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Achieving successful early mobilization for the intubated, critically ill child is dependent on optimizing sedation and analgesia. Finding the fine balance between oversedation and undersedation can be challenging. The ideal is for a child to be lucid and interactive during the daytime and demonstrate normal circadian rhythm for sleep with rest at night. Being alert during the day facilitates active participation in therapy including potential ambulation, while decreasing the risk of delirium during mechanical ventilation. An active state during the day with frequent mobilization promotes restorative sleep at night, which brings with it multiple benefits for healing and recovery. Indeed, this ideal may not be physiologically feasible given a child’s critical illness and trajectory, but defining it as the “gold standard” for early mobilization provides a consistent goal for the pediatric intensive care unit (PICU) hospitalization. As such, goal-directed, patient-specific sedation plans are integral to creating a culture of mobility in the PICU. We review currently available sedation strategies for mechanically ventilated children for successful implementation of early mobilization in the PICU, as well as pharmacologic considerations for specific classes of sedative-analgesics.
Ongoing research and technical advances have translated to more adults and children surviving their critical illness. As a result, it has become increasingly evident that many patients experience morbidity that is unrelated to their original disease process but instead as a result of our therapies. Long periods of immobility, sleep disturbances, and delirium have been found to negatively impact long-term functional outcome in critically ill patients.1 These risk factors are further compounded by administration of sedative and analgesic drugs associated with mechanical ventilation, ventricular assist devices, and extracorporeal membrane oxygenation.
Historical perspectives on early mobility in intensive care date back to World War II.2 During and after the war in the mid to late 1940s, there is literature that suggested that bed rest was not always in the best interest of the patient.3 An editorial written during that time espouses the benefits of ambulation including better morale, health, and strength with a more rapid convalescence.4 Needham2 also examined reports published in the 1970s that support those original findings.5,6 All in all, these early publications warned of the dangers of immobility, which were never fully acknowledged by the critical care community until the last decade.
Intensive care unit (ICU)-acquired weakness has been described in adults based on physical examination and electrophysiological studies. De Jonghe et al7 documented ICU-acquired weakness in one out of every four patients they studied based on physical exam who were mechanically ventilated for longer than a week. If we were to study patients who could not cooperate because of heavy sedation or coma, the incidence of neuromuscular weakness would conceivably be higher. Even studies looking at the effect of bed rest on healthy persons found deleterious effects.8 In 1997, Berg et al8 produced experimental data that revealed muscle strength can decrease 4 to 5% per week of immobility in healthy persons. Add this to an already compromised ICU patient and it is clear that weakness may have a negative impact on weaning mechanical ventilation. As a result, some adult clinicians and researchers have begun to shift their approach to sedating patients in ICUs that are ventilated because of respiratory failure.9 There is a growing body of adult literature that emphasizes the importance of early mobility as one way to decrease adverse outcomes that exist because of lifesaving treatments.2,10–13 Unfortunately, literature from the pediatric community with regard to the concept of ICU-acquired weakness is lacking compared with our adult counterparts, even though polyneuropathy and myopathy have been described in children and could contribute to long-term morbidity.14
A formidable barrier to early mobilization is the oversedation of ICU patients to help them tolerate noxious therapies, decrease anxiety, and relieve pain.15 Much of our approach to sedation and analgesia in children is adapted from adult studies. However, the process of generalizing adult data, especially with regard to sedation, is very difficult in a population of vastly different ages and developmental levels. Maintaining safety in the pediatric population (i.e., prevention of inadvertent extubation or removal of vascular access devices) often translates to keeping the child “still” or immobile. Furthermore, anxiety and pain can be difficult to accurately assess and differentiate in children, potentially increasing the risk of oversedation in an effort to optimize safety and avoid discomfort. One also needs to consider the pharmacodynamics and pharmacokinetics of the medications that are routinely used when formulating a sedation strategy. Clearly, what is effective for a school age child with acute respiratory distress syndrome may not be equally efficacious in a toddler who remains intubated after cardiac surgery. As children are sedated to ensure comfort and safety, they often become the victims of physiological dependence, hyperalgesic states, agitation, sleep disturbances, and delirium.16–19 Unfortunately, the symptoms of pediatric delirium are frequently treated with more sedation, leading to a vicious cycle and contributing to increased morbidity and mortality. Additionally, some of these medications may pose a threat to neurocognitive development in children who are in vulnerable stages of development.20 Any decrease in sedative use even without significant differences in ventilation time or length of stay (LOS) would be of benefit.
While intubated, successful early mobilization is dependent on optimizing a child’s sedation and analgesia. Finding the fine balance between oversedation and undersedation can be challenging. The ideal is for a child to be lucid and interactive during the daytime and demonstrate normal circadian rhythm for sleep with rest at night. Being alert during the day facilitates active participation in therapy including potential ambulation, while decreasing the risk of delirium during mechanical ventilation. An active state during the day with frequent mobilization promotes restorative sleep at night, which brings with it multiple benefits for healing and recovery. Indeed, this ideal may not be physiologically feasible given a child’s critical illness and trajectory, but defining it as the “gold standard” for early mobilization provides a consistent goal for the pediatric intensive care unit (PICU) hospitalization. As such, goal-directed, patient-specific sedation plans are integral to creating a culture of mobility in the PICU.
Sedative and analgesic choices can vary based on practitioner’s preference, fellowship training, individual institutional resources, and limitations, as well as areas of the world.21 Moreover, if a child’s PICU hospitalization is prolonged, the sedation regimen can vary, as different providers are introduced to the PICU care team. The reality of the PICU environment is that nurses change shifts, go to lunch, and take vacation. Attending physicians cover for the afternoon, overnight, and have weekend call. Without a formal method of examining sedation and analgesic needs, the danger is under- or oversedation with the morbidity inherent to these scenarios. Considering the alternatives, a logical standardized written approach to sedating critically ill children is the goal.
There is evidence in the adult and pediatric literature that standardized treatment protocols decrease duration of mechanical ventilation and reduce hospital LOS.22,23 In addition, there are adult studies that go one step further and associate treatment protocols with facilitation of early ambulation.9 However, many PICUs still cling to the practice of heavy sedation despite evidence that it may be detrimental. These concerns about safety and comfort are valid, but need to be balanced with goal-directed sedation plans. Recently, our group examined sedation, sleep promotion, and delirium screening practices for mechanically ventilated children among pediatric intensivists internationally.21 We found that few intensivists use formalized methods for sedation assessment or drug choice and delivery. Only 27% of the participants’ PICUs have written sedation protocols with treatment algorithms. Sedation scoring systems that are used to assess and guide sedation administration are available in most of the respondent’s PICUs, but less than half use them routinely to formulate daily patient care goals. Indeed, 11% of respondents had sedation scoring systems in place but never used them. With regard to delirium assessment, the data are even more concerning despite the contribution of sedative-analgesic medications and sleep disruption to delirium and the implications of delirium for prolonged mechanical ventilation. Only 2% of respondents report consistent delirium screening.
Sedation strategies described in the adult and pediatric literature include sedation interruption and nurse/physician-driven sedation protocols.22,24–26 In theory, sedation interruption involves stopping drugs for a given period of time to reduce accumulation of the drug and increase time spent awake so that there is a decrease in ventilator time, total drug consumed, and LOS. Sedation interruption has been studied more extensively in adults than in children. Pediatric care providers may be more hesitant to stop sedation in children, particularly the younger ages, because of their developmental level and a very real fear of undersedation and inadvertent removal of life-saving devices. However, a few studies have been done that point to the feasibility of this strategy in children with an associated decrease in mechanical ventilation time.25,27–29 Interestingly, Wildschut et al28 looked at interrupting sedation in neonates on extracorporeal membrane oxygenators. This group of patients is usually heavily sedated to prevent accidental decannulation and bleeding as a result of movement. They noted no accidental extubations, decannulations, or bleeding despite median time without sedation being 10.5 hours.
Alternatively, sedation protocols are standardized titration plans or algorithms that are goal directed. These can be physician, nurse, or pharmacist driven. These strategies are based on assessment tools that help adjust drugs to daily goals. The COMFORT scale, State behavioral scale, and Ramsay scale are just a few of the more commonly used instruments. Some institutions have devised their algorithms based on sedation scales that they have developed for use in their own units.23 Regardless of the tool used, it is apparent that these strategies favor less drug, use shorter ventilation times, and decreased ICU LOS in both pediatric and adult populations.22,23,30,31
Clearly, if we are to reap the potential benefits of early mobility in the critically ill pediatric population, we must examine the drugs we use and how we use them. Patients must be awake enough to respond if active engagement in early mobilization is the goal. In terms of initial drug selection and delivery for children with respiratory failure, the majority of intensivists responding to Kudchadkar’s survey preferred an opioid and a benzodiazepine for sedation and more than 80% preferred continuous infusions. The most consistent drug choice was fentanyl and midazolam, although a minority used an opioid alone. For those not using fentanyl, morphine was the drug of choice as was lorazepam for those not using midazolam. There were a minority of respondents who chose an opioid with dexmedetomidine, a benzodiazepine with dexmedetomidine, ketamine with an opioid and benzodiaz-epine, and very few who chose dexmedetomidine alone.
In the following section, commonly used classes of sedatives and analgesics are presented along with their potential role in early mobilization for critically ill children.
The choice of an opioid as one of the front-line choices for sedation is interesting because this class of drug does not have amnestic or anxiolytic properties. Opioids are analgesics. In high doses, they can be sedating but can also cause euphoria or dysphoria. As long ago as 1998, Kollef et al32 reported finding that continuous sedation infusions were independent predictors of increased ICU LOS, hospital LOS, and duration of mechanical ventilation. Presumably, fentanyl in particular is chosen because of its short duration of action, lack of active metabolites, and favorable hemodynamic profile. However, using it as a sedative, especially as the only sedative, could lead to rapid dose escalation as the patient develops tolerance and withdrawal without clear sedative benefits.21 In 2010, Anand et al19 identified several studies that suggest that narcotic withdrawal can occur in up to 57% of PICU patients. Shorter duration opioids, especially remifentanil, have also been implicated in the development of hyperalgesia, which may not be identified as such leading to further dose escalation. This propensity to use fentanyl as a continuous infusion also negates the short duration of action seen after single doses. Continuous infusions or frequent intermittent dosing does increase context-sensitive half-time, so its duration of action increases. In fact, if one examines the context half-life of all synthetic opioids, fentanyl accumulates most rapidly. Morphine as a potential alternative to fentanyl may be a better choice for pain management even with its known association with histamine release and hemodynamic effects. Morphine is inexpensive and has been found to result in less dose escalation, tolerance, and a better withdrawal profile than continuous fentanyl infusions.33,34 In our practice, we advocate for the use of a morphine patient-controlled analgesia for analgesia with a low-dose basal infusion for mechanically ventilated children to alleviate the pain and discomfort from the endotracheal tube without sedation. For the appropriate patient population, this approach enables the child to be awake and alert during the day and participating in activities, while promoting normal day–night cycles and treating pain and discomfort as needed.
Along with fentanyl, midazolam is the most commonly used sedative drug during mechanical ventilation in children. It has a quick onset and short half-life that lends it to be used as a continuous infusion. It provides amnesia, anxiolysis, and sedation but very little, if any, pain relief. Like fentanyl, its half-life increases with frequent dosing or continuous infusion and it has active metabolites that can accumulate in renal failure. Unfortunately, tolerance develops quickly with mid-azolam infusions and it has been implicated as an independent risk factor for the development of delirium.35,36 Benzodiazepines are detrimental to slow-wave or non-REM sleep, leading to sleep disturbances that contribute further to delirium risk.16 Lorazepam is being used in some PICUs as an alternative to midazolam, but there have been no studies comparing the two drugs. It is an intermediate acting benzodiazepine that is recommended for use in the adult population because these infusions require less dosage manipulations, less time for adequate sedation, and have more predictability.37,38 However, lorazepam is not without its own issues. Intravenous lorazepam is potentially toxic because of the diluent propylene glycol that has been shown to cause metabolic acidosis and renal tubular necrosis with long-term or high-dose therapy. Lorazepam has been shown to be an independent risk factor for delirium.36 Therefore, it seems that the very drugs that we are using in an attempt to decrease anxiety can actually worsen outcomes by contributing to delirium. As with any polypharmacy, combining benzodiazepines with other drugs such as opioids may compound the individual effects of these drugs and lead to increased risk of delirium. If children are not able to interact with their environment in a meaningful way, active engagement in early mobilization is impossible. If benzodiazepines are absolutely necessary, passive engagement in mobilization in the bed or chair can still be promoted.
Like the benzodiazepines described earlier, propofol creates a state of amnesia and sedation by interacting with the GABA receptor. At first glance, its rapid onset and offset would make it an ideal sedative and it is widely used in adult ICU. However, its use fell from favor in the pediatric population because of its association with metabolic acidosis, rhabdomyolysis, and heart failure in the 1990s. Prolonged infusions and high doses were implicated in the development of a propofol infusion syndrome that led to fatalities in mechanically ventilated children.39 More recently, propofol infusion syndrome has been described in adult patients as well.40 Because infusions longer than 48 hours and doses greater than 4 mg/kg/h were risk factors for the infusion syndrome, propofol should not be the first-line sedative chosen and would be counterproductive in attempts to mobilize patients. Rather, it could be used in a limited fashion as a short-term sedative for a bridge to extubation or for procedural sedation. Of note, propofol in low doses does promote restorative sleep and a feeling of being “refreshed”; therefore, its use for short-term procedural sedation in lieu of benzodiazepines and opioids may be ideal.41–43
Ketamine deserves mention because it is and has been used both for its sedative and analgesic properties. It was not a front-line drug as outlined by Kudchadkar’s survey on sedation management by PICU intensivists. However, its use in critically ill children has been questioned because of potential neurotoxicity in developing brains by virtue of its effect on NMDA receptors.44–46 Moreover, neurotoxicity has been attributed to combining the effects of NMDA receptor antagonist with GABAergic drugs such as benzodiazepines.20 Although most of these studies are animal studies, it certainly should give us reason to question our widespread use of these classes of drugs. Overall, ketamine’s action as a dissociative agent makes it less favorable, as it induces a deliriogenic state and prevents lucidity, which is critical for optimization of early mobilization efforts.
Over the past 10 years, dexmedetomidine has emerged as a viable option for sedation of critically ill children. Even though its use is limited in many North American PICUs, dexmedetomidine is attractive because of its favorable he-modynamics and lack of respiratory depression.47 Moreover, it has some analgesic as well as anxiolytic and sedative properties and induces an electroencephalogram pattern with characteristics similar to natural sleep which may help decrease delirium development.48–50 Unfortunately, it has been associated with tolerance, withdrawal, and transient adrenal insufficiency, which can limit its long-term effective-ness.51–54 Dexmedetomidine has been used as a rescue medication in children who are on high doses of opiates and benzodiazepines in hopes of decreasing doses of those medications, although this practice may merely add to the polypharmacy without clear benefit. In fact, a recent retrospective study published in Pediatric Critical Care Medicine did not find any opioid or benzodiazepine sparing with the initiation of dexmedetomidine and noted withdrawal symptoms in 30%.55
While it seems that we still have more questions than answers, the current state of the literature favors a standard protocolized approach to sedating critically ill children that is based on clearly identified daily goals through the use of sedation scoring tools. If we examine data gathered concerning PICU intensivists screening practices, it is obvious that pharmacological sedation is a near universal practice but goal-directed sedation with use of screening tools is not. Children present a unique challenge with regard to sedation management and early mobility not found in adult patients. Various ages and developmental levels as well as pharmaco-kinetic and pharmacodynamics differences make standardization difficult but goal setting based on scoring systems imperative. We are especially sensitive to issues of under-sedation with safety concerns and the resultant potential posttraumatic stress disorder. Much less thought is placed on the issues of oversedation which has been shown to increase time on mechanical ventilation and LOS as well as impede attempts at early mobility.
The first step to a logical approach to sedation in children is to separate pain and amnesia/anxiolysis needs. The use of opioids for sedation only leads to escalation of dosages with tolerance. Continuous infusions have also been implicated as a causative factor in the development of opioid tolerance and have been identified as an independent predictor for increased mechanical ventilation time as well as intensive care and hospital LOS.32 Anand et al19 advocate for short-acting opioids for procedural or breakthrough pain with scheduled intermittent doses of long-acting opioids to substitute for infusions. In addition, they underline an important point in discouraging the use of opioids for control of movement.
In 2014, Czarnecki et al56 investigated the use of a parent/nurse-controlled analgesia (PNCA) in the neonatal ICU for pain control and found a significant decrease in opioid consumption in the PNCA group. Many PICUs use PNCAs for treatment of postsurgical pain, but using this modality in nonsurgical mechanically ventilated patients would be a novel approach to analgesia and worth further study.
Addressing analgesic needs is easier than addressing sedative needs. Our present armamentarium of drugs that provide anxiolysis/amnesia is certainly not optimal. With the emerging evidence on neurotoxicity related to NMDA antagonists and GABAergic drugs, neither the benzodiazepines nor ketamine are attractive options. Additionally, the benzodiazepines contribute to delirium, which, if undiagnosed, leads to escalation of therapy. Both midazolam and diazepam have active metabolites and midazolam will accumulate in peripheral tissues only after 24 hours of continuous infusion.57 Lorazepam has no active metabolites, but its diluent is potentially toxic and has been shown to cause delirium. Regardless, if a sedative is needed to achieve a child’s medical goals, the importance of goal-directed titration “start low, go slow” cannot be emphasized enough.
In conclusion, given that the “perfect” sedative and analgesic does not exist for the intubated, critically ill child, it is no wonder that these children are management conundrums. However, it is clear that a streamlined approach through goal-directed sedation protocols or algorithms is necessary to prevent under- or oversedation and related morbidities. Sedation, pain, and delirium assessment tools validated in the pediatric population are available and we must move as a pediatric critical care community to consistently and universally using these resources. Although there is no clear advantage of one protocol over another, the common theme is the need to identify sedation and analgesia needs separately with a team-based decision regarding daily goals. As evidence accumulates in the adult literature that favors early mobility to improve long-term outcomes, it is intuitive that we need to study the effects of early mobilization in PICU patients to identify potential benefits. To that end, optimizing sedation is integral to the successful implementation of early mobilization programs for critically ill children.
Issue Theme Physical Therapy and Rehabilitation in Pediatric Critical Care; Guest Editor: Karen Choong, MB, BCh, FRCP(C), MSc