University of Groningen Perfect pitstops Loeffen, Erik

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Perfect pitstops

Loeffen, Erik

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2019

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Loeffen, E. (2019). Perfect pitstops: Towards evidence-based supportive care in children with cancer.

Rijksuniversiteit Groningen.

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reducing procedure-related

pain and distress in children

with cancer: a clinical

practice guideline

CHAPTER 7

Submitted Loeffen EAH Mulder RL Font-Gonzalez A Leroy PLJM Dick BD Taddio A Ljungman G Jibb LA Tutelman PR Liossi C Twycross A Positano K Knops RR

Wijnen M van de Wetering MD

Kremer LCM Dupuis LL

Campbell F Tissing WJE

on behalf of the Pain in Children with Cancer Working Group

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7.1 ABSTRACT

PURPOSE

Children with cancer often have to undergo long treatment trajectories, including repeated needle procedures that potentially cause pain and distress. We aimed to provide recommendations on pharmacological, physical and psychological management of procedure-related pain in children with cancer.

METHODS

An international inter-disciplinary guideline development panel was assembled, consisting of 44 individuals with expertise in pediatric oncology, anesthesiology, psychology, and other relevant areas. The panel was divided into six working groups, of which two focused on procedural pain (recommendations on tumor and treatment related pain, and on assessment of pain will be presented in the near future). The GRADE methodology was adhered to, including the use of the recently introduced evidence-to-decision frameworks. In February 2018, the guideline panel met in Amsterdam to discuss these frameworks and formulate recommendations. The draft recommendations were discussed with a patient/parent-panel consisting of four survivors and five parents.

RESULTS

Quality of evidence ranged from very low to moderate. The panel formulated five strong recommendations, six weak recommendations, and three ungraded good practice statements. Strong recommendations focused on use of topical anesthetics in all needle procedures, use of deep sedation/general anesthesia in children under 12 years undergoing lumbar puncture, use of deep sedation/general anesthesia in major procedures in children of all ages, use of hypnosis in all needle procedures, and use of active distraction in all needle procedures.

CONCLUSION

In this clinical practice guideline an evidence-based approach to manage procedure-related pain and distress in children with cancer is presented. As children with cancer often undergo repeated needle procedures during treatment, high-quality care to prevent and alleviate procedure-related pain and distress is of the utmost importance to increase quality of life in these children and their families.

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7.2 INTRODUCTION

Due to the introduction of intensive treatment protocols, survival rates for childhood cancer in high-income countries have increased from 40% in the 1970s to 80% currently.[1,2] The drawback of these intensive and prolonged treatments, encompassing chemotherapy, radiotherapy, and/or surgery, is that they are associated with significant morbidity. Of these side-effects, pain was considered a key area in which health professionals seek guidance.[3]

In contrast to adult cancer patients, in whom pain is mostly tumor-related, pain in children with cancer is mostly related to treatment or procedures.[4] Children with cancer undergo various potentially painful and/or distressing needle procedures, for instance accessing the central venous access port, administration of intrathecal chemotherapy, or bone marrow aspiration. The pain and distress that these procedures might cause can put great burden upon patients and their families. It is increasingly acknowledged that children are at risk of long-term sequelae from inadequate pain management during needle procedures, e.g. increased levels of anxiety and non-compliance with care.[5] Age and developmental stage play an important role in pain and distress experience.[6] Pain should be measured with assessment instruments that are appropriate for the developmental stage of the specific child, and managed adequately, bearing in mind constantly that children are not little adults and require a developmentally appropriate approach.

To our knowledge, there are no clinical practice guidelines (CPGs) that address the management of needle procedures for children with cancer. CPGs include “recommendations intended to optimize patient care that are informed by a systematic review of evidence and an assessment of the benefits and harms of alternative care options”.[7] CPGs assist clinicians and patients in determining the best course of action based upon the best available evidence and a comprehensive assessment of desirable and undesirable consequences.

Guidance is urgently needed for procedural pain in children with cancer. For example, in a recent study only 10% of institutions reported having standards for pediatric bone marrow aspiration pain management.[8] In addition, presently there are major practice variations across centers that could negatively influence care.[9]

In this CPG we provide recommendations regarding pharmacological, physical, and psychological interventions for reducing distress and pain related to needle procedures in children with cancer and to provide recommendations for clinical care. This CPG is targeted to clinicians that care for children with cancer, among others pediatric oncologists, nurses, anesthesiologists, and child life specialists. This CPG is the first of three parts focusing on pain in children with cancer; part

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7.3 METHODS

The full methodology including an overview of the evidence, is given separately. See Chapter 6. A brief summary is provided here.

GUIDELINE DEVELOPMENT PANEL

The total guideline development panel comprised 44 panel members from various countries. Two of six working groups focused on reviewing the evidence base for needle procedures and making recommendations. One working group focused on pharmacological interventions and consisted of two pediatric oncologists, a pediatric oncology nurse, pediatric anesthesiologist, academic pharmacist, pediatric intensivist, and pediatric surgeon. The other working group focused on physical and psychological interventions, and consisted of a pediatric oncologist, pediatric oncology nurse, clinical psychologist, pediatric psychologist, child life specialist, and pediatric oncology researcher. A core group of eight individuals with extensive experience in CPG development supervised the process and provided methodological expertise.

The draft recommendations were reviewed by a patient/parent-panel (four survivors and five parents), to consider the values and preferences of children and families. They received a short training session on evidence-based medicine and guideline development training and contributed to the formulation of recommendations and implementation considerations (see Supplemental material 7/S1).

SCOPE, DEFINITIONS, CLINICAL QUESTIONS

Needle procedures were divided into three groups: minor procedures, lumbar puncture procedures, and major procedures. Minor procedures were: blood sampling, finger prick, peripheral intravenous access, and access to central venous access port. Lumbar punctures (LPs) comprised both diagnostic and therapeutic LPs. Major procedures were: bone marrow aspiration (BMA), bone marrow puncture (BMP), combined LP with BMA/ BMP, bone biopsy, organ biopsy, and echo-/radiographically guided punctures.

Prioritization of outcomes of the clinical questions was determined using a simple voting procedure, and was in accordance with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology.

SYSTEMATIC LITERATURE REVIEW

The systematic review consisted of clinical questions, evidence searches, evidence summaries and conclusions of evidence. See Table 7.1 for a full list of clinical questions

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.1 . I nc lu d ed c lin ic al q ue st io ns a nd h ie ra rc hy o f o ut co m es . PA TI ENT INT ER VE NT IO N COM PARI SO N PRI O RI TI ZE D O U TC OM ES C hi ld re n wit h c an cer u nd erg oi ng a re le van t m in or p ro ce d ure To p ic al a ne st he tic A ny a ct iv e o r p as si ve co m p ar at or 8 - P ai n i nt en si ty , s el f-ra te d 8 - D is tr es s, s el f-ra te d 8 - A d ve rs e e ff ec ts 7 - B eh av io ra l d is tr es s 6 - D is tr es s, r at ed b y p ro xy 6 - S uc ce ss o f p ro ce d ur e 6 - T im e o f p ro ce d ur e 6 - N ee d f or s ed at io n 5 - D ur at io n o f t he ra p eu tic e ff ec t 5 - G lo b al j ud g m en t o f s at is fa ct io n w ith t re at m en t 5 - S el f-re p or te d d is tr es s i n p ar en ts 4 - P hy si ol og ic al r es p on se s 4 - C at as tr op hi si ng t ho ug ht s i n p ar en ts 4 - C os ts C hi ld re n wit h c an cer u nd erg oi ng a re le van t m in or p ro ce d ure O ral a nal g es ic s A ny a ct iv e o r p as si ve co m p ar at or Ide nt ic al t o # 1 C hi ld re n wit h c an cer u nd erg oi ng a re le van t m in or p ro ce d ure Se d ativ es A ny a ct iv e o r p as si ve co m p ar at or Ide nt ic al t o # 1 C hi ld re n wit h c an cer u nd erg oi ng a l um b ar p un ct ur e p ro ce d ur e Le ve l o f s ed at io n A ny a ct iv e ( m ai nl y o th er le ve l o f s ed at io n) o r p as si ve co m p ar at or 8 - P ai n i nt en si ty , s el f-ra te d 8 - D is tr es s, s el f-ra te d 7 - B eh av io ra l d is tr es s 7 - A d ve rs e e ff ec ts 7 - S uc ce ss o f p ro ce d ur e 6 - D is tr es s, r at ed b y p ro xy 6 - N ee d f or s ed at io n 5 - G lo b al j ud g m en t o f s at is fa ct io n w ith t re at m en t 5 - P hy si ol og ic al r es p on se s 5 - D ur at io n o f p ro ce d ur e 5 - S el f-re p or te d d is tr es s i n p ar en ts 5 - C at as tr op hi si ng t ho ug ht s i n p ar en ts 4 - D ur at io n o f t he ra p eu tic e ff ec t 4 - C os ts

07

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bl e 7 .1 . C on tin ue d PA TI ENT INT ER VE NT IO N COM PARI SO N PRI O RI TI ZE D O U TC OM ES C hi ld re n wit h c an cer u nd erg oi ng a r el ev an t m aj or p ro ce d ur e Le ve l o f s ed at io n A ny a ct iv e ( m ai nl y o th er le ve l o f s ed at io n) o r p as si ve co m p ar at or 8 - P ai n i nt en si ty , s el f-ra te d 8 - D is tr es s, s el f-ra te d 7 - B eh av io ra l d is tr es s 7 - A d ve rs e e ff ec ts 6 - D is tr es s, r at ed b y p ro xy 6 - N ee d f or s ed at io n 5 - G lo b al j ud g m en t o f s at is fa ct io n w ith t re at m en t 5 - P hy si ol og ic al r es p on se s 5 - S uc ce ss o f p ro ce d ur e 5 - D ur at io n o f p ro ce d ur e 5 - S el f-re p or te d d is tr es s i n p ar en ts 5 - C at as tr op hi si ng t ho ug ht s i n p ar en ts 4 - D ur at io n o f t he ra p eu tic e ff ec t 4 - C os ts C hi ld re n wit h c an cer u nd erg oi ng a re le van t p ro ce d ure H ypn os is A ny a ct iv e o r p as si ve co m p ar at or 8 - P ai n i nt en si ty , s el f-ra te d 8 - D is tr es s, s el f-ra te d 7 - D is tr es s, r at ed b y p ro xy 7 - B eh av io ra l d is tr es s 7 - G lo b al j ud g m en t o f s at is fa ct io n w ith t re at m en t 7 - F ea r o f f ut ur e m ed ic al p ro ce d ur es 7 - A d ve rs e e ff ec ts 6 - U se o f a na lg es ic s 6 - D ur at io n o f t he ra p eu tic e ff ec t 6 - P hy si ol og ic al r es p on se s 6 - S uc ce ss o f p ro ce d ur e 6 - N ee d f or s ed at io n 5 - S el f-re p or te d d is tr es s i n p ar en ts 5 - C at as tr op hi si ng t ho ug ht s i n p ar en ts 4 - T im e o f p ro ce d ur e 4 – C os ts C hi ld re n wit h c an cer u nd erg oi ng a re le van t p ro ce d ure D is tr ac tio n A ny a ct iv e o r p as si ve co m p ar at or Ide nt ic al t o # 6 C hi ld re n wit h c an cer u nd erg oi ng a re le van t p ro ce d ure C omb in ati on o f m o d al iti es A ny s in g le m o d al it y Ide nt ic al t o # 6

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A comprehensive literature search was performed (last update March 13th_{2018, details}

see Chapter 6). Only randomized controlled trials (RCTs) studying children with cancer were eligible for inclusion. Study selection (three-step fan-out approach) and data extraction was performed by two reviewers independently (1: EL, 2: working group members). The quality of the evidence was assessed using the Cochrane Risk of Bias Tool and the GRADE methodology.[10-12] Evidence summaries including conclusions of evidence were disseminated within the relevant working groups. For additional details, see our methodology paper (Chapter 6).

FROM EVIDENCE TO RECOMMENDATIONS

Evidence to Decision (EtD) frameworks were used to formulate recommendations in a systematic and transparent manner.[13] The EtD frameworks were discussed during an in-person consensus meeting in Amsterdam attended by 36 members (80%), in February 2018. Decisions were made through group discussion and consensus, final recommendations had to be supported unanimously. For questions where the evidence was deemed insufficient to base a recommendation on, an approach to lower quality evidence identification was established. After this meeting, draft recommendations were refined and finalized using repeated working group and total group conversations through email and telephone. In this entire process, the guideline development panel prioritized the perspective of the patient and his/her family as most important when formulating recommendations.

Standard-of-care statements were formulated for practice points for which no evidence search was possible, but that according to the panel should be emphasized in a comprehensive guideline. In line with the GRADE methodology, these practice points are entitled ‘good practice statements’, with the addition of the prefix ‘ungraded’ to underline that no formal grading of evidence has been performed.[14]

7.4 RESULTS

STUDY SELECTION

11.159 citations were retrieved. See Figure 7.1 for a flowchart of the selection process. In all, 48 primary studies were included (total number of participants = 2271). 33 studies (n=1.602) focused on pharmacological interventions; including minor procedures (7 studies, n=367), lumbar puncture procedures (8 studies, n=236), and major procedures (18 studies, n=999). Fifteen studies (n=669) focused on physical or psychological

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Figure 7.1. Flowchart of the selection process. Working groups are indicated using their working group number; 2C for pharmacological management of procedure-related pain, 3B for physical/ psychological management of procedure related pain.

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SYSTEMATIC REVIEWS

For conclusions of evidence, see Table 7.2. See Supplemental materials 7/S2 and 7/S3 for the full evidence summaries.

Table 7.2. Conclusions of evidence.

Topical anesthetics

Minor procedures Quality of evidence

Reduced self-rated pain intensity with lidocaine-prilocaine 5% (60 min)

vs. placebo ⨁⨁◯◯ LOW17

Reduced proxy-rated distress with lidocaine-prilocaine 5% (60 min) vs.

placebo ⨁⨁◯◯ LOW17

No significant difference in adverse effects with lidocaine-prilocaine

5% (60 min) vs. placebo ⨁⨁◯◯ LOW17

Reduced self-rated pain intensity with lidocaine-prilocaine 5% (60 min)

vs. lidocaine-prilocaine 5% (40 min) ⨁⨁◯◯ LOW16

No significant difference in proxy-rated distress with

lidocaine-prilocaine 5% (60 min) vs. lidocaine-lidocaine-prilocaine 5% (40 min) ⨁⨁◯◯ LOW16 No significant difference in self-rated pain intensity with

lidocaine-prilocaine 5% (60 min) vs amethocaine gel (30 min) ⨁◯◯◯ VERY LOW18 No significant difference in proxy-rated distress with

lidocaine-prilocaine 5% (60 min) vs amethocaine gel (30 min) ⨁◯◯◯ VERY LOW18 No significant difference in adverse effects with lidocaine-prilocaine

5% (60 min) vs amethocaine gel (30 min) ⨁◯◯◯ VERY LOW18 No significant difference in success of procedure with

lidocaine-prilocaine 5% (60 min) vs amethocaine gel (30 min) ⨁◯◯◯ VERY LOW18

Lumbar puncture procedures Quality of evidence

Varying results (benefit in 2 studies, no significant difference in 1 study)

with lidocaine-prilocaine 5% vs. placebo ⨁⨁◯◯ LOW19-21 Reduced proxy rated distress with lidocaine-prilocaine 5% vs. placebo ⨁⨁◯◯ LOW19-21

No significant difference in success of procedure with

lidocaine-prilocaine 5% vs. placebo ⨁⨁◯◯ LOW

19-21

Oral analgesics

No significant difference in self-rated pain intensity with paracetamol

vs. placebo ⨁⨁⨁◯ MODERATE5

Reduced self-rated distress with paracetamol vs. placebo ⨁⨁⨁◯ MODERATE5

Reduced behavioral distress with paracetamol vs. placebo ⨁⨁⨁◯ MODERATE5

No significant difference in self-rated pain intensity with morphine vs.

placebo ⨁⨁⨁◯ MODERATE6

Increased self-rated distress with morphine vs. placebo ⨁⨁⨁◯ MODERATE7

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Use of sedation

No significant difference in self-rated pain intensity with midazolam vs.

placebo ⨁⨁◯◯ LOW7.8

No significant difference in self-rated distress (distress, needle

discomfort) with midazolam vs. placebo ⨁⨁◯◯ LOW7,8

Reduced self-rated distress (fear) with midazolam vs. placebo ⨁⨁◯◯ LOW7

Reduced behavioral distress with midazolam vs. placebo ⨁⨁◯◯ LOW7

Increased adverse effects with midazolam vs. placebo ⨁⨁◯◯ LOW7

No significant difference in self-rated distress with general anesthesia

vs. deep sedation ⨁⨁◯◯ LOW9

No significant difference in adverse effects with general anesthesia vs.

deep sedation ⨁⨁◯◯ LOW9

No significant difference in success of procedure with general

anesthesia vs. deep sedation ⨁⨁◯◯ LOW9

No significant difference in duration of procedure with general

Major procedures Quality of evidence

No significant difference in self-rated pain intensity with general

anesthesia vs. no sedation ⨁◯◯◯ VERY LOW10

vs. no sedation ⨁◯◯◯ VERY LOW10

Reduced behavioral distress with general anesthesia vs. no sedation ⨁◯◯◯ VERY LOW10

No significant difference in self-rated pain intensity with general

No significant difference in behavioral distress with general anesthesia

No significant difference in adverse effects with general anesthesia vs.

deep sedation ⨁⨁◯◯ LOW11

Hypnosis

Reduced self-rated pain intensity with hypnosis vs. standard care ⨁⨁⨁◯ _MODERATE_12-15 Reduced self-rated distress with hypnosis vs. standard care ⨁⨁⨁◯ _MODERATE12-15

Reduced behavioral distress with hypnosis vs. standard care ⨁⨁⨁◯ _MODERATE12-15

Reduced fear of future medical procedures with hypnosis vs. standard

care ⨁⨁⨁◯ MODERATE14,15

Reduced self-reported distress in parents with hypnosis vs. standard

care ⨁⨁⨁◯ MODERATE15

Varying results (benefit in 5 studies, no significant difference in 1 study)

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Hypnosis

Reduced self-rated distress with hypnosis vs. non-hypnotic attention

techniques ⨁⨁◯◯ LOW12-16

Reduced behavioral distress with hypnosis vs. non-hypnotic attention

techniques ⨁⨁◯◯ LOW12-15

Reduced fear of future medical procedures with hypnosis vs.

non-hypnotic attention techniques ⨁⨁⨁◯ MODERATE14,15

Reduced self-reported distress in parents with hypnosis vs.

non-hypnotic attention techniques ⨁⨁⨁◯ MODERATE15

Active distraction

No significant difference in self-rated pain intensity with active

distraction vs. standard care ⨁⨁◯◯ LOW17,18

No significant difference in self-rated distress with active distraction vs.

standard care ⨁⨁◯◯ LOW17,18

Reduced behavioral distress with hypnosis vs. standard care ⨁⨁◯◯ LOW18

No significant difference in proxy-rated distress with active distraction

vs. standard care ⨁⨁◯◯ LOW18,19

Passive distraction

Reduced self-rated pain intensity during and after procedure with

passive distraction vs. standard care ⨁⨁◯◯ LOW20

No significant difference in self-rated pain intensity before procedure

with passive distraction vs. standard care ⨁⨁◯◯ LOW20 No significant difference in self-rated pain intensity with passive

distraction vs. standard care ⨁◯◯◯ VERY LOW21

Reduced self-rated distress with passive distraction vs. standard care ⨁⨁◯◯ LOW20

Combining modalities

Major procedures Quality of evidence

Reduced self-rated pain intensity post-intervention with combining

strategies vs. single procedure ⨁⨁◯◯ LOW

52

No significant difference in self-rated pain intensity pre-intervention

with combining strategies vs. single procedure ⨁⨁◯◯ LOW

52

Reduced self-rated distress pre-intervention with combining strategies

vs. single procedure ⨁⨁◯◯ LOW

52

No significant difference in self-rated distress post-intervention with

combining strategies vs. single procedure ⨁⨁◯◯ LOW

52

Varying results (with no formal testing) with hypnosis vs. non-hypnotic

attention techniques ⨁◯◯◯ VERY LOW

53

Reduced behavioral distress post-intervention with combining

strategies vs. single procedure ⨁⨁◯◯ LOW

52

No significant difference behavioral distress pre-intervention with

combining strategies vs. single procedure ⨁⨁◯◯ LOW

52

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FROM EVIDENCE TO RECOMMENDATIONS

In Supplemental materials 7/S4 and 7/S5 the EtD frameworks as completed by the working groups are presented. For a condensed overview of the evidence and EtD frameworks see Supplemental material 7/S6. Recommendations are presented in Table 7.3. For a flowchart to guide clinical care, see Figure 7.2.

Table 7.3. List of recommendations and good practice statements.

# GRADE Recommendation text Strength Quality of

evidence Pharmacological interventions

1 We recommend the use of a topical anesthetic for all needle procedures

Strong Low 2 We recommend the use of deep sedation or anesthesia for major

procedures

Strong Very low 3 We recommend the use of deep sedation or general anesthesia

for lumbar punctures in children younger than 12 years Strong Very low 4 We suggest the use of deep sedation or general anesthesia for

lumbar punctures in children aged 12 years and older

Weak Very low 5 We suggest against the use of sedatives for minor procedures Weak Low 6 We suggest against the use of oral analgesics for minor procedures Weak Low

Psychological interventions

7 We recommend the use of hypnosis for all needle procedures Strong Moderate 8 We recommend the use of active distraction for all needle

procedures Strong Low

9 We suggest the use of passive distraction for all needle procedures Weak Very low 10 We suggest hypnosis over non-hypnotic attention techniques for

all needle procedures

Weak Very low Combining intervention modalities

11 We suggest combining psychological interventions with pharmacological interventions during all needle procedures

Weak Very low Ungraded good practice statements

A Children and parents should be educated and prepared regarding needle procedures and interventions to reduce pain and distress, prior to all procedures that the child has to undergo

N/A N/A

B Parents/caregivers should have the option to be present during their child’s needle procedures if the child wishes to, when clinically appropriate

N/A N/A

C Throughout the course of treatment, children should have ongoing assessments and re-assessments of pain and distress and appropriateness of interventions to determine effectivity of strategies to reduce procedural pain and distress

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Figure 7.2. Flowchart summarizing the recommendations to reduce procedural pain and distress, for use in clinical practice

Below the evidence and formulated recommendations are discussed. For pharmacological interventions this entails use of topical anesthetics in all needle procedures, use of sedation in major, lumbar puncture, and minor procedures, and use of oral analgesics in minor procedures. For psychological interventions this entails use of hypnosis, active distraction, passive distraction, and non-hypnotic attention techniques in all needle procedures. Also one recommendation on combining intervention modalities is discussed. For each recommendation we present a summary of the conclusions of evidence and considerations of the EtD framework including the balance of desirable and undesirable consequences, the formulated recommendation, and subgroup and implementation considerations.

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PHARMACOLOGICAL INTERVENTIONS

Clinical questions one to five focused on pharmacological interventions. Critical outcomes for all these questions included self-rated pain intensity, self-rated distress, behavioral distress, and adverse effects. For the clinical questions on LPs, success of procedure was also a critical outcome. Most outcomes were primarily measured during and shortly after the procedure. In procedures where sedation was administered, self-rated outcomes were measured after the procedure. Trials focusing on use of sedation were eligible if different levels of sedation were compared. Levels of sedation were defined according to the five levels specified by the American Society of Anesthesiologists (ASA): no sedation, minimal sedation, moderate sedation, deep sedation (DS), and general anesthesia (GA). [15]

TOPICAL ANESTHETICS

EVIDENCE

This clinical question focused on the use of topical anesthetics in all included needle procedures. Regarding minor procedures, three studies (n=173) evaluated the use of lidocaine-prilocaine 5% (EMLA®) with a 60 minutes’ application time in children with cancer. The comparators differed per study.[16-18] One study (n=47) suggested that lidocaine-prilocaine 5% (60 min) is associated with reduced self-rated pain intensity and proxy-rated distress as compared to a placebo, with no significant differences in adverse effects (low quality evidence).[17] One study (n=87) suggested that lidocaine-prilocaine 5% (60 min) is associated with reduced self-rated pain intensity as compared to lidocaine-prilocaine 5% (40 min), with no significant difference in proxy-rated distress (low quality evidence).[16] The last study (n=39) suggested that there are no significant differences in self-rated pain intensity, proxy-rated distress, adverse effects, and success of procedure for lidocaine-prilocaine 5% (60 min) compared to amethocaine gel (30 min) (very low quality evidence).[18]

With regard to lumbar punctures, three studies (n=46) compared lidocaine-prilocaine 5% with a placebo.[19-21] For self-rated pain intensity findings varied (benefit for lidocaine-prilocaine 5% in two studies, not significant in one study) (low quality evidence). Two studies (n=36) suggested that lidocaine-prilocaine 5% is associated with reduced proxy-rated distress compared to placebo, with no difference in success of procedure (low quality evidence).[19,21] Adverse effects were reported in one study (limited to minor local reactions in both groups), but no test was performed.[19]

In the search for additional evidence (general pediatrics) two evidence syntheses were included; one on pain during dermal laceration repair and one on vaccine injection

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pain.[22,23] In both syntheses it was concluded that topical anesthetics are effective in reducing pain.

EVIDENCE TO DECISION AND RECOMMENDATION 1

The panel concluded that the desirable consequences of topical anesthetics clearly outweigh the undesirable consequences (i.e. erythema, itchiness). Required resources are small relative to the benefits, and topical anesthetics are acceptable to key stakeholders and feasible to implement.

Therefore, we recommend the use of a topical anesthetic for all needle procedures (strong recommendation, low quality of evidence).

SUBGROUP AND IMPLEMENTATION CONSIDERATIONS

Topical anesthetics used in the included studies were lidocaine-prilocaine 5% cream or patch (e.g. EMLA®) and amethocaine 4% gel (e.g. Ametop™). In time application (e.g. for lidocaine-prilocaine 5% at least 60 minutes before procedure) is important, and in pediatric oncology feasible as most procedures are planned procedures. Patients and parents should be educated regarding in time application (when leaving for the hospital, or coming early to apply), but also on how to remove a patch to minimize distress. For clinicians, it is important to emphasize the importance of adhering to application times as well, and to introduce topical anesthetics to alleviate procedural distress as early in the treatment trajectory as possible. However, clinicians should be aware of the use of these drugs in neonates, as there are published case reports describing methemoglobinemia in infants treated with EMLA.[24,25]

SEDATION IN MAJOR PROCEDURES

EVIDENCE

Our initial evidence search resulted in the inclusion of 12 studies, with a wide spectrum of drugs and levels of sedation included (see Supplemental material 7/S7). In only two of 12 studies, different sedation levels were compared.[26,27] One study (n=18) suggested that general anesthesia is associated with reduced behavioral distress as compared to no sedation (very low quality evidence).[26] No significant differences between groups were found in this study for self-rated pain intensity and self-rated distress (very low quality evidence). One study (n=31) suggested that there are no differences for self-rated pain intensity, self-rated distress, behavioral distress, and adverse effects between general anesthesia and deep sedation (low quality evidence).[27] The two included systematic

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reviews identified in our search for additional evidence did not reach unequivocal conclusions.[28,29]

The panel concluded that the desirable consequences of deep sedation or general anesthesia probably outweigh the undesirable consequences. Although the required resources are probably not small, the panel deemed the option feasible to implement and acceptable to stakeholders. In fact, from previous studies we know that procedural pain is reported by children with cancer to be the greatest cause of pain during the initial phase of treatment, and continues to be a major factor in pain and distress throughout treatment.[30,31] Taking this into account, the panel judged that there would be virtually no patient who would want to undergo a major procedure under a lower level of sedation than DS/GA. Also the panel judged clinicians would not want to do these procedures under any other level than DS/GA. Taking these standpoints into consideration and focusing on the comfort during a procedure as a goal, the panel acknowledged a strong recommendation in favor of DS/GA during major procedures was justified, despite a weak evidence base. This was discussed with the patient/parent-panel and they supported this recommendation unanimously. In fact, patients who did not receive DS/GA for major procedures stated explicitly that they would have wanted so had they had the choice.

Therefore, we recommend the use of deep sedation or anesthesia for major procedures (strong recommendation, very low quality evidence).

We realize the stratification of the sedation spectrum is relatively artificial, therefore this recommendation should be seen in the light of what we truly aim to achieve: optimal patient comfort, absence of restraint and sufficient immobility. Nevertheless, to guide uniform practice we decided to adhere to the levels as established by the ASA. We did not identify evidence for recommending specific medications for both sedation and analgesia. Nevertheless, the panel was convinced that some guidance regarding medications should be provided in this CPG, to improve comprehensiveness and to guide clinicians in situations where there is no established practice. Therefore, the panel summarized sedation medication that they were experienced with and judged to be contemporary medication. See Table 7.4 for the most important points, or Supplementary material 7/S7 for more extensive information.

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. O ve rv ie w o f A m er ic an S oc ie ty o f A ne sth es io lo g is ts (A SA ) l ev el s o f se d at io n, in cl ud in g d efi ni tio n a cc or d in g t o th e A SA , c on te m p or ar y d ru g s th at ed as ju d g ed b y th e p an el , a nd re q ui re d m on ito ri ng . T he se d efi ni tio ns an d re co m m en d at io ns ar e ap p lic ab le on ly in lo w -r is k ch ild re n (i. e. A SA 1 or ir w ay ; a b se nc e o f r es p ir at or y i nf ec tio n) . I n a ll c as es d ru g s s ho ul d o nl y b e u se d b y p ro fe ss io na ls w ho a re t ra in ed a nd c om p et en t i n t he ir u se w ith g o f a p ro ce d ur al s ed at io n o f a s ic k c hi ld . ev el o f Sh or t d efi ni tio n ( A SA ) Co nt em po ra ry d ru gs u se d t o a ch ie ve le ve l o f se da tio n ( pan el ju dgem en t) Re quir ed m on ito ring (A SA ) ed at io n “d ru g -i nd uc ed s ta te d ur in g w hi ch p at ie nt s re sp o nd n or m al ly t o v er b al c o m m an d s” N itr ou s o xi d e (u p t o 5 0% )* D ex me d et o m idi ne ** M id az ol am (‘ st ar t l ow a nd g o s lo w ’ - u p t o a n IV d os e o f 0 ,1 m g /k g; a n I N d os e o f 0 ,3 m g /k g; an o ra l d os e o f 0 ,5 m g /k g ) Inte rm it te nt a ss es sm ent of le ve l of s ed at io n V is ua l o b se rv at io n o f a ir w ay a nd b re at hi ng If d ire ct o b se rv at io n i s n ot p os si b le , p ul se o xi m et ry ma y b e a r ea so na b le a lte rna tiv e. ed at io n “d rug -in d uce d d ep re ss io n of c on sc io us ne ss d ur in g w hi ch p at ie nt s r es p on d p ur p os ef ul ly to v er b al c o m m an d s, e it he r a lo ne o r ac co m p an ie d b y l ig ht t ac til e s tim ul at io n” Se e d ru g s f or d ee p s ed at io n. A ny d ru g o r d ru g c o m b in at io n i nt en d ed fo r m o d er at e s ed at io n m ay e nd u p l ea d in g to d e e p s e d ati o n. T here fo re m o d er at e se d at io n a nd d ee p s ed at io n r eq ui re t he s am e p re ca uti o ns a nd m o nit or in g re q ui re m en ts. Pul se o xi m et ry H ea rt r ate B lo o d p re ss ure Re sp ir at io n (E C G & c ap no g ra p hy s tr on g ly re co m m en d ed , n ot re q ui re d ) tio n “d rug -in d uce d d ep re ss io n of c on sc io us ne ss d ur in g w hi ch p at ie nt s c an no t b e e as ily ar ou se d b ut r es p on d p ur p os ef ul ly f ol lo w in g re p ea te d o r p ai nf ul s tim ul at io n” De ep Se d at io n a nd G en er al A ne st he si a co m bi ne d: 1. P ro p o fo l-b as ed r eg im en ( N B . n ee d f o r an al g es ia ) 2. K et am in e 3. C o m bi na ti o ns o f b enz o d ia ze pi ne a nd o p ioi d s 4. B ar b it ur at es ( sh ou ld o nl y b e u se d w he n n o ot he r a lte rn ativ es a re a va ila bl e) D ee p Se d at io n an d G en er al A ne st he si a co m bi ne d: Pul se o xi m et ry ECG Hea rt r ate B lo o d p re ss ure Re sp ir at io n C ap no g rap hy ne st he si a “d rug -in d uce d l os s o f co ns ci ou sne ss d ur in g w hi ch p at ie nt s a re n ot a ro us ab le , e ve n b y p ai nf ul s tim ul at io n” na lg es ia : p ro ce d ur al p ai n m an ag em en t d ep en d s o n t he u se o f t op ic al a ne st he tic s ( if o nl y t he s up er fic ia l s ki n i s t o b e p er fo ra te d b y a n ee d le ) a nd st he tic i nfi ltr at io n w ith b uf fe re d l id oc ai ne ( if n ee d le s r ea ch d ee p er t is su es ) a nd /o r i nt ra ve no us ( IV ) F en ta ny l ( if t he p re vi ou s t w o a re u nl ik el y t o nt ly e ff ec tiv e) . I f a n I V a cc es s i s l ac ki ng , i nt ra na sa l f en ta ny l h as b ee n s ho w n t o b e e q ua lly e ff ec tiv e a s I V a d m in is tr at io n. b in at io n o f n itr ou s o xi d e w ith i nt ra na sa l f en ta ny l m ay r es ul t i n a d ee p er l ev el o f s ed at io n w ith ou t s ub st an tia lly i nc re as in g r is k t o p at ie nt s. et om id in e c au se s a d ee p, ‘ na tu ra l’ s le ep w ith ou t i nt er fe ri ng w ith a ir w ay r efl ex es a nd /o r b re at hi ng . C hi ld re n w ith a n i nt ac t a ir w ay a nd v en til at io n ir o w n n at ur al s le ep p ha se s, w ill s ho w n o r es p ir at or y a d ve rs e e ve nt s d ur in g a d ex m ed et om id in e s ed at io n t ha t i s b as ed o n s ta nd ar d d os es . af et y r ec om m en d at io ns f or d ex m ed et om id in e a re c la ss ifi ed u nd er ‘ m in im al s ed at io n’ . D ex m ed et om id in e i s a r el at iv el y e xp en si ve s ed at iv e t ha t ot ( ye t) a va ila b le i n m any c ou nt rie s.

07

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To implement this option, the facilities to provide DS/GA should be readily available, including the presence of an expert to administer the anesthetic drugs and monitor the patient. This expert should be independent of the person performing the procedure (panel judgement). Minimal monitoring requirements should comply with local laws and regulations. In the absence of an existing local policy, we suggest complying with the American Academy of Pediatrics 2016 Guideline on monitoring of sedation in children (see Table 7.4).[32]

SEDATION IN LUMBAR PUNCTURES

EVIDENCE

Our search for evidence resulted in the inclusion of eight studies, which included a wide spectrum of drugs and levels of sedation (see Supplemental material 7/S7). In only two of eight studies, different sedation levels were compared.[26,27] In one of these studies, data was not presented in a comprehensible or extractable manner.[33] In the other study (n=22) there were no differences between general anesthesia and deep sedation with respect to self-rated distress, success of procedure, adverse effects, or duration of procedure (low quality evidence).[34] The systematic reviews identified in our search for additional evidence did not provide unequivocal conclusions.[35]

EVIDENCE TO DECISION AND RECOMMENDATIONS 3 AND 4

To inform what level of comfort should be achieved in the different procedures and age groups the panel took the patients values and preferences as the most important perspective. Overall the panel concluded that the desirable consequences probably outweigh the undesirable consequences, and that the option is feasible to implement. Furthermore, the panel took into account the need for motion control in LPs, the body of evidence for major procedures (several studies focused on combined BMAs/LPs) that favored higher levels of sedation, and the experience of the panel. Given this, the panel judged a recommendation in favor of deep sedation or general anesthesia was justifiable. As motion control is often difficult to achieve without sedation in younger children (<12 years), a strong recommendation was formulated for these patients. From experience and from the meeting with the patient/parent-panel, the guideline panel noted that here is a subgroup of older children who are able to lay still and might prefer not to have sedation and only use local analgesia and appropriate psychological strategies. Therefore, the recommendation for this specific age group (≥12 years) was categorized as weak. The patient/parent-panel unanimously supported these recommendations.

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Therefore, we recommend the use of deep sedation or general anesthesia for lumbar punctures in children younger than 12 years (strong recommendation, very low quality evidence). We suggest the use of deep sedation or general anesthesia for lumbar punctures in children aged 12 years and older with cancer (weak recommendation, very low quality evidence).

See the subgroup and implementation considerations paragraph of the use of sedation in major procedures for considerations on implementation and monitoring. For older children (≥12 years), the patient/parent-panel emphasized that although the decision to have sedation or not should lie in the hands of the patient, sedation should at least always be offered. They also noted that the option to receive sedation in subsequent LPs, should the child prefer this after one or more LPs without sedation, should repeatedly be offered over time.

SEDATION IN MINOR PROCEDURES

EVIDENCE

Two studies with a total of 93 participants compared the use of midazolam to placebo, with one focusing on oral administration and one on nasal administration.[36,37] No differences were found between midazolam and placebo for self-rated outcomes (pain intensity and distress), except for reduced self-rated fear in one study (low quality evidence).[36,37] One study suggested that midazolam is associated with reduced behavioral distress, but also with increased adverse effects (e.g. anger, over-sedation, diplopia) as compared to placebo (low quality evidence).[36]

Appraising the limited evidence, the panel concluded that the desirable consequences of the use of sedation do probably not outweigh the undesirable consequences (associated adverse effects). In addition, the panel was not convinced the option is acceptable to key stakeholders and feasible to implement. Given the associated adverse effects, the panel thus judged that the standard of care is not to use sedation for minor procedures.

Therefore, we suggest against the use of sedatives for minor procedures (weak recommendation, low quality evidence).

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In children whom are extremely anxious before and/or during minor procedures, consider

the use of sedatives. Regarding this, the panel preferred the use of nitrous oxide (N₂O up

to 50% inhalational concentration) over that of midazolam (ungraded panel judgement).

ORAL ANALGESICS IN MINOR PROCEDURES

EVIDENCE

Two studies (n=101) were included, one focusing on paracetamol (acetaminophen) and one on morphine.[38,39] One study suggested that paracetamol is associated with reduced self-rated distress and behavioral distress as compared to placebo (moderate quality evidence).[39] The other study suggested that morphine is associated with increased self-rated distress as compared to placebo (moderate quality evidence).[38] In both studies there was no significant difference between groups for self-rated pain intensity.

A CPG on vaccine pain that was included in the search for additional evidence, recommended against paracetamol due to a lack of evidence.

In all, the panel concluded that the undesirable consequences (e.g. known adverse effects of morphine, possible thrombopathy in non-steroid anti-inflammatory drugs) probably outweigh the desirable consequences. In addition, pain during a needle procedure generally consists of a short peak of pain, which makes it difficult to effectively time oral analgesics.

Therefore, we suggest against the use of oral analgesics for minor procedures (weak recommendation, low quality evidence).

As the body of evidence was limited to paracetamol and morphine, one might doubt to provide other types of oral analgesics to children during minor procedures. However, the panel suggests that, should one have valid arguments to test a different or novel oral analgesic this population, this should firstly be done in a research context only.

PSYCHOLOGICAL INTERVENTIONS

Clinical questions six and seven focused on psychological interventions, critical outcomes for all these questions included self-rated pain intensity, self-rated distress, proxy-rated distress, behavioral distress, fear of future medical procedures, and adverse effects. For

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the questions on active and passive distraction, global judgement of satisfaction with treatment was also considered a critical outcome.

Hypnosis is a trance-like state awareness, where a child is highly focused on (suggested or self-created) images or ideas. Non-hypnotic attention techniques include a variety of distraction techniques (e.g. preprocedure nonmedical verbal interactions) and exercises (e.g. deep breathing). Active distraction was defined as distraction in which the child actively participates, for example completing a puzzle or playing a (computer) game. Passive distraction was defined as distraction in which the child does not actively participates, for example reading a cartoon, listening to music or watching a movie.

The panel believed that the success of a psychological intervention is dependent upon developmental age and personality of the child. In addition, there might be gender and/or cultural differences in preference of distractors. Health care providers should always engage a child and his/her parents/caregivers in discussing effective interventions, but even more so regarding psychological interventions to reduce pain and distress during procedures. Together an informed decision on the preferred strategy should be made. The patient/parent-panel emphasized that specific focus should be given to the autonomy of the child: put the patient in charge.

HYPNOSIS

EVIDENCE

In four studies (n=120), that were all from one study group, the use of hypnosis was compared to standard care during minor procedures.[40-43] All studies suggested that hypnosis is associated with reduced self-rated pain intensity, self-rated distress, and behavioral distress as compared to standard care (moderate quality evidence). Two studies suggested that hypnosis is associated with reduced fear of future medical procedures (moderate quality evidence), and one study suggested that hypnosis is associated with reduced self-reported distress in parents, as compared to standard care (moderate quality evidence).[42,43]

The panel concluded that the desirable consequences of hypnosis clearly outweigh the undesirable consequences. In addition, the option is feasible to implement (although formal training is required) and acceptable for stakeholders. None of the members of the patient/parent-panel had experience with hypnosis. However, after discussing the evidence and justification, the panel unanimously supported a strong recommendation.

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Therefore, we recommend the use of hypnosis for all needle procedures (strong recommendation, moderate quality evidence).

It should be noted that in procedures where deep sedation or general anesthesia is used, the use of hypnosis is limited to the preparation phase. The patient/parent-panel emphasized that hypnosis should be explained properly (to eliminate the woolly association that some patient representatives had with the concept of hypnosis), with the child making the eventual decision to use it or not. An assessment of the hypnotizability of the child could help in this decision.

ACTIVE DISTRACTION

EVIDENCE

Five studies (n=171) evaluated the use of active distraction compared to standard care during minor procedures.[44-47] Studies were of low quality and various critical outcomes were not reported in sufficient detail to extract data. One study suggested that active distraction is associated with reduced behavioral distress as compared to standard care (low quality evidence).[47] For other included outcomes, no significant differences between groups were found for self-rated pain intensity (one study, low quality evidence), self-rated distress (two studies, low quality evidence), and proxy-rated distress (two studies, low quality evidence).

Although the evidence is relatively scarce, the panel put heavy emphasis on their judgement that distraction does not cause harm. Therefore, even small benefits can be of value, and the panel concluded that the desirable consequences probably outweigh the undesirable consequences (if any). The ability to implement low-cost distraction interventions (or have patients bring their own if preferred) means that it is accessible in nearly all settings.

Therefore, we recommend the use of active distraction for all needle procedures (strong recommendation, low quality evidence).

The parent/patients-panel agreed with the recommendation and put emphasis on taking the time, together with the child, to select the preferred distractor. Also, one patient added that there might be children, as herself, who benefit from knowing and seeing

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what is going on and therefore prefer not to be distracted. It should be noted that in procedures where deep sedation or general anesthesia is used, the use of active distraction is limited to the preparation phase.

PASSIVE DISTRACTION

EVIDENCE

Two studies (n=70) evaluated the use of passive distraction compared to standard care during lumbar puncture procedures.[48,49] One study suggested that passive distraction is associated with reduced rated anxiety (low quality evidence) and reduced self-rated pain intensity during and after (but not before) the procedure (very low quality evidence), as compared to standard care.[48] In one study, there was no significant difference between groups for self-rated pain intensity (very low quality evidence).[49] EVIDENCE TO DECISION AND RECOMMENDATION 9

The panel concluded that the desirable consequences probably outweigh the undesirable consequences. Also the option was deemed feasible to implement and acceptable to key stakeholders. However, as there were only a few studies available, the overall quality of the evidence was very low, and the included studies only focused on LPs, the panel categorized this recommendation as weak.

Therefore, we suggest the use of passive distraction in children with cancer undergoing painful procedures (weak recommendation, very low quality evidence). SUBGROUP AND IMPLEMENTATION CONSIDERATIONS

See the subgroup and implementation considerations paragraph of active distraction.

NON-HYPNOTIC ATTENTION TECHNIQUES

EVIDENCE

In six studies (n=173) the use of hypnosis was compared to non-hypnotic attention techniques (e.g. nonmedical play, deep breathing).[40-43,50,51] Four out of five studies that reported on self-rated pain-intensity suggested that hypnosis is associated with reduced self-rated pain-intensity as compared to non-hypnotic attention techniques, while in the other study no significant difference was found (very low quality evidence). Hypnosis was also associated with reduced self-rated distress (five studies, low quality evidence), behavioral distress (four studies, low quality evidence), fear of future medical procedures (two studies, moderate quality evidence), self-reported distress in

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parents (one study, moderate quality evidence) as compared to non-hypnotic attention techniques.

Hypnosis was more effective in reducing pain and distress during procedures than non-hypnotic attention techniques.

Therefore, we suggest hypnosis over non-hypnotic attention techniques for all needle procedures (weak recommendation, very low quality evidence).

See the subgroup and implementation considerations paragraph of hypnosis.

COMBINING INTERVENTION MODALITIES

Critical outcomes for this questions were self-rated pain intensity, self-rated distress, proxy-rated distress, behavioral distress, fear of future medical procedures, and adverse effects.

EVIDENCE

Two studies (n=175) evaluated the use of combining pharmacological strategies with psychological strategies.[52,53] One study suggested that combining interventions modalities is associated with reduced self-rated pain intensity post-intervention (but not pre-intervention), reduced self-rated distress pre-intervention (but not post-intervention), and reduced behavioral distress post-intervention (but not pre-intervention), as compared to single interventions (low quality evidence).[52] One study reported varying results on the effect of combining intervention modalities on proxy-rated distress, with no formal testing (very low quality evidence).[53]

Although the scarcity of evidence and the balance of consequences (varies per combination and is not known for all combinations) might imply that formulating a recommendation would not be feasible, the panel judged a weak recommendation for combining appropriate interventions as justifiable. The option is generally feasible to implement, and is acceptable to key stakeholders. Also this recommendation was based on the wide body of evidence on psychological interventions that included pharmacological interventions as part of standard care (see e.g. included studies on hypnosis and distraction).

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Therefore, we suggest combining psychological interventions with pharmacological interventions during all needle procedures (weak recommendation, very low quality evidence).

SUBGROUP AND IMPLEMENTATION CONSIDERATIONS

Combining recommended pharmacological interventions (e.g. topical anesthetics for minor procedures) with recommended psychological interventions (e.g. active distraction for minor procedures) is of importance to deliver the most high-quality, patient-friendly care to children with cancer who have to undergo repeated procedures. Naturally there are situations where this is not applicable (e.g. during deep sedation), but other than that the panel judged that clinicians should always strive to combine appropriate interventions to reduce pain as much as possible. This importance is underlined by previous research in which it was found that combining analgesic interventions can have an additive or synergetic pain relief effect, and by the biopsychosocial model of pain.

UNGRADED GOOD PRACTICE STATEMENTS

EDUCATION AND PREPARATION

Although no studies were identified that focused on the effects of preparation and education, both the guideline development panel and the patient/parent-panel deemed education and preparation (starting as early as possible in the treatment process) of great importance to high-quality patient-centered clinical care for children undergoing procedures. A recent systematic review focusing specifically on children with cancer concluded preparation plays an important role in decreasing distress and increasing coping and compliance during a variety of medical procedures.[54] Children and parents should be informed about the meaning and process of each procedure, and about what measures can be taken to reduce pain and distress.

Therefore, children and parents should be educated and prepared regarding procedures and interventions to reduce pain and distress, prior to all needle procedures that the child has to undergo (ungraded good practice statement).

PRESENCE OF PARENTS/CAREGIVERS

If a child and his/her parent/caregivers wishes, there should be the option for parental presence during procedures, when clinically appropriate. The panel believed this is part of high-quality care and might facilitate distraction and/or comfort. In addition, parents/ caregivers can be offered the opportunity to act as a coach for their child if desired by

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caregivers should be informed about what behavior is helpful to decrease distress and increase coping, for instance nonverbal behaviors such as eye contact and touch distance. [55] There might be instances, when staying present for the procedure is not of added value (e.g. after general anesthesia has been induced).

Therefore, parents/caregivers should have the option to be present during their child’s needle procedures if the child wishes to, when clinically appropriate (ungraded good practice statement).

ONGOING PAIN ASSESSMENTS

During cancer treatment circumstances might change that influence pain assessment and experience, for example the developmental age of a child and/or the pain and distress experienced during procedures. The latter, in particular, may not have a linear trajectory. For instance, a negative procedure experience (e.g. more distressing, multiple attempts before success) can provoke increased levels of fear, which might call for a different approach with regard to psychological and/or pharmacological management. Therefore, it is of great importance that throughout the course of treatment, pain and distress are continuously and repeatedly assessed. In addition, appropriateness of or preference for strategies used to reduce pain and distress might change. It is thus important that clinicians repeatedly engage in this conversation with the child and his/her parents/ caregivers. In doing so, optimal strategies to reduce pain and distress can be determined. Therefore, throughout the course of treatment, children should have ongoing assessments and re-assessments of pain and distress and appropriateness of interventions to determine effectivity of strategies to reduce procedural pain and distress (ungraded good practice statement).

RECOMMENDATIONS FOR RESEARCH

The panel formulated several specific recommendations per PICO for future research to build upon. For a complete list see the EtD frameworks (Supplemental materials 7/ S4 and 7/S5).

Overall, the panel calls for large, multicenter (and multinational if needed) RCTs that take into account at least the PICO-specific critical outcomes as defined in this guideline. Specific research priorities were head-to-head and cost-effectiveness trials for sedation drugs, use of nitrous oxide, virtual reality for distraction, and trials in which different combinations of treatment modalities are compared. Also it would be interesting to put more focus on developing tailor-fit guidance, given the variety in age, but also the gender

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and cultural differences that may exist. Developing specific guidance for children with a developmental disorder would also be of interest.

In addition, the panel felt that future studies should take into account the long treatment trajectories with repeated procedures that children with cancer often have to undergo. Most current studies focus on one procedure. However, hypothetically an intervention can be effective for one procedure but there can still be an increase in pain and/or distress over time given the number and frequency of the procedures. Therefore, studies should have a longitudinal design taking into account pain and distress over multiple procedures, and other relevant outcomes such as psychological sequelae, compliance behavior, and quality of life.

The patient/parent-panel emphasized that attention should be put on identifying optimal ways to put the child in charge of their own procedure experience. Children should be fully and optimally facilitated to explore possibilities and formulate their own approach to pharmacological and psychological management of procedure-related pain and distress, within the boundaries of what is clinically possible and appropriate. Several projects are being undertaken to facilitate this, for example the CARD (Comfort, Ask, Relax, Distract) project by Taddio et al.(unpublished work)

7.5 DISCUSSION

Current treatment strategies for childhood cancer are associated with high survival rates, but come at the cost of several adverse effects among which pain is one of the most prevalent. Children with cancer frequently have to undergo repeated procedures throughout the course of treatment, e.g. to administer chemotherapy, to examine bone marrow, or to draw a blood count. These procedures are often associated with high levels of pain and distress.[4] In this CPG we have formulated recommendations to reduce pain and distress during painful procedures, which have the potential to substantially improve health-related quality of life for children with cancer, and their families.

This CPG endeavor benefited from a large, international, interprofessional guideline development panel. We believe this contributed significantly to the generalizability of the recommendations. Also, discussing the draft recommendations with patients and parents and integrating their perspective, increased the usefulness of this CPG in daily practice. Another strength of our CPG is the profound adherence to the methodology of the GRADE working group, increasing its rigor.[12] The detailed reporting of the justification for a recommendation and accompanying considerations facilitate clinicians in making the

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A main limitation to this project is the scarcity of evidence; few high-quality studies have been performed that focus on alleviating procedural pain and distress. The GRADE group acknowledges the frustration of clinicians when a guideline does not succeed in providing guidance, and therefore encourages guideline developers to attempt to formulate recommendations even when confidence in effect estimate is low.[56] We underlined this approach and therefore strived to formulate recommendations for practice whenever possible. The panel put high value on employing a patient-centered approach, as is also increasingly advocated for in recent literature.[57,58] Vetting the draft recommendations with the patient/parent-panel and receiving their feedback was of great value in this process.

The scarcity of evidence calls for high-quality, large RCTs to be conducted in this field. We encourage clinicians from different centers and countries to work together to achieve adequately-powered studies. As it is difficult to carry out these studies, it would also be interesting to explore other methods of acquiring relevant knowledge, e.g. by using registry studies.

7.6 CONCLUSION

Pain and distress from repeated procedures is often a great burden for children with cancer and their families. Our group has formulated recommendations to guide daily practice, aimed at reducing this suffering. It is critical that clinicians recognize the great variability between patients in levels of procedural pain and distress. Therefore, tailoring our recommendations to the individual child is of utmost importance. This approach will result in improved care for children with cancer undergoing painful procedures, thereby reducing suffering and potentially enhancing health related quality of life.

ACKNOWLEDGEMENTS

We thank the Dutch pediatric oncology patient and parent association “Vereniging Ouders, Kinderen en Kanker” for playing an active role in the recruitment of parent representatives. Also, we thank Edith Leclercq (who sadly passed away in 2018) and Cochrane Childhood Cancer for assistance in designing and commencing the literature searches. Lastly, we thank iPOG for helping in member recruitment, and providing the international network to learn and benefit from one another in developing and implementing childhood cancer supportive care guidelines.

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SUPPLEMENTAL MATERIALS

The following supplemental materials are available upon request:

7/S1 Meeting with patient representatives (4 pages)

7/S2 Evidence summaries working group 2C (126 pages)

7/S3 Evidence summaries working group 3B (55 pages)

7/S4 Evidence-to-decision frameworks working group 2C (51 pages)

7/S5 Evidence-to-decision frameworks working group 3B (37 pages)

7/S6 Recommendations – Overview of evidence and EtD-frameworks (30 pages)

7/S7 Practice guidance for sedation and analgesia practice (4 pages)

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7.7 REFERENCES

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[3] Loeffen EAH, Mulder RL, Kremer LCM, Michiels EMC, Abbink FCH, Ball LM, et al. Development of clinical practice guidelines for supportive care in childhood cancer—prioritization of topics using a Delphi approach. Support Care Cancer. 2015 Jul 18;23(7):1987–95.

[4] van de Wetering MD, Schouten-van Meeteren NYN. Supportive Care for Children With Cancer. Semin Oncol. 2011 Jun;38(3):374–9.

[5] McMurtry CM, Pillai Riddell R, Taddio A, Racine N, Asmundson GJG, Noel M, et al. Far From "Just a Poke": Common Painful Needle Procedures and the Development of Needle Fear. Clin J Pain. 2015 Oct;31(10 Suppl):S3-11.

[6] Association AM. Module 6 Pain Management : Pediatric Pain Management. Vol. 7. 2012. [7] Graham R, Mancher M, Wolman DM. Clinical Practice Guidelines We Can Trust. The

National Academies Press, Washington D.C., United States of America; 2011. [8] Kato Y, Maeda M, Aoki Y, Ishii E, Ishida Y, Kiyotani C, et al. Pain management

during bone marrow aspiration and biopsy in pediatric cancer patients. Pediatr Int. 2014;56(3):354–9.

[9] Loeffen EAH, Mulder RL, Van De Wetering MD, et al. Current variations in childhood cancer supportive care in the Netherlands. Cancer. 2016;122(4):642–50.

[10] Higgins JPT GS (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [Internet]. The Cochrane Collaboration; 2011. Available from: handbook.cochrane.org.

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