Sedation and analgesia in pediatric mechanical ventilation: are we doing it optimally?

Transcription

1 Sedation and analgesia in pediatric mechanical ventilation: are we doing it optimally? Dick Tibboel; Erwin Ista; Nienke Vet; Monique van Dijk Erasmus MC Sophia Children s Hospital Rotterdam, The Netherlands d.tibboel@erasmusmc.nl

2 Sleep deprivation Environment (Light and Noise) Sedatives Critical illness Caregiver interaction Post-traumatic stress (trauma/burns) Changes in sleep-wake cycle Circadian rhythm disturbance Sleep loss / fragmentation Kudchadar et al. (2014) Sleep Medicine Reviews Physiologic sedative Dependence ( iatrogenic withdrawal) Prolonged MV Delirium Changes in long-term neurocognition

3 Finding the optimal balance between analgesia, sedation, anxiolysis and sleep is integral to the care of PICU patients

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5 CCM 2013

6 Adult patients!

7 CCM 2013

8 Prevention of iatrogenic withdrawal Change of sedation practice: Daily interruption of sedation Gupta et al Change drug: from benzo s to dexmedetomidine/clonidine Nursing-controlled sedation management protocol Drug rotation e.g. Morphine fentanyl

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17 COMFORTneo scale Six behavioral items Alertness (redefined) Calmness Respiratory response or crying (in nonventilated patients Facial tension Body movements Muscle tone (mere observation no touch)

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23 Midazolam Short acting benzodiazepine Short elimination half life, time to peak sedation is 5 10 min. after IV use Duration of action min. Metabolised by CYP450 enzym 3A4 and Glucuronidated Main adverse effects: tolerance, dependency and withdrawal; respiratory depression Licensed throughout the EU and in the USA

24 Clonidine Alpha-2 adrenoreceptor agonist Long eliminiation half life of 9 17 hours Loading dose required for therapeutic steady state concentrations Produces sedation without respiratory depression and exerts anxiolytic effects together with analgesic effects Is a hypotensive agent for treatment of arterial hypertension Adverse effects: hypotension and bradycardia

25 PCCM, 2014 Editorial PCCM, 2014

26 SLEEPS-study RCT of IV Midazolam versus IV Clonidine Calculated sample size 1000 PICU patients PICU s in the UK Outcome: efficacy of sedation Study stopped preterm due to low inclusion of N=200 patients No PK-data available

27 Propofol (2,6-diisopropyl phenol) Used for short or long term sedation Commercially available as 1%. 2% and 6% Only advised for short duration procedures FDA warning for children less than 12 years of age due to the propofol infusion syndrome

28 Dexmedetomidine Central acting Alpha-2 adrenoreceptor agonist Same physiological effects as Clonidine Half life time 2 3 hours, titration by IV administration Approved by FDA for short term sedation of adult! patients during mechanical ventilation and for monitored anesthesia care No specific pediatric indications but extensively used in PICU s and operating rooms predominantly in the US So far high costs euro 65 compared to midazolam euro 2,50

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31 Pediatric Cardiac Intensive Care Society 2014 Consensus Statement: Pharmacotherapies in Cardiac Critical Care: Sedation, Analgesia and Muscle Relaxant Lucas SS et al. Pediatr Crit Care Med, 2016;17:S3-S-15

32 Conclusions: Multiple pharmacological therapies exist to achieve these goals and should be selected based on the patient s underlying physiology, hemodynamic vulnerabilities, desired level of sedation and analgesia, and the projected shortor long-term recovery trajectory. Lucas SS et al. Pediatr Crit Care Med, 2016;17:S3-S-15

33 CONCLUSION: Neonates and young infants have a decreased metabolism of common opioids like fentanyl and therefore are more prone to respiratory depression. Remifentanil could be the ideal opioid for analgesia and sedation of mechanically ventilated infants.

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36 Withdrawal Syndrome in ventilated children IATROGENIC WITHDRAWAL

37 Undersedation Risk of oversedation: Prolonged mechanical ventilation Agitation Risk of displacement of tubes, etc. Higher incidence of Delirium Withdrawal syndrome Increased health care costs

38 Definition of terms Tolerance: Decreasing clinical effects of a drug after prolonged exposure to it (Tobias, 2000; Anand, 2010) Physical dependence: A physiologic and biochemical adaptation of neurons such that removing a drug leads to withdrawal or an abstinence syndrome (Cunliffe et al., 2004; Anand, 2010)

39 Withdrawal Syndrome in Children Withdrawal syndrome: A set of symptoms that manifests when a drug which causes physical dependence is stopped, reduced too quickly or antagonized (Cunliffe et al., 2004; Anand & Arnold, 2010) Onset depends on half-life of drug and its metabolite Onset depends on clearance of active metabolites Signs and symptoms of withdrawal may present 1 hour to 5 days after discontinuation

40 Withdrawal syndrome, a problem?? Opioid withdrawal: Neonates (ECMO): 57% (Arnold et al. 1990; Franck et al. 1995) Children (57%) (Katz et al., 1994) Benzodiazepine withdrawal: 17 to 35% (Hughes et al., 1994; Fonsmark et al., 1999) Combined - benzo s / opioids: 34 to 76% (Sfoggia et al. 2003; Fernandez et al. 2012; Franck et al & 2012; Ista et al. 2013)

41 Risk factors Duration of infusion 5 days Dosages (maximum, cumulative dose) Fentanyl: mg/kg (Arnold et al., 1990; Katz et al., 1994) Midazolam: 60 mg/kg, >70mg/kg (Fonsmark et al., 1999; Ista et al., 2008)

42 Withdrawal symptoms Behavioral (CNS) Gastrointestinal Physiological / other Agitation Vomiting Heart rate (tachycardia) Anxiety Diarrhea Arterial blood pressure (hypertension) Increased muscle tone Poor feeding Breathing rate (tachypnea) Tremors Fever Motor disturbance Inconsolable crying Sleeping pattern Grimacing Sweating Sneezing Yawning Mottling Pupil dilation Convulsions / seizure Hallucinations High-pitched crying Hyperactive Moro-Reflex Ista et al. 2007

43 Withdrawal syndrome assessment tools - Children Instrument (author, year) Patients Observation items CZS GI Auto Others Reliability & validity Sedation withdrawal score (SWS) (Cunliffe, 2004) Opioid Benzodiazepine Withdrawal Score (OBWS) (Franck et al., 2004) Withdrawal Assessment Tool version 1 (WAT-1) (Franck et al., 2008) Sophia Observation withdrawal Symptoms-scale (SOS) (Ista et al., 2009) Children X X X - Children X X X X +/- Children X X X X + Children X X X +

44 (Franck et al., 2008 Cut & 2012) off score: 3 withdrawal

45 Sophia Observation withdrawal Symptomsscale (SOS) Cut off score: 4 withdrawal Ista et al. Intensive Care Med 2009

46 Weaning protocol Sedatives/opioids 5-9 day Sedatives/opioids 10 days Decrease sedatives/opioids 10% per 8hrs Decrease sedatives/opioids 10% per 24hrs e.g. Morphine methadone If necessary: 1. Switch IV to oral 2. Decrease sedatives/ opioids 10% per 8hrs 1. Switch IV to oral administration 2. Decrease sedatives/ opioids 10% per 48hrs Monitor level of sedation with COMFORT behaviour scale Monitor withdrawal symptoms with SOS CAVE: switching takes ± 48 hrs per drug; One drug at the time

47 body movements Vomiting and diarrhea irritable anxiety Sleep problems agitation Pulling out lines fidgety tremors confusion

48 Pediatric Delirium in ventilated children DELIRIUM

49 Delirium Acute Brain failure DSM-IV definition: (Diagnostic and Statistical Manual of Mental Disorders) 1. Disturbance of consciousness 2. Change of cognition 3. Acute onset and fluctuation 4. Physiological consequence

50 Phenomenology There are 3 subtypes which often switch during day and NIGHT ( sun downing ) Hyperactive Agitation pulling lines out, motor disturbance - restlessness, impaired alertness etc. Hypoactive ( still or quietly delirium ) Apathy, slow/sparse speech, hallucinations Mixed hypo- and hyperactive

51 Delirium.. a problem?! Danger for the patient himself Neurometabolic stress Traumatic event for parents, caregivers 1/3 of patients suffers from PTSD (Colville et al. 2008) Colville G, Kerry S, Pierce C. Children's factual and delusional memories of intensive care. Am Respir Crit Care Med 2008;177(9):

52 % Prevalence of Delirium

53 Risk factors for developing delirium Sleep deprivation Sedatives / opioids (iatrogenic withdrawal) Environmental factors (light, noise) Infection

54 Assessment of Pediatric Delirium in PICU patients Cognitive function Pediatric Confusion Assessment Method-ICU (Smith et al. Crit Care Med 2011) Observational / behavioral Pediatric Anesthesia Emergence Delirium Scale (Sikich et al. Anesthesiology 2004) Cornell Asssessment of Pediatric Delirium, CAP-D (Silver et al. Intensive Care Medicine 2012; Traube et al Crit Care Med) Adapted Sophia Observation withdrawal Symptoms-Pediatric Delirium scale (Van Dijk, Knoester, Beusekom, Ista, Intensive Care Medicine 2012)

55 Instrument (author, year) Population Sensitivity * Specificity * Cutoff pcam-icu (Smith, 2011) N=68 > 5 yrs. 83% (66-93%) 99% (95-100) Pos./neg. PAED (Janssen, 2011) N= yrs. 91% (ND) 98% (ND) 8 PAED (Blankespoor, 2012) N= yrs. 100 (ND) 91.7 (ND) 8 CAP-D (Silver 2010) N=50 3m - 21yrs. 97% (ND) 91% (ND) 10 CAP-D (Traube 2013) N= yrs. 94% (84-99%) 79% (74-85%) 9 SOS-PD (Ista, Unpublished) N=14 3m - 18yrs. 91% (76-98%) 97 (83-99%) 4 * (95% Confidence Interval)

56 Treatment and Prevention of delirium Non pharmacological parental presence, pictures of familiar people and objects, familiar music Promoting normal day-night cycle Pharmacological Haloperidol / Risperidone Change sedation practice

57 Summary Be aware of effects of ventilation and sedation Sleep deprivation Withdrawal syndrome Pediatric Delirium - neglected phenomenon Assessment first step, recognition Sleep promotion Exploration of initiatives of new sedation practices

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64 Challenges and solutions Easy acces to training modules in different languages in a web based way Structured collaboration between hospital pharmacists and treatment teams Application of population PK-PD approaches for future trial design and dosing Detailed psychometric analysis of the existing pain assessments instruments and prevent the use of 90 percent of the instruments

65 Challenges and solutions To perform research beyond acute pain such as for neuropathic- and (sub) acute and chronic pain Take into account the multidimensional character of pain;agitation and fear Do not score in the absence of a pharmacological sound treatment algorithm based on population PK-PD and Physiology based PK methodology

66 Future perspectives: The Perfect Neonatal Pain Measurement Instrument (Sinno Simons 2004) ; still searching for the holy grail?! PAIN MEASURE Pain: 6.8 GIVE MORPHINE

67 Questions - Discussion Acknowledgements: Monique van Dijk Dick Tibboel Harma te Beest Matthijs de Hoog Enno Wildschut Saskia de Wildt

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107 Conclusion

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109 Gaps in our knowledge The uncertainty of the level of modulation of the nociceptive stimulus by (non)-pharmacological interventions The effect of previous pain experiences and its therapy on new painful events (pain memory??) The difficulty to visualize pain The proven validity of many of the pain scales and their sensitivity to change The lack of a real interdisciplinary approach

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111 Questions of parents after admission Will our child survive? How long will our child stay in the PICU? Will there be remaining problems after discharge? Do you guarantee that our child will not suffer from pain and/or anxiety

112 PAIN:is there a real difference?? The use of biomarkers is widely accepted to determine therapy in Sepsis Acute kidney injury Traumatic brain injury, but Debatable in the assessment of pain and eventually anxiety??

113 From No-scoring to One size fits All Important methodological short comings The quality of the studies using pain scores and it s relative significance is very variable In many institutions appropiate training and subsequent implementation is not well established The real pharmacodynamic parameter for the use of analgesic drugs is the change in pain score and the sensitivity to change of the score

114 Pain is composed of 4 levels ( Loeser) Nociception The central nervous system Perception Behaviour is a bio-psycho-social phenomenom

115 No scoring of PAIN in your unit means: Continuation of subjectivity of individual nurses and physicians Denial of solid scientific data showing that validated PD parameters have a major effect on drug dosing and even the choice of analgesic drugs Lack of transfer of objective parameters to your collagues resulting in continuation of drug overdosing to keep the patient quiet Lack of transferable approaches for Precision Medicine in the best interest of the individual child

116 Why do we monitor pain? Pain is considered the 5th vital sign Untreated pain results in increased mortality Inadequate pain treatment, mainly overdosing, leads to prolonged duration of artificial ventilation and LOS To prevent suffering as the most important argument to treat and monitor pain is: to be HUMANE

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121 The significant lack of articles on PICU patients is a real problem!!!

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124 Improving sleep quality in ventilated children SLEEP DEPRIVATION

125 Normal sleep pattern Newborns: Up to 18hrs per day (irregular schedule) 0-12 months Becomes consolidated 3-12 years: One period at night Sleep 9-10hrs per nights

126 Sleep problems Recollection unable to sleep 16-18% (Playfor et al. 2000; Karande et al. 2005) Observational studies (n=9) (Kudchadkar et al. 2014) Decease REM sleep Catnaps, frequently awake Noise Level dba (< 30 dba WHO recommendation)

127 Oral Clonidine 5 micrograms/kg versus placebo

128 Intervention to improve Sleep-wake cycle Non invasive Earplugs, noise reduction protocols, lighting optimization, sleep hygiene Pharmacological Melatonin, change of sedation practice (clonidine, dexmedetomidine) Culture change

129 Downregulation of opioid receptors Inhibition proteins Increased production NO (Anand et al. 2010)

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