperative interview: This is the most important step to build trust and develop rapport with the child and family. Explanation of details of OR, surgery and anesthesia in age and education appropriate terms not only helps to alleviate anxiety of the parents but also develops a sense of self confidence in the child.

Preoperative information programme: The children and the parent should be informed adequately regarding the perioperative incidences beforehand through any or multiple communications appropriate to their age, education and intellect [6,33,34] in preoperative clinic within 2 weeks of surgery [35]. Modes include leaflet [36], children’s book [37,38], pamphlets [39], videos [40], tours of the facility [41] etc.

Researchers have found variable responses to the child and the parent by this method. Fincher et al., [42] observed preoperative preparation to be more effective in parents than children. In children it permitted to reduce pain experience in the postoperative period [42,43]. Tourigny and Chartrand [44] found no significant improvement after preoperative virtual tour. Deyirmenjia et al., [45] found no improvement in terms of preoperative and postoperative anxiety in Lebanese patient and emphasised on assessment of patient’s social and cultural background. Kain and co-workers [46] examined effect of combination of different modes of preoperative information programme and concluded; extensive preoperative preparation is helpful to lower levels of anxiety during the preoperative period, but not during the intraoperative or postoperative periods.

Behavioural education programme: Several behavioural interventions have been used successfully to reduce preoperative anxiety and among them development of coping skill was found to be most effective [6]. Other modes include modeling, therapeutic play [43,47], operating room tour and printed material [6], music therapy, clown nurse or clown doctors therapy [48-55]. Coping therapy may include deep breathing, counting, watching a video or handheld game. Distraction is very effective form of coping for young children [56-58]. A child-life specialist (or play specialist) may have an important role in this respect [6].

Music therapy: Music therapy has been found to be effective in adults as anxiolytic and its effectiveness has also been extended to reduction of requirement of anesthetics and muscle relaxants [59]. Kain and co-workers found interactive music therapy to be effective on separation and entrance to the operating room but less effective during the induction of anesthesia [60].

Behavioural interventions targeting healthcare providers: Behavioural adaptation of the healthcare personnel to a child friendly one had been proved to be significantly important in management of preoperative anxiety in children. Coping promoting behaviour are desired from the parents and health care delivery.

‘Let us play Doctor- Doctor’: The authors practise a method of pretend play which is immensely helpful to relieve preoperative anxiety and very easy to conduct in any set up. Although the authors don’t have any strong statistics or comparative model to support its usefulness, this technique is being employed for a long time and the authors’ found it’s quite helpful to alleviate operating room related anxiety in children. At the weekend, after the end of preoperative clinic session, the children posted for surgery in the next 2 weeks are taken to the preoperative preparation room. Each of them is allotted a role to play (e.g, surgeon, anaesthesiologist, patient, sister, ot assistant etc depending on number of children). The anaesthesiologist guides them by preparation of a script and the parents help them to follow their roles. A bed as an OT table, an unused anesthesia machine, face mask without attached circuit, empty saline bottles, infusion sets, venous cannulas, ecg leads are used to mimic a perioperative situation. The cannula is attached (not introduced) to the child (playing the role of a patient) with adhesive tapes. Fake injections are administered through tubing. The end point of the play is regaining consciousness in recovery room. The primary target of this play is to make the children aware of the perioperative environment and thereby reduction of anxiety at several stress points, such as, separation from the parents and/ or trusted adults, entry to operating room, placement on O.T. table, visualisation of syringes, attachment of monitors, placement of mask and to some extent intravenous cannulation. This period also helps in development of rapport with the child as well as the parents and creates a feel good effect on the child’s mind (Table 2).

Pharmacological Management

Pharmacological measures against preoperative anxiety in children include use of sedative premedication in the preoperative room (Table 3). Oral route is preferred although parenteral route is also used where the child allows a venous access. Painful intramuscular injections are usually avoided. Colourful syrup with a sweet taste and flavour is usually preferred and may be administered by the mother prior to surgery in the preparation room. Ideal drug for this purpose should be effective via the oral route, with immediate onset and short duration, should produce amnesia, should not precipitate respiratory depression, should not delay recovery, should not have any serious adverse effect of its own and should not produce paradoxical agitation. The practice of sedative premedication varies widely among different set ups, age groups, regions as well as the choice of the anaesthesiologists [41].

Future trend in pharmacological management

Future research efforts are directed not only towards discovery of better, safer, more tolerable drugs, but also evaluation of newer modes of drug delivery systems. Melatonin, a drug used to treat sleep onset insomnia and delayed sleep phase syndrome is being evaluated for this purpose [64]. Among newer delivery routes transdermal application of drugs with iontophoresis has gained popularity in the recent period for its painless application, early and predictable onset and is being investigated [66,67].

Conclusion

Control of preoperative anxiety in children is an important challenge to the anesthesiologists and considered as a primary objective in current day anesthesia practice. Sedative premedications, parental presence at induction of anaesthesia and behavioural intervention forms the mainstay of anxiety management. Identification of ‘stress points’ are important and significant improvements are noted if these periods are taken care of appropriately. Parental presence should not be mandatory, rather should be case specific. An informed consent should be obtained from the parents for medicolegal purposes. Preoperative interview, videos, clowns, virtual tour all is effective if practiced appropriately. Distractions in the form of deep breathing, videos or toys are very effective and should be used particularly during the ‘stress points’. The authors strongly recommend use of pretend play, as described in the article, to get better control over the stress points.

Tables at a glance

Table 1 Table 2 Table 3

8003

References

1. Visintainer MA, Wolfer JA (1975) Psychological preparation for surgery pediatric patients: the effects on children's and parents' stress responses and adjustment. Pediatrics 56: 187-202.
2. Squires VL (1995) Child-focused perioperative education: helping children understand and cope with surgery. SeminPerioperNurs 4: 80-87.
3. Kain ZN, Mayes LC, O'Connor TZ, Cicchetti DV (1996) Preoperative anxiety in children. Predictors and outcomes. Arch PediatrAdolesc Med 150: 1238-1245.
4. McCann ME, Kain ZN (2001) The management of preoperative anxiety in children: an update. AnesthAnalg 93: 98-105.
5. Kain ZN, Maclaren J, Mayes LC (2009) Perioperative Behavior Stress in Children. In: Cote CJ, Lerman J, and ID Todres, Eds. A Practice of Anesthesia for Infants and Children. Philadelphia, PA: Saunders Elsevier 27.
6. Ahmed MI, Farrell MA, Parrish K, Karla A (2011) Preoperative anxiety in children risk factors and non-pharmacological management. Middle East J Anaesthesiol 21: 153-164.
7. Turner JC (2009) Theoretical Foundation of Child Life Practice, in The Handbook of Child Life, a Guide for Pediatric Psychosocial Care. Thompson RH Editor, Springfield, Illinois: Charles Thomas 28.
8. Wollin SR, Plummer JL, Owen H, Hawkins RM, Materazzo F (2003) Predictors of preoperative anxiety in children. Anaesth Intensive Care 31: 69-74.
9. Forsyth D (1934) Psychological effects of bodily illness in children. Lancet 227: 15-18.
10. Wright KD, Stewart SH, Finley GA, Buffett-Jerrott SE (2007) Prevention and intervention strategies to alleviate preoperative anxiety in children: a critical review. BehavModif 31: 52-79.
11. Burkhardt U, Vetter B, Wild L, Olthoff D (1995)Plasma catecholamine level and clinical parameters--quality criteria for premedication in childhood. AnaesthesiolReanim 20: 88-96.
12. Kiefer RT, Weindler J, Ruprecht KW (1998) The endocrine stress response after oral premedication with low-dose midazolam for intraocular surgery in retrobulbar anaesthesia. Eur J Ophthalmol 8: 239-245.
13. Li HC, Lopez V (2006) Assessing children's emotional responses to surgery: a multidimensional approach. J AdvNurs 53: 543-550.
14. Corman HH, Hornick EJ, Kritchman M, Terestman N (1958) Emotional reactions of surgical patients to hospitalization, anesthesia and surgery. Am J Surg 96: 646-653.
15. Fell D, Derbyshire DR, Maile CJ, Larsson IM, Ellis R, et al. (1985) Measurement of plasma catecholamine concentrations. An assessment of anxiety. Br J Anaesth 57: 770-774.
16. Ramsay MA (1972) A survey of pre-operative fear. Anaesthesia 27: 396-402.
17. Tannesen E (1989) Immunological aspects of anaesthesia and surgery--with special reference to NK cells. Dan Med Bull 36: 263-281.
18. Schulman JL, Foley JM, Vernon DT, Allan D (1967) A study of the effect of the mother's presence during anesthesia induction. Pediatrics 39: 111-114.
19. Hannallah RS, Rosales JK (1983) Experience with parents' presence during anaesthesia induction in children. Can AnaesthSoc J 30: 286-289.
20. Hickmott KC, Shaw EA, Goodyer I, Baker RD (1989) Anaesthetic induction in children: the effects of maternal presence on mood and subsequent behaviour. Eur J Anaesthesiol 6: 145-155.
21. Bevan JC, Johnston C, Haig MJ, Tousignant G (1990) Preoperative parental anxiety predicts behavioural and emotional responses to induction of anaesthesia in children. Can J Anaesth 37: 177-182.
22. Kain ZN, Mayes LC, Caramico LA, Silver D (1996) Parental presence during induction of anesthesia. A randomized controlled trial. Anesthesiology 84: 1060-1067.
23. Kain ZN, Mayes LC, Wang SM, Caramico LA, Hofstadter MB (1998) Parental presence during induction of anesthesia versus sedative premedication: which intervention is more effective? Anesthesiology 89: 1147-1156.
24. Kain ZN, Caldwell-Andrews AA, Maranets I, Nelson W, Mayes LC (2006) Predicting which child-parent pair will benefit from parental presence during induction of anesthesia: a decision-making approach. AnesthAnalg 102: 81-84.
25. Caldwell-Andrews AA, Kain ZN, Mayes LC, Kerns RD, Ng D (2005) Motivation and maternal presence during induction of anesthesia. Anesthesiology 103: 478-483.
26. Wang SM, Maranets I, Weinberg ME, Caldwell-Andrews AA, Kain ZN (2004) Parental auricular acupuncture as an adjunct for parental presence during induction of anesthesia. Anesthesiology 100: 1399-1404.
27. Kita T, Yamamoto M (2009) Parental presence is a useful method for smooth induction of anesthesia in children: a postoperative questionnaire survey. Masui 58: 719-723.
28. Chundamala J, Wright JG, Kemp SM (2009) An evidence-based review of parental presence during anesthesia induction and parent/child anxiety. Can J Anaesth 56: 57-70.
29. Manyande A, Cyna AM, Yip P, Chooi C, Middleton P (2015) Non-pharmacological interventions for assisting the induction of anaesthesia in children. Cochrane Database Syst Rev 7:CD006447.
30. Ryder IG, Spargo PM (1991) Parents in the anaesthetic room. A questionnaire survey of parents' reactions. Anaesthesia 46: 977-979.
31. Braude N, Ridley SA, Sumner E (1990) Parents and paediatric anaesthesia: a prospective survey of parental attitudes to their presence at induction. Ann R CollSurgEngl 72: 41-44.
32. Kain ZN, Caldwell-Andrews AA, Mayes LC, Wang SM, Krivutza DM, et al. (2003) Parental presence during induction of anesthesia: physiological effects on parents. Anesthesiology 98: 58-64.
33. Franck LS, Spencer C (2005) Informing parents about anaesthesia for children's surgery: a critical literature review. Patient EducCouns 59: 117-125.
34. Astuto M, Rosano G, Rizzo G, Disma N, Raciti L, et al. (2006) Preoperative parental information and parents' presence at induction of anaesthesia. Minerva Anestesiol 72: 461-465.
35. Spencer C, Franck LS (2005) Giving parents written information about children's anesthesia: are setting and timing important? PaediatrAnaesth 15: 547-553.
36. Bellew M, Atkinson KR, Dixon G, Yates A (2002) The introduction of a paediatric anaesthesia information leaflet: an audit of its impact on parental anxiety and satisfaction. PaediatrAnaesth 12: 124-130.
37. Felder PR, Maksys A, Noestlinger C, Gadner H, Stark H, et al. (2003) Using a children's book to prepare children and parents for elective ENT surgery: results of a randomized clinical trial. Int J PediatrOtorhinolaryngol 67: 35-41.
38. Margolis JO, Ginsberg B, Dear GL, Ross AK, Goral JE, et al. (1998) Paediatric preoperative teaching: effects at induction and postoperatively. PaediatrAnaesth 8: 17-23.
39. Chan CS, Molassiotis A (2002) The effects of an educational programme on the anxiety and satisfaction level of parents having parent present induction and visitation in a postanaesthesia care unit. PaediatrAnaesth 12: 131-139.
40. McEwen A, Moorthy C, Quantock C, Rose H, Kavanagh R (2007) The effect of videotaped preoperative information on parental anxiety during anesthesia induction for elective pediatric procedures. PaediatrAnaesth 17: 534-539.
41. Karimi R, Fadaiy Z, Nikbakht NA, Godarzi Z, Mehran A (2014) Effectiveness of orientation tour on children's anxiety before elective surgeries. Jpn J NursSci 11: 10-15.
42. Fincher W, Shaw J, Ramelet AS (2012) The effectiveness of a standardised preoperative preparation in reducing child and parent anxiety: a single-blind randomised controlled trial. J ClinNurs 21: 946-955.
43. He HG, Zhu L, Li HC, Wang W, Vehviläinen JK, et al. (2014) A randomized controlled trial of the effectiveness of a therapeutic play intervention on outcomes of children undergoing inpatient elective surgery: study protocol. J AdvNurs 70: 431-442.
44. Tourigny J, Chartrand J (2009) Evaluation of a preoperative virtual tour for parents and children. RechSoinsInfirm : 52-57.
45. Deyirmenjian M, Karam N, Salameh P (2006) Preoperative patient education for open-heart patients: a source of anxiety? Patient EducCouns 62: 111-117.
46. Kain ZN, Caramico LA, Mayes LC, Genevro JL, Bornstein MH, et al. (1998) Preoperative preparation programs in children: a comparative examination. AnesthAnalg 87: 1249-1255.
47. Paladino CM, Carvalho Rd, Almeida FdeA (2014) Therapeutic play in preparing for surgery: behavior of preschool children during the perioperative period. Rev Esc Enferm USP 48: 423-429.
48. Yun OB, Kim SJ, Jung D (2015) Effects of a Clown-Nurse Educational Intervention on the Reduction of Postoperative Anxiety and Pain Among Preschool Children and Their Accompanying Parents in South Korea. J PediatrNurs S0882-5963(15)00084-6.
49. Golan G, Tighe P, Dobija N, Perel A, Keidan I (2009) Clowns for the prevention of preoperative anxiety in children: a randomized controlled trial. PaediatrAnaesth 19: 262-266.
50. Meiri N, Ankri A, Hamad SM, Konopnicki M, Pillar G (2015) The effect of medical clowning on reducing pain, crying, and anxiety in children aged 2-10 years old undergoing venous blood drawing-a randomized controlled study. Eur J Pediatr.
51. Messina M, Molinaro F, Meucci D, Angotti R (2014) Preoperative distraction in children: hand-held videogames vs clown therapy. Pediatr Med Chir 36: 98.
52. Wolyniez I, Rimon A, Scolnik D, Gruber A, Tavor O, et al. (2013) The effect of a medical clown on pain during intravenous access in the pediatric emergency department: a randomized prospective pilot study. ClinPediatr (Phila 52: 1168-1172.
53. Agostini F, Monti F, Neri E, Dellabartola S, de Pascalis L, et al. (2014) Parental anxiety and stress before pediatricanesthesia: a pilot study on the effectiveness of preoperative clown intervention. J Health Psychol 19: 587-601.
54. Vagnoli L, Caprilli S, Robiglio A, Messeri A (2005) Clown doctors as a treatment for preoperative anxiety in children: a randomized, prospective study. Pediatrics 116: e563-567.
55. Patel A, Schieble T, Davidson M, Tran MC (2006) Distraction with a hand-held video game reduces pediatric preoperative anxiety. PaediatrAnaesth 16: 1019-1027.
56. Moadad N, Kozman K, Shahine R, Ohanian S, Badr LK (2015) Distraction Using the BUZZY for Children During an IV Insertion. J PediatrNurs S0882-5963(15)00239-0.
57. Trottier ED, Ali S, Le May S, Gravel J (2015) Treating and Reducing Anxiety and Pain in the Paediatric Emergency Department: The TRAPPED survey. Paediatr Child Health 20: 239-244.
58. Goldberger J, Gaynard L (1990) Helping children cope with health care procedures. Contemporary Pediatrics 158.
59. Kar SK, Ganguly T, Roy SS, Goswami A (2015) Effect of Indian Classical Music (Raga Therapy) on Fentanyl, Vecuronium, Propofol Requirements and Cortisol levels in Cardiopulmonary Bypass. J AnesthCrit Care Open Access 2: 00047.
60. Kain ZN, Caldwell-Andrews AA, Krivutza DM, Weinberg ME, Gaal D, et al. (2004) Interactive music therapy as a treatment for preoperative anxiety in children: a randomized controlled trial. AnesthAnalg 98: 1260-1266.
61. Burton L (1984) Anxiety relating to illness and treatment. In V. Verma (Ed.), Anxiety in Children (pp. 151-172). New York: Methuen Croom Helm.
62. LeRoy S, Elixson EM, O'Brien P, Tong E, Turpin S, et al. (2003) American Heart Association Pediatric Nursing Subcommittee of the Council on Cardiovascular Nursing; Council on Cardiovascular Diseases of the Young. Recommendations for preparing children and adolescents for invasive cardiac procedures: a statement from the American Heart Association Pediatric Nursing Subcommittee of the Council on Cardiovascular Nursing in collaboration with the Council on Cardiovascular Diseases of the Young. Circulation 108: 2550-2564.
63. Schwartz BH, Albino JE, Tedesco LA (1983) Effects of psychological preparation on children hospitalized for dental operations. J Pediatr 102: 634-638.
64. O'Sullivan M (2013) Wong GK. Preinduction techniques to relieve anxiety in children undergoing general anaesthesia. ContinEducAnaesthCrit Care Pain 13: 196-199.
65. Suresh S, Cohen IJ, Matuszczak M (1998) Dose ranging, safety, and efficacy of a new oral midazolam syrup in children [abstract]. Anesthesiology89: A1313.
66. Rosenbaum A, Kain ZN, Larsson P, Loniqvist PA, Wolf AR (2009) The place of premedication in pediatric practice. PaediatrAnaesth 19: 817-828.
67. McCann ME, Kain ZN (2001) The management of preoperative anxiety in children: an update. AnesthAnalg 93: 98-105.
68. Marhofer P, Glaser C, Krenn CG, Grabner CM, Semsroth M (1999) Incidence and therapy of midazolam induced hiccups in paediatric anaesthesia. PaediatrAnaesth 9: 295-298.
69. Huber D, Kretz FJ (2005) Efficacy of clonidine in paediatric anaesthesia. AnasthesiolIntensivmedNotfallmedSchmerzther 40: 567-575.
70. Nishina K, Mikawa K, Shiga M, Obara H (1999) Clonidine in paediatric anaesthesia. aediatrAnaesth 9: 187-202.
71. Sahoo S, Kaur M, Tripathy HK, Kumar A, Kohli S, et al. (2013) Comparative evaluation of midazolam and clonidine as pediatric oral premedication. Anesth Essays Res 7: 221-227.
72. Alizadeh R, Mireskandari SM, Azarshahin M, Darabi ME (2012) Oral clonidine premedication reduces nausea and vomiting in children after appendectomy. Iran J Pediatr 22: 399-403.
73. Mitra S, Kazal S, Anand LK (2014)Intranasal clonidine vs. midazolam as premedication in children: a randomized controlled trial. Indian Pediatr 51: 113-118.
74. Larsson P, Eksborg S, Lannqvist PA (2012) Onset time for pharmacologic premedication with clonidine as a nasal aerosol: a double-blind, placebo-controlled, randomized trial. PaediatrAnaesth 22: 877-883.
75. Almenrader N, Larsson P, Passariello M, Haiberger R, Pietropaoli P, et al. (2009) Absorption pharmacokinetics of clonidine nasal drops in children. PaediatrAnaesth 19: 257-261.
76. Bergendahl HT, Lönnqvist PA, Eksborg S, Ruthström E, Nordenberg L, et al. (2004) Clonidine vs. midazolam as premedication in children undergoing adeno-tonsillectomy: a prospective, randomized, controlled clinical trial. ActaAnaesthesiolScand 48: 1292-1300.
77. Lönnqvist PA, Bergendahl HT, Eksborg S (1994) Pharmacokinetics of clonidine after rectal administration in children. Anesthesiology 81: 1097-1101.
78. Talon MD, Woodson LC, Sherwood ER, Aarsland A, McRae L, et al. (2009) Intranasaldexmedetomidine premedication is comparable with midazolam in burn children undergoing reconstructive surgery. J Burn Care Res30: 599-605.
79. Sheta SA, Al-Sarheed MA, Abdelhalim AA (2013) Intranasaldexmedetomidinevs midazolam for premedication in children undergoing complete dental rehabilitation: a double-blinded randomized controlled trial. PaediatrAnaesth 24: 181-189.
80. Bhadla S, Prajapati D, Louis T, Puri G, Panchal S, Bhuva M (2013) Comparison between dexmedetomidine and midazolam premedication in pediatric patients undergoing ophthalmic day-care surgeries. Anesth Essays Res 7: 248-256.
81. Malinovsky JM, Servin F, Cozian A, Lepage JY, Pinaud M (1996) Ketamine and norketamine plasma concentrations after i.v., nasal and rectal administration in children. Br J Anaesth 77: 203-207.
82. Funk W, Jakob W, Riedl T, Taeger K (2000) Oral preanaesthetic medication for children: double-blind randomized study of a combination of midazolam and ketamine vs midazolam or ketamine alone. Br J Anaesth 84: 335-340.
83. Filatov SM, Baer GA, Rorarius MG, Oikkonen M (2000) Efficacy and safety of premedication with oral ketamine for day-case adenoidectomy compared with rectal diazepam/diclofenac and EMLA. ActaAnaesthesiolScand 44: 118-124.
84. Friesen RH, Lockhart CH (1992) Oral transmucosal fentanyl citrate for preanesthetic medication of pediatric day surgery patients with and without droperidol as a prophylactic anti-emetic. Anesthesiology 76: 46-51.
85. Epstein RH, Mendel HG, Witkowski TA, Waters R (1996) The safety and efficacy of oral transmucosal fentanyl citrate for preoperative sedation in young children. AnesthAnalg 83: 1200-1205.
86. Ginsberg B, Dear RB, Margolis JO, Dear GD, Ross AK (1998) Oral transmucosal fentanyl citrate as an anaesthetic premedication when dosed to an opioid effect vs total opioid consumption. PaediatrAnaesth 8: 413-418.
87. Visintainer MA, Wolfer JA (1975) Psychological preparation for surgery pediatric patients: the effects on children's and parents' stress responses and adjustment. Pediatrics 56: 187-202.
88. Squires VL (1995) Child-focused perioperative education: helping children understand and cope with surgery. SeminPerioperNurs 4: 80-87.
89. Kain ZN, Mayes LC, O'Connor TZ, Cicchetti DV (1996) Preoperative anxiety in children. Predictors and outcomes. Arch PediatrAdolesc Med 150: 1238-1245.
90. McCann ME, Kain ZN (2001) The management of preoperative anxiety in children: an update. AnesthAnalg 93: 98-105.
91. Kain ZN, Maclaren J, Mayes LC (2009) Perioperative Behavior Stress in Children. In: Cote CJ, Lerman J, and ID Todres, Eds. A Practice of Anesthesia for Infants and Children. Philadelphia, PA: Saunders Elsevier 27.
92. Ahmed MI, Farrell MA, Parrish K, Karla A (2011) Preoperative anxiety in children risk factors and non-pharmacological management. Middle East J Anaesthesiol 21: 153-164.
93. Turner JC (2009) Theoretical Foundation of Child Life Practice, in The Handbook of Child Life, a Guide for Pediatric Psychosocial Care. Thompson RH Editor, Springfield, Illinois: Charles Thomas 28.
94. Wollin SR, Plummer JL, Owen H, Hawkins RM, Materazzo F (2003) Predictors of preoperative anxiety in children. Anaesth Intensive Care 31: 69-74.
95. Forsyth D (1934) Psychological effects of bodily illness in children. Lancet 227: 15-18.
96. Wright KD, Stewart SH, Finley GA, Buffett-Jerrott SE (2007) Prevention and intervention strategies to alleviate preoperative anxiety in children: a critical review. BehavModif 31: 52-79.
97. Burkhardt U, Vetter B, Wild L, Olthoff D (1995)Plasma catecholamine level and clinical parameters--quality criteria for premedication in childhood. AnaesthesiolReanim 20: 88-96.
98. Kiefer RT, Weindler J, Ruprecht KW (1998) The endocrine stress response after oral premedication with low-dose midazolam for intraocular surgery in retrobulbar anaesthesia. Eur J Ophthalmol 8: 239-245.
99. Li HC, Lopez V (2006) Assessing children's emotional responses to surgery: a multidimensional approach. J AdvNurs 53: 543-550.
100. Corman HH, Hornick EJ, Kritchman M, Terestman N (1958) Emotional reactions of surgical patients to hospitalization, anesthesia and surgery. Am J Surg 96: 646-653.
101. Fell D, Derbyshire DR, Maile CJ, Larsson IM, Ellis R, et al. (1985) Measurement of plasma catecholamine concentrations. An assessment of anxiety. Br J Anaesth 57: 770-774.
102. Ramsay MA (1972) A survey of pre-operative fear. Anaesthesia 27: 396-402.
103. Tannesen E (1989) Immunological aspects of anaesthesia and surgery--with special reference to NK cells. Dan Med Bull 36: 263-281.
104. Schulman JL, Foley JM, Vernon DT, Allan D (1967) A study of the effect of the mother's presence during anesthesia induction. Pediatrics 39: 111-114.
105. Hannallah RS, Rosales JK (1983) Experience with parents' presence during anaesthesia induction in children. Can AnaesthSoc J 30: 286-289.
106. Hickmott KC, Shaw EA, Goodyer I, Baker RD (1989) Anaesthetic induction in children: the effects of maternal presence on mood and subsequent behaviour. Eur J Anaesthesiol 6: 145-155.
107. Bevan JC, Johnston C, Haig MJ, Tousignant G (1990) Preoperative parental anxiety predicts behavioural and emotional responses to induction of anaesthesia in children. Can J Anaesth 37: 177-182.
108. Kain ZN, Mayes LC, Caramico LA, Silver D (1996) Parental presence during induction of anesthesia. A randomized controlled trial. Anesthesiology 84: 1060-1067.
109. Kain ZN, Mayes LC, Wang SM, Caramico LA, Hofstadter MB (1998) Parental presence during induction of anesthesia versus sedative premedication: which intervention is more effective? Anesthesiology 89: 1147-1156.
110. Kain ZN, Caldwell-Andrews AA, Maranets I, Nelson W, Mayes LC (2006) Predicting which child-parent pair will benefit from parental presence during induction of anesthesia: a decision-making approach. AnesthAnalg 102: 81-84.
111. Caldwell-Andrews AA, Kain ZN, Mayes LC, Kerns RD, Ng D (2005) Motivation and maternal presence during induction of anesthesia. Anesthesiology 103: 478-483.
112. Wang SM, Maranets I, Weinberg ME, Caldwell-Andrews AA, Kain ZN (2004) Parental auricular acupuncture as an adjunct for parental presence during induction of anesthesia. Anesthesiology 100: 1399-1404.
113. Kita T, Yamamoto M (2009) Parental presence is a useful method for smooth induction of anesthesia in children: a postoperative questionnaire survey. Masui 58: 719-723.
114. Chundamala J, Wright JG, Kemp SM (2009) An evidence-based review of parental presence during anesthesia induction and parent/child anxiety. Can J Anaesth 56: 57-70.
115. Manyande A, Cyna AM, Yip P, Chooi C, Middleton P (2015) Non-pharmacological interventions for assisting the induction of anaesthesia in children. Cochrane Database Syst Rev 7:CD006447.
116. Ryder IG, Spargo PM (1991) Parents in the anaesthetic room. A questionnaire survey of parents' reactions. Anaesthesia 46: 977-979.
117. Braude N, Ridley SA, Sumner E (1990) Parents and paediatric anaesthesia: a prospective survey of parental attitudes to their presence at induction. Ann R CollSurgEngl 72: 41-44.
118. Kain ZN, Caldwell-Andrews AA, Mayes LC, Wang SM, Krivutza DM, et al. (2003) Parental presence during induction of anesthesia: physiological effects on parents. Anesthesiology 98: 58-64.
119. Franck LS, Spencer C (2005) Informing parents about anaesthesia for children's surgery: a critical literature review. Patient EducCouns 59: 117-125.
120. Astuto M, Rosano G, Rizzo G, Disma N, Raciti L, et al. (2006) Preoperative parental information and parents' presence at induction of anaesthesia. Minerva Anestesiol 72: 461-465.
121. Spencer C, Franck LS (2005) Giving parents written information about children's anesthesia: are setting and timing important? PaediatrAnaesth 15: 547-553.
122. Bellew M, Atkinson KR, Dixon G, Yates A (2002) The introduction of a paediatric anaesthesia information leaflet: an audit of its impact on parental anxiety and satisfaction. PaediatrAnaesth 12: 124-130.
123. Felder PR, Maksys A, Noestlinger C, Gadner H, Stark H, et al. (2003) Using a children's book to prepare children and parents for elective ENT surgery: results of a randomized clinical trial. Int J PediatrOtorhinolaryngol 67: 35-41.
124. Margolis JO, Ginsberg B, Dear GL, Ross AK, Goral JE, et al. (1998) Paediatric preoperative teaching: effects at induction and postoperatively. PaediatrAnaesth 8: 17-23.
125. Chan CS, Molassiotis A (2002) The effects of an educational programme on the anxiety and satisfaction level of parents having parent present induction and visitation in a postanaesthesia care unit. PaediatrAnaesth 12: 131-139.
126. McEwen A, Moorthy C, Quantock C, Rose H, Kavanagh R (2007) The effect of videotaped preoperative information on parental anxiety during anesthesia induction for elective pediatric procedures. PaediatrAnaesth 17: 534-539.
127. Karimi R, Fadaiy Z, Nikbakht NA, Godarzi Z, Mehran A (2014) Effectiveness of orientation tour on children's anxiety before elective surgeries. Jpn J NursSci 11: 10-15.
128. Fincher W, Shaw J, Ramelet AS (2012) The effectiveness of a standardised preoperative preparation in reducing child and parent anxiety: a single-blind randomised controlled trial. J ClinNurs 21: 946-955.
129. He HG, Zhu L, Li HC, Wang W, Vehviläinen JK, et al. (2014) A randomized controlled trial of the effectiveness of a therapeutic play intervention on outcomes of children undergoing inpatient elective surgery: study protocol. J AdvNurs 70: 431-442.
130. Tourigny J, Chartrand J (2009) Evaluation of a preoperative virtual tour for parents and children. RechSoinsInfirm : 52-57.
131. Deyirmenjian M, Karam N, Salameh P (2006) Preoperative patient education for open-heart patients: a source of anxiety? Patient EducCouns 62: 111-117.
132. Kain ZN, Caramico LA, Mayes LC, Genevro JL, Bornstein MH, et al. (1998) Preoperative preparation programs in children: a comparative examination. AnesthAnalg 87: 1249-1255.
133. Paladino CM, Carvalho Rd, Almeida FdeA (2014) Therapeutic play in preparing for surgery: behavior of preschool children during the perioperative period. Rev Esc Enferm USP 48: 423-429.
134. Yun OB, Kim SJ, Jung D (2015) Effects of a Clown-Nurse Educational Intervention on the Reduction of Postoperative Anxiety and Pain Among Preschool Children and Their Accompanying Parents in South Korea. J PediatrNurs S0882-5963(15)00084-6.
135. Golan G, Tighe P, Dobija N, Perel A, Keidan I (2009) Clowns for the prevention of preoperative anxiety in children: a randomized controlled trial. PaediatrAnaesth 19: 262-266.
136. Meiri N, Ankri A, Hamad SM, Konopnicki M, Pillar G (2015) The effect of medical clowning on reducing pain, crying, and anxiety in children aged 2-10 years old undergoing venous blood drawing-a randomized controlled study. Eur J Pediatr.
137. Messina M, Molinaro F, Meucci D, Angotti R (2014) Preoperative distraction in children: hand-held videogames vs clown therapy. Pediatr Med Chir 36: 98.
138. Wolyniez I, Rimon A, Scolnik D, Gruber A, Tavor O, et al. (2013) The effect of a medical clown on pain during intravenous access in the pediatric emergency department: a randomized prospective pilot study. ClinPediatr (Phila 52: 1168-1172.
139. Agostini F, Monti F, Neri E, Dellabartola S, de Pascalis L, et al. (2014) Parental anxiety and stress before pediatricanesthesia: a pilot study on the effectiveness of preoperative clown intervention. J Health Psychol 19: 587-601.
140. Vagnoli L, Caprilli S, Robiglio A, Messeri A (2005) Clown doctors as a treatment for preoperative anxiety in children: a randomized, prospective study. Pediatrics 116: e563-567.
141. Patel A, Schieble T, Davidson M, Tran MC (2006) Distraction with a hand-held video game reduces pediatric preoperative anxiety. PaediatrAnaesth 16: 1019-1027.
142. Moadad N, Kozman K, Shahine R, Ohanian S, Badr LK (2015) Distraction Using the BUZZY for Children During an IV Insertion. J PediatrNurs S0882-5963(15)00239-0.
143. Trottier ED, Ali S, Le May S, Gravel J (2015) Treating and Reducing Anxiety and Pain in the Paediatric Emergency Department: The TRAPPED survey. Paediatr Child Health 20: 239-244.
144. Goldberger J, Gaynard L (1990) Helping children cope with health care procedures. Contemporary Pediatrics 158.
145. Kar SK, Ganguly T, Roy SS, Goswami A (2015) Effect of Indian Classical Music (Raga Therapy) on Fentanyl, Vecuronium, Propofol Requirements and Cortisol levels in Cardiopulmonary Bypass. J AnesthCrit Care Open Access 2: 00047.
146. Kain ZN, Caldwell-Andrews AA, Krivutza DM, Weinberg ME, Gaal D, et al. (2004) Interactive music therapy as a treatment for preoperative anxiety in children: a randomized controlled trial. AnesthAnalg 98: 1260-1266.
147. Burton L (1984) Anxiety relating to illness and treatment. In V. Verma (Ed.), Anxiety in Children (pp. 151-172). New York: Methuen Croom Helm.
148. LeRoy S, Elixson EM, O'Brien P, Tong E, Turpin S, et al. (2003) American Heart Association Pediatric Nursing Subcommittee of the Council on Cardiovascular Nursing; Council on Cardiovascular Diseases of the Young. Recommendations for preparing children and adolescents for invasive cardiac procedures: a statement from the American Heart Association Pediatric Nursing Subcommittee of the Council on Cardiovascular Nursing in collaboration with the Council on Cardiovascular Diseases of the Young. Circulation 108: 2550-2564.
149. Schwartz BH, Albino JE, Tedesco LA (1983) Effects of psychological preparation on children hospitalized for dental operations. J Pediatr 102: 634-638.
150. O'Sullivan M (2013) Wong GK. Preinduction techniques to relieve anxiety in children undergoing general anaesthesia. ContinEducAnaesthCrit Care Pain 13: 196-199.
151. Suresh S, Cohen IJ, Matuszczak M (1998) Dose ranging, safety, and efficacy of a new oral midazolam syrup in children [abstract]. Anesthesiology89: A1313.
152. Rosenbaum A, Kain ZN, Larsson P, Loniqvist PA, Wolf AR (2009) The place of premedication in pediatric practice. PaediatrAnaesth 19: 817-828.
153. McCann ME, Kain ZN (2001) The management of preoperative anxiety in children: an update. AnesthAnalg 93: 98-105.
154. Marhofer P, Glaser C, Krenn CG, Grabner CM, Semsroth M (1999) Incidence and therapy of midazolam induced hiccups in paediatric anaesthesia. PaediatrAnaesth 9: 295-298.
155. Huber D, Kretz FJ (2005) Efficacy of clonidine in paediatric anaesthesia. AnasthesiolIntensivmedNotfallmedSchmerzther 40: 567-575.
156. Nishina K, Mikawa K, Shiga M, Obara H (1999) Clonidine in paediatric anaesthesia. aediatrAnaesth 9: 187-202.
157. Sahoo S, Kaur M, Tripathy HK, Kumar A, Kohli S, et al. (2013) Comparative evaluation of midazolam and clonidine as pediatric oral premedication. Anesth Essays Res 7: 221-227.
158. Alizadeh R, Mireskandari SM, Azarshahin M, Darabi ME (2012) Oral clonidine premedication reduces nausea and vomiting in children after appendectomy. Iran J Pediatr 22: 399-403.
159. Mitra S, Kazal S, Anand LK (2014)Intranasal clonidine vs. midazolam as premedication in children: a randomized controlled trial. Indian Pediatr 51: 113-118.
160. Larsson P, Eksborg S, Lannqvist PA (2012) Onset time for pharmacologic premedication with clonidine as a nasal aerosol: a double-blind, placebo-controlled, randomized trial. PaediatrAnaesth 22: 877-883.
161. Almenrader N, Larsson P, Passariello M, Haiberger R, Pietropaoli P, et al. (2009) Absorption pharmacokinetics of clonidine nasal drops in children. PaediatrAnaesth 19: 257-261.
162. Bergendahl HT, Lönnqvist PA, Eksborg S, Ruthström E, Nordenberg L, et al. (2004) Clonidine vs. midazolam as premedication in children undergoing adeno-tonsillectomy: a prospective, randomized, controlled clinical trial. ActaAnaesthesiolScand 48: 1292-1300.
163. Lönnqvist PA, Bergendahl HT, Eksborg S (1994) Pharmacokinetics of clonidine after rectal administration in children. Anesthesiology 81: 1097-1101.
164. Talon MD, Woodson LC, Sherwood ER, Aarsland A, McRae L, et al. (2009) Intranasaldexmedetomidine premedication is comparable with midazolam in burn children undergoing reconstructive surgery. J Burn Care Res30: 599-605.
165. Sheta SA, Al-Sarheed MA, Abdelhalim AA (2013) Intranasaldexmedetomidinevs midazolam for premedication in children undergoing complete dental rehabilitation: a double-blinded randomized controlled trial. PaediatrAnaesth 24: 181-189.
166. Bhadla S, Prajapati D, Louis T, Puri G, Panchal S, Bhuva M (2013) Comparison between dexmedetomidine and midazolam premedication in pediatric patients undergoing ophthalmic day-care surgeries. Anesth Essays Res 7: 248-256.
167. Malinovsky JM, Servin F, Cozian A, Lepage JY, Pinaud M (1996) Ketamine and norketamine plasma concentrations after i.v., nasal and rectal administration in children. Br J Anaesth 77: 203-207.
168. Funk W, Jakob W, Riedl T, Taeger K (2000) Oral preanaesthetic medication for children: double-blind randomized study of a combination of midazolam and ketamine vs midazolam or ketamine alone. Br J Anaesth 84: 335-340.
169. Filatov SM, Baer GA, Rorarius MG, Oikkonen M (2000) Efficacy and safety of premedication with oral ketamine for day-case adenoidectomy compared with rectal diazepam/diclofenac and EMLA. ActaAnaesthesiolScand 44: 118-124.
170. Friesen RH, Lockhart CH (1992) Oral transmucosal fentanyl citrate for preanesthetic medication of pediatric day surgery patients with and without droperidol as a prophylactic anti-emetic. Anesthesiology 76: 46-51.
171. Epstein RH, Mendel HG, Witkowski TA, Waters R (1996) The safety and efficacy of oral transmucosal fentanyl citrate for preoperative sedation in young children. AnesthAnalg 83: 1200-1205.
172. Ginsberg B, Dear RB, Margolis JO, Dear GD, Ross AK (1998) Oral transmucosal fentanyl citrate as an anaesthetic premedication when dosed to an opioid effect vs total opioid consumption. PaediatrAnaesth 8: 413-418.