Pediatric Cardiac Intensive Care Society 2014 Consensus Statement

Pharmacotherapies in Cardiac Critical Care

Sedation, Analgesia and Muscle Relaxant

Sarah Scarpace Lucas, PharmD, BCPS, FCSHP; Viviane G. Nasr, MD; Angelica J. Ng, PharmD, BCPS; Charlene Joe, PharmD; Meredyth Bond, PharmD; James A. DiNardo, MD

Disclosures

Pediatr Crit Care Med. 2016;17(S1):S3-S15.

Abstract and Introduction

Abstract

Objective: This article reviews pharmacotherapies currently available to manage sedation, analgesia, and neuromuscular blockade for pediatric cardiac critical patients.

Data Sources: The knowledge base of an expert panel of pharmacists, cardiac anesthesiologists, and a cardiac critical care physician involved in the care of pediatric cardiac critical patients was combined with a comprehensive search of the medical literature to generate the data source.

Study Selection: The panel examined all studies relevant to management of sedation, analgesia, and neuromuscular blockade in pediatric cardiac critical patients.

Data Extraction: Each member of the panel was assigned a specific subset of the studies relevant to their particular area of expertise (pharmacokinetics, pharmacodynamics, and clinical care) to review and analyze.

Data Synthesis: The panel members each crafted a comprehensive summary of the literature relevant to their area of expertise. The panel, as a whole, then collaborated to cohesively summarize all the available, relevant literature.

Conclusions: In the cardiac ICU, management of the cardiac patient requires an individualized sedative and analgesic strategy that maintains hemodynamic stability. 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 short- or long-term recovery trajectory.

Introduction

Children in the cardiac ICU can suffer from pain, fear, and anxiety. Separation from family and home; the fear of machines and procedures; disruption of sleep, alarms, and noises are common reasons for anxiety in children requiring sedation.^[1] The cause of pain can be surgical or can result from diagnostic and therapeutic procedures such as suctioning, position changes, and peripheral IV placement.^[2] Management of pain and anxiety is challenging with the potential of harm secondary to under- and overtreatment. Undertreatment can result in behavioral and biochemical consequences, resulting in delayed healing and stress for the patients and the caregivers.^[3,4] By contrast, overtreatment delays recovery, can cause tolerance, and possibly withdrawal upon discontinuation of therapy.^[5]

Therefore, pain and sedation scales should be used routinely to provide an objective assessment while managing patients in the ICU. The COMFORT-Behavioral Scale^[6,7] has been validated to assess both pain and sedation, whereas other scales such as the State Behavioral Scale have been validated to assess sedation only. These scales should be used on initiation of sedation or pain treatment, and after subsequent changes in dosing of the medications to determine appropriate management.

Maintaining ideal analgesia while at the same time promoting early extubation and ICU discharge can be difficult to achieve. Different algorithms and recommendations have been proposed for short- and long-term extubation goals in the ICU.^[8–10] The decision to use a specific agent is also based on the patient's hemodynamic/respiratory status, the physiologic rationale, severity of the disease, the desired level of sedation, and the potential for adverse effect.

The World Health Organization's analgesic ladder classifies pain in three categories: mild, moderate, and severe. Nonopioids should be considered for children with mild to moderate pain or as an adjuvant agent for moderate to severe pain to reduce the need for opioids. Sedative agent may be used to keep a child comfortable and avoid excessive opioid exposure. Intermittent IV opioids and benzodiazepines could be used for minor bedside procedures or in mechanically ventilated children. However, continuous infusions of sedatives and analgesics such as dexmedetomidine, morphine, or midazolam may be more practical for long-term use. Propofol should be used only for procedural sedation and short-term sedation because of the risk for propofol infusion syndrome (PRIS).^[11]

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Next Section

Abstract and Introduction
Pharmacokinetic and Pharmacodynamic Considerations
Nonopioid Analgesics
Opioids
Benzodiazepines
Ketamine
Dexmedetomidine
Clonidine
Propofol
Neuromuscular Blocking Agents
Conclusions
References

Table 1. Ketorolac
References	Patient Population (Age Range)	Study Design	No. of Doses/Length of Therapy	Conclusions
Gupta et al (26)	Children s/p congenital heart surgery (2 d to 18 yr old)	Prospective, randomized, controlled trial (ketorolac vs no ketorolac)	36–48 hr	Ketorolac group did not have an increased risk of bleeding complications
Moffett et al (27)	Infants s/p cardiac surgery (< 6 mo old)	Retrospective chart review	3 d	Ketorolac was not associated with adverse hematologic or renal effects
Inoue et al (24)	Children s/p low risk cardiac surgery (5 mo to 18 yr old)	Retrospective cohort study (ketorolac vs no ketorolac)	Median: five doses	No difference in increase in SCr between groups Less exposure to opioids in POD0 and POD1 in ketorolac group
Dawkins et al (28)	Infants s/p cardiothoracic surgery (< 6 mo old)	Retrospective case-control chart review (ketorolac vs no ketorolac)	Mean length of therapy: 3.1 d	No significant difference in renal or hemorrhagic complications
Aldrink et al (25)	Surgical infants (0–3 mo old)	Retrospective chart review	Eight to nine doses	Bleeding events associated age < 2 wk old and concurrent medications

s/p = status-post, POD = postoperative day.

Table 2. Ketamine
References	Patient Population (Age Range)	Study Design	Dosing	Length of Therapy	Conclusion
Morray et al (48)	Children 11 mo to 12 yr old s/p cardiac catheterization (n = 20)	Prospective cohort study	Bolus: 2 mg/kg IV	Duration of cardiac catheterization	Ketamine resulted in small increases in heart rate (106.8–109.9 beats/min), mean PA pressure (20.6–22.8 mm Hg), and pulmonary:systemic resistance (0.12–0.14), but these changes did not clinically effect the status of the patients
Berman et al (45)	Children 4–161 mo old (n = 28)	Prospective cohort study	Bolus: 1 mg/kg IV	Duration of cardiac catheterization	Ketamine increased pulmonary:systemic vascular resistance, increased oxygen consumption, heart rate, cardiac output, and PA pressure Ketamine may not be appropriate for patients with chronic lung disease or pulmonary vascular hyper-reactivity
Hartvig et al (47)	1 wk to 30 mo old s/p cardiac catheterization (n = 10)	Prospective study	Ketamine continuous infusion: 1–2 mg/kg/hr (±midazolam 0.1–0.2 mg/kg)	18.5–50.2 hr	Ketamine infusions along with intermittent doses of midazolam were successfully used to wean patients off the ventilator and no adverse effects were noted such as: confusion, vivid dreams, excitation or salivation
Singh et al (46)	Infants 10 hr to children 14 yr old s/p cardiac catheterization (n = 107)	Retrospective clinical study	Bolus: 1 mg/kg IV followed by CI: 50–75 μg/kg/min Average infusion dose: 51.4 ± 3.54 μg/kg/min	Procedure duration: 45–120 min	Ketamine is safe and effective for patients undergoing cardiac catheterization

PA = pulmonary artery.

Table 3. Dexmedetomidine
References	Patient Population (Age Range)	Study Design	Dosing	Length of Therapy	Conclusions
Chrysostomou et al (58)	n = 38 Age: 8 ± 1.1 yr Seven patients < 1 yr	Retrospective case series	No loading dose Infusion: 0.3 ± 0.05 μg/kg/hr (range, 0.1–0.75 μg/kg/hr)	14.7 ± 5.5 hr (range, 3–36 hr)	Patients < 1 yr required greater no. of bolus analgesic doses 15% (n = 6) patients with documented hypotension requiring infusion dosing changes, one patient with bradycardia No adverse respiratory effects, no abdominal effects
Chrysostomou et al (59)	n = 80 Infants and neonates (14) Age: 4.1 ± 3.1 mo	Retrospective three groups: dexmedetomidine, dexmedetomidine + bolus conventional sedatives/analgesics, dexmedetomidine + fentanyl + bolus sedative/analgesics	Loading dose: 0.5–1 μg/kg in selected patients (n = 24) Infusion: 0.66 ± 0.26 μg/kg/hr	25 ± 13 hr	No differences between groups in rescue bolus dose requirements Infants required significantly higher dexmedetomidine infusion rates, lower HR, and higher SBP than neonates Patients on dexmedetomidine exhibited significant decreases in HR and SBP along with blood gas changes: decreased pH, PO₂ and increased Co₂ No nonventilated patients on dexmedetomidine required ventilation, 5/24 intubated patients required reintubation due to nondexmedetomidine reasons, 21 patients (26%) fed during dexmedetomidine infusions, one episode vomiting
Tokuhira et al (60)	n = 14 Age: 1.3 yr (range, 14 mo to 11 yr)	Retrospective	No loading dose Infusion: 0.3–0.4 μg/kg/hr	84.2 ± 50.9 hr	Mechanical ventilation, length of stay in the ICU, and level of sedation similar between the groups. HR significantly lower in the patients receiving dexmedetomidine and required pacing in six of nine patients Patients receiving dexmedetomidine tended to have lower Paco₂ levels than control patients
Lazol et al (61)	n = 22 Age: 7.9 yr	Prospective observational study	Loading dose: 0.5–1 (average 0.62 μg/kg) Infusion: 0.5–0.65 μg/kg/hr	Measurements at T0 (baseline), T1 (6 min after load), T2 (1 hr after maintenance infusion)	No patients exhibited increased PA pressures dexmedetomidine significantly decreased PA pressures at T1 (30–24 mm Hg) at T2 (26 mm Hg) dexmedetomidine-treated patients exhibited significant decreased PA pressure to systemic SBP ratio from 33% at T0 to 23% (T1) and 25% (T2)
Hosokawa et al (62)	n = 141 Age: 1 mo to 15 yr (mean, 3.6 ± 5.4 yr) Two groups usual postoperative care (n = 85), dexmedetomidine (n = 56)	Prospective observational study	No loading dose Infusion: 0.4–0.6 μg/kg/hr	Usual care: 2.8 ± 0.8 d dexmedetomidine: 2.7 ± 1.6 d	Sedative rescue doses and sedation scores were similar between groups. dexmedetomidine patients exhibited significant effects in the following: Greater amounts of bradycardia or hypotension (21.4% dexmedetomidine vs 8.4% control) Requirement of interventions to restore hemodynamic stability Usual care group had significantly higher rates of respiratory depression and involuntary movements
Lam et al (63)	n = 50 Age: 3.53 ± 2.64 mo Neonates and infants	Retrospective observational study	No loading dose Infusion: 0.1–0.5 μg/kg/hr	78 hr (range, 40–290 hr)	Significant decrease in HR, mean arterial pressure, central venous pressure, use of additional opioids and benzodiazepine infusions All patients remained hemodynamically stable No adverse respiratory effects, no abdominal effects

HR = heart rate, SBP = systolic blood pressure, PA, pulmonary artery.

Table 4. Clonidine
References	Patient Population (Age Range)	Study Design	Dose	No. of Doses/Length of Therapy	Conclusions
Ambrose et al (72)	1 d to 3 mo	Open dose ranging study	0.2–1 μg/kg/hr	Median duration 7 d	No changes in cardiac effects
Pohl-Schickinger et al (76)	0–24 mo	Single-center retrospective review	0.18–3.6 μg/kg/hr	Median duration 3 d	Reduced opioid analgesics and no side effects on cardiac rhythm

Table 5. Propofol
References	Patient Population (Age Range)	Study Design	Dose	No. of Doses/Length of Therapy	Conclusions
Cornfield et al (85)	2 mo to 18 yr old	Retrospective review	Continuous infusion not to exceed 50 μg/kg/hr	Median duration 16.5 hr	Safe and effective way to provide sedation to critically ill infants and children
Koroglu et al (86)	1–7 yr	Randomized, prospective study	Induction: 3 mg/kg Maintenance: 100 μg/kg/min	Median duration 1 hr	Provided adequate sedation with rapid rates of induction and recovery
Machata et al (87)	Infants: 19 yr old	Prospective review	Induction: 1 mg/kg Maintenance: 5 mg/kg/hr	Median duration 1 hr	Short induction time, rare demand for addition sedation, low respiratory events, and a rapid recovery

Table 6. Muscle Relaxants
Neuromuscular Blocking Agent	IV Bolus Dose (mg/kg) (4)	Onset and Duration (min) (4)	Dose Adjustments (4)
Vecuronium	0.1	Onset: 1–3 Duration: 30–40	Adjust dose for liver dysfunction
Rocuronium	0.6–1.2	Onset: < 1 Duration: 26–40	Adjust dose for liver dysfunction
Succinylcholine	1–2	Onset: < 1 Duration: 4–6	Adjust dose for liver and renal dysfunction
Cisatracurium	0.1–0.15	Onset: 2–3 Duration: 35–45	N/A
Pancuronium	0.1–0.15	Onset: 2–5 Duration: 24–100	Adjust dose in renal dysfunction