Welcome to PICU Doc On Call, A Podcast Dedicated to Current and Aspiring Intensivists.

I’m Pradip Kamat and I’m Kate Phelps, a second-year pediatric critical care fellow joining Pradip and Rahul today!

I’m Rahul Damania and we are coming to you from Children’s Healthcare of Atlanta – Emory University School of Medicine.

Today we are honored to have Dr. John Berkenbosch- senior author of the Prevention and Management of Pain, Agitation, Neuromuscular Blockade, and Delirium in Critically Ill Pediatric Patients with consideration of the ICU Environment and Early Mobility (PANDEM) guidelines recently published in February 2022 issue of the Pediatric Critical Care journal.

Dr. Berkenbosch is a Professor of Pediatrics and Pediatric Critical Care at the University of Louisville School of Medicine, and continues to be nationally recognized as an expert in pediatric procedural sedation with multiple publications relating to sedation practices, particularly novel uses of procedural sedation medications and regimens. He currently also serves as co-chair for the American College of Critical Care Medicine’s Task Force guidelines for sedation and analgesia in critically ill children which we will be discussing in today’s episode. Dr. Berkenbosch’s research interests have primarily focused on pediatric procedural sedation and implementation of technology advances in Pediatric Critical Care and have resulted in 57 publications as well as several book chapters

Rahul: Dr. Berkenbosch welcome to the PICU Doc ON call podcast. I would also like to point out that the free full access to the PANDEM guidelines is available online at pccmjournal.org

Dr. Berkenbosch: Thanks Rahul and Pradip. I am excited to be on the PICU Doc on Call Podcast to discuss the PANDEM guidelines. I want to first start by giving a huge shout-out to all the team members who contributed to these guidelines’ development. This is a topic about which I am quite passionate but also one that provides much-needed guidance regarding pain/agitation/delirium to our entire pediatric critical care community!

KATE: Dr. Berkenbosch, the rationale for the development of the PANDEM guidelines was the high variability in pediatric sedation and analgesia. Can you speak to this variability and why it was important to address that variability?

That is a great question, the variability has been one of the key motivators in the creation of these guidelines. We also wanted to develop a guideline that was broader in scope than what was currently available. The ICU Liberation bundle provided a paradigm for liberating critically ill patients from mechanical ventilation and the ICU environment and as we delved into developing these guidelines, we realized that many elements of the ICU liberation bundle aligned very closely with PICU sedation and analgesia so it made imminent sense to incorporate all of these topics into the guidelines, an acknowledgment if you will, that PICU liberation & sedation go hand in hand!

Absolutely, as we have stated in our prior episodes, the paradigm is: intubate → ventilate → liberate, and sedation/analgesia is intertwined in each of these processes.

Dr. Berkenbosch, as we get into the guidelines, can you please highlight how the search strategy for these guidelines were derived?

Of course, this was a remarkable group effort solicited by the Society of Critical Care Medicine. We were initially modeled after the adult PAD (pain, agitation, and delirium) guidelines task force but, as described already, extended beyond that to include Pediatric Pain, Agitation, Neuromuscular Blockade, and Delirium in addition to the PICU Environment and Early Mobility. It was comprised of 29 national experts who collaborated over a ten-year period. The full task force gathered annually in person during the Society of Critical Care Medicine Congress for progress reports and further strategizing with the final face-to-face meeting occurring in February 2020, in addition to periodic teleconferences to keep us on track between congresses. Throughout this process, the Society of Critical Care Medicine standard operating procedures Manual for Guidelines development was adhered to.

KATE: Dr. Berkenbosch, what a robust process, what were some research principles you can highlight in the development of this content?

We created a created descriptive and actionable Population, Intervention, Comparison, and Outcome set of questions. An experienced medical information specialist developed search strategies to identify relevant literature between January 1990 and January 2020. Controlled vocabulary was incorporated (such as, “ICUs, Pediatric,” “Critical Illness,” “Ventilators,” “Mechanical”) along with keywords (e.g., “PICU,” “critically ill,” “intubation”) in addition to a sensitive pediatric filter to identify records specific to this population.

Dr. Berkenbosch, as we look into the guidelines, we see the term conditional cited frequently. Do you mind highlighting how this term relates to the strength of recommendation as well as the quality of evidence?

This relates heavily to the available literature addressing each question we asked. Based on the quality of available evidence, recommendations were considered strong where the available evidence made additional data unlikely to alter our recommendations, conditional where we felt that new data might alter recommendations. Where evidence was inadequate to make a formal recommendation but we felt a practice was very low risk and likely beneficial, we made what we referred to as Good Practice statements.

How should a resident or a fellow in training approach these guidelines? There are almost 37 pages worth of content as well as a large very informative supplement.

Add an initial glance, this document can look daunting. We placed a table with all of the recommendations alone at the beginning of the guidelines for quick reference. We also created an infographic, also found near the beginning of the article which graphically shows how all the domains we discuss are related and highlights specific recommendations. We really felt that this diagram put the recommendations themselves into a picture that makes clinical and intuitive sense. Additional discussing guidelines at a Divisional level -especially fellow conferences, examining your institutional practices, etc. may additionally be valuable to aid trainees in unpacking everything.

If you have not checked out our most recent episode, role & reach of the Librarian in Pediatric Critical Care Medicine, please definitely check this out!

Let’s transition and talk about the PANDEM Guidelines: We will divide up the recommendations into broad categories, namely: Analgesia, Sedation, Neuromuscular blockade, ICU delirium, Withdrawal, and Environment Optimization. Let’s start with Analgesia. This Portion of the guidelines addresses The utility of developmentally appropriate pain scores as well as certain analgesics.

What pain assessment tools do the PANDEM guidelines recommend? why not vitals signs as a way to assess postoperative pain in the critically-ill pediatric patient?

Let me start with what we don’t recommend here, that being reliance on vital signs alone. As we all know, vital sign abnormalities are common in PICU patients and these abnormalities can have multiple causes including the underlying medical or surgical reason for PICU admission, medications we use to treat the diseases kids admitted to our PICUs, or pain and/or agitation. Hence, while helpful, vital sign changes are just not very sensitive to pain or agitation. Now to tools. First off, we wanted to recommend the use of tools validated within PICU patients as we discovered literature describing multiple tools, many of which had not been formally validated. As kids’ developmental capacities also change over time, we wanted to make sure that the tools we recommend cover the spectrum of age and developmental capabilities. Ultimately, we came to recommend the use of 4 self-report scales for children over 6 years of age who can communicate their pain and 2 observational scales which cover kids unable to communicate their pain for whatever reason (being intubated, underlying diseases with mental status changes, developmental inability for example). These 2 categories of tools also do not have to be mutually exclusive and can be used concurrently.

RAHUL: As a follow-up, what about non-opioid analgesia – I see a huge push from surgeons to focus more on nonopioid adjuncts, rather than opioid infusions—whereas the PANDEM guidelines say that for moderate to severe pain opioid infusions are recommended (strong):

Thanks for the question – and we agreed with the importance of this question as opioids are not benign drugs for multiple reasons. We extensively evaluated the literature discussing adjunct use of acetaminophen or non-steroidal agents and, in the end, made strong or conditional recommendations supporting the use of both of these agents/classes of analgesics to aid in postoperative analgesia and to decrease opioid exposure. Due to inadequate literature, we were not able to extend these recommendations to patients admitted with medical diseases. Similarly, due to a lack of adequate evidence, we did not differentiate between the use of IV versus enteral formulations of these adjunct medications. Related to this, I think it is important to also mention that the guidelines also address non-pharmacologic adjuncts or interventions that can further aid in pain control. 2 such areas where we were able to make recommendations were the addition of music therapy which is applicable to the entire age range we admit to the PICU and non-nutritive sucking with or without sucrose to aid in analgesia for infants undergoing painful procedures. And I want to make it clear, these non-pharmacologic interventions are adjuncts, and should not be viewed as replacements for analgesic medications – they’re complimentary.

RAHUL: Lets now discuss Sedation:

We noticed that use of a scale to assess the depth of sedation such as comfort-B or state behavioral scale or Richmond agitation sedation Scale received a strong recommendation. What is the rationale for this? How does this help decrease the use of sedatives especially benzodiazepines in the PICU?

So, just as with analgesia assessment tools, we wanted to only recommend sedation scales that have been formally validated, hence the 3 you just listed. While we only made a conditional recommendation for use of the RASS scale, we felt it important to include it as it is the scale used to determine the appropriateness of a patient for delirium screening. These tools allow us as bedside providers to have a more objective means with which to assess patient comfort which should, then, guide when and if patients require additional sedation. This is important as a follow-up to the need for doing periodic sedation screening is our recommendation that each patient has a target level of sedation defined at least once a day. This represents a recognition that the sedation needs of a patient in the PICU change over the course of their disease evolution, perhaps requiring deeper sedation early on when they are at their highest acuity but with needs reducing as they improve and move towards a transition to extubation for example. Deeper sedation may also be required early on to protect lines and devices, especially endotracheal tubes, which may not be as critical or may be removed as the child improves and, again, sedation can be lightened. Without this reassessment, patients run the risk of oversedation or prolonged exposure to sedative medications. As we have also emphasized the value of early mobility, it also stands to reason that sedation targets should lighten as it becomes appropriate to mobilize patients more and more – it’s hard for a deeply sedated patient to do much of this on their own. That said, it is really important for providers to find a proper balance between over-and under-sedation. Over sedation increases the risk of delirium, lengthens time on the ventilator, and limits things like mobility whereas undersedation can, in addition to what we just discussed, contribute to adverse psychological effects which may not manifest until after the child has left the PICU and even the hospital, such as post-intensive care syndrome.

We see that guidelines suggest the use of protocolized sedation although the RESTORE study found no difference between the institutions, which used protocolized vs non protocolized sedation for MV patients?

This is true although data in addition to the Restore trial informed our suggestion to use protocolized sedation. The main advantages of protocolization are that medications can be given or infusions adjusted based on the desired sedation target automatically without calling a physician for every change. In most reports available, including the RESTORE trial, this person was the bedside nurse and this makes the most intuitive sense to me as that is the provider who is most frequently at the bedside and, therefore, has the best idea of what the patient is doing from a comfort perspective throughout their shift. When tied to a target sedation level, protocols also should aid in ensuring that patients are less likely to be exposed to excessive amounts of medications although, as a task force, we certainly recognize that this is a topic for which further study is definitely needed. Related to this, while I think most of us think about sedation protocols being useful during the acute phase of illness while the patient is intubated, we were also able to find a reasonable amount of literature describing the use of protocolized weaning of sedatives and that this practice resulted in more rapid discontinuation of sedative and analgesic infusions without increasing the risk of development of withdrawal syndromes. This allowed us to also make a conditional recommendation for the use of sedation wean protocols.

KATE: Dr. Berkenbosch so no more daily sedation holidays or daily sedation interruptions?

This is a great question. With the increasing desire to limit sedative exposure, for good reasons, there was a lot of early interest in the use of daily sedation interruptions and some of this initial evidence appeared to show promising advantages. However, A more recent and larger multicenter RCT found that adverse outcomes were actually increased in the arm of patients randomized to daily sedation interruptions. Additionally, since so few patients in the protocolized arm of the RESTORE trial required DSI due to oversedation, the use of protocolized sedation seems to be unnecessary as appropriately used protocols can be the mechanism whereby sedative exposure is already minimized.

KATE The guidelines advocate for the use of alpha2 agonists as the primary sedative class in critically ill pediatric patients requiring MV. What are the advantages of using Dexmedetomidine for sedation?

I suspect a lot of your listeners are already aware of the attractive properties of alpha agonists including minimal respiratory depression, mild analgesic effects which can aid in reducing opioid exposure, and they are a class of sedative that, based on EEG studies, facilitate a sedated state that closely mimics that seen in natural sleep. In head-to-head comparisons with benzodiazepines, they are equally efficacious from a sedation perspective. Given increasing data regarding the risk of delirium development with benzodiazepine exposure, these properties all tipped the scales to favor alpha-agonist-based sedation regimens. While some have expressed concerns that bradycardia and hypotension are more common with alpha-agonists, the data available suggested no difference in the occurrence of either event in the need for intervention for drug-related cardiovascular adverse events although the qualifier about the concern with alpha-agonist addition to patients already on heart rate reducing medications remains relevant.

Dexmedetomidine is also recommended as the primary agent for sedation in critically ill pediatric postoperative cardiac surgical patients with expected early extubation. They also recommend the use of dexmedetomidine for sedation in critically ill pediatric postoperative cardiac surgical patients to decrease the risk of tachyarrhythmias.

An important transition period for the critically-ill patient is the peri-extubation period. We see that PANDEM has a bundle approach along with the use of propofol. Dr. Berkenbosch can you give us more information on the approach to sedation/analgesia during the periextubation period.

This is true. To quote the guidelines, “During the peri-extubation period when sedation is typically lightened, we suggest the following bundle strategies to decrease the risk of inadvertent device removal:

a) Assign a target depth of sedation at an increasing frequency to adapt to changes in patient clinical status and communicate strategies to reach the titration goal.

b) Consider a sedation weaning protocol.

c) Consider unit standards for securement of endotracheal tubes and safety plan.

d) Restrict nursing workload to facilitate frequent patient monitoring, decrease sedation requirements, and risk of self-harm.”

I want to be sure that with this recommendation, it is also recognized that restricted nursing workloads may not always be feasible as many areas are experiencing nursing shortages. However, when feasible, the literature supported this addition to the bundle to reduce the likelihood of unintended or accidental extubation.

Given a relative paucity of data, we were only able to make a good practice statement regarding the value of propofol during the periextubation period, specifically suggesting that short term infusions for up to 48 hours may facilitate reductions in other analgo-sedative agents, specifically those that have respiratory suppressing properties to them, prior to extubation and use the short half-life of propofol to then facilitate rapid extubation following its discontinuation.

KATE: After extubation, we are concerned with iatrogenic withdrawal syndrome (IWS). Dr. Berkenbosch what are some of the take-aways from PANDEM regarding IWS?

Quite honestly, this was an area where we struggled a bit outside of some of the obvious.

As with sedation and analgesia assessment, we recommend the use of validated withdrawal assessment tools. However, these tools are only validated for assessing opioid and benzodiazepine withdrawal. This is where I think we struggle a bit since we also suggest the use of alpha-agonist-based sedation but we don’t really have a full characterization of what alpha-agonist withdrawal looks like, nor do we have a validated alpha-agonist withdrawal assessment tool. We also tried to make some concrete suggestions about WHEN to screen as this remains a topic of debate. Based on risk factors identified for withdrawal, we suggest routine withdrawal screening after as little as 3–5 days of drug exposure, especially when higher doses were required. Despite stating above that we haven’t fully characterized alpha-agonist withdrawal, we did feel we should comment on screening for withdrawal. Specifically, and until a validated screening tool is developed, monitoring for alpha-agonist withdrawal should be performed using a combination of associated symptoms (unexplained hypertension or tachycardia) with adjunct use of a validated benzodiazepine or opioid screening tool. Not surprisingly, from a treatment perspective, when withdrawal does develop, it should be treated by replacement, either via the IV or enteral route, with a drug from the class it is deemed that the patient is withdrawing from. We were unable to find any literature describing a formula from which to base the replacement dosing determinations so this, along with the characterization of alpha-agonist withdrawal remain areas that require future investigation.

KATE: Can you comment on medications we can use for patients who are unable to maintain as optimal sedation depth?

Sure, unlike with analgesics, there are several sedative options available beyond the most commonly used ones which include benzodiazepines and alpha agonists. Propofol and ketamine are probably the most commonly used 2nd tier agents. We understand that propofol has many attractive properties and suggest that it can be used as a 2nd tier agent but with important limitations on dose (less than 4 mg/kg/hr) and duration (less than 48 hrs) in order to reduce the risk of propofol infusion syndrome development. While it is true that this syndrome continues to be a source of controversy within the pediatric critical care community, based on the literature available, these limitations are well-supported. Similarly, We suggest that consideration of adjunct sedation with ketamine may be reasonable in patients unable to be adequately sedated with more “conventional” agents.

To summarize, complications of prolonged sedation include prolonged MV, Prolonged PICU stay, Delirium, and iatrogenic withdrawal.

RAHUL: Switching gears to the use of neuromuscular blockade, what do the guidelines suggest with regards to neuromuscular blockade use in the PICU?

This was another area where we as a task force struggled to be able to address all the questions about neuromuscular blockade use we had. The simple reason for this is that, while NMB use remains pretty pervasive in our patients, literature evaluating appropriate indications and/or benefits of their use is extremely limited. We do suggest that if deemed to be clinically necessary, practitioners use the lowest dose required to achieve desired clinical effects and manage undesired breakthrough movement. This may include incomplete muscular blockade. We also suggest that, when used, routine monitoring of the neuromuscular blockade depth be performed to prevent excessive NMB exposure, which may delay the ability to wean sedation and mechanical ventilation. We suggest monitoring blockade depth using train-of-four monitoring unless a strategy of the incomplete blockade is used as the presence of spontaneous movement argues against the excessive blockade. While some have described the use of NMB holidays to prevent excessive blockade, this was an area where available literature was insufficient to allow us to make a recommendation. Related to the depth of blockade is the question of the adequacy of sedation during NMB use. While we suggest that sedation and analgesia should be adequate to prevent awareness, we recognize that assessing this during NMB use is challenging and that this may be one area where reliance on vital signs may play a bigger role. We also suggest that the use of EEG-based sedation monitors might be helpful in this helpful although there is very limited literature regarding their actual application during NMB use in PICU patients. Lastly, We were able to recommend the routine use of passive eyelid closure and eye lubrication for the prevention of corneal abrasions in critically ill children receiving NMBAs.

Let’s wrap up our episode and discuss delirium Dr. Berkenbosch PANDEM recommends routine screening for ICU Delirium using a validated tool in PICU patients upon admission, discharge, and transfer. What tools are we talking about?

I think this is a really important section of the guidelines as I feel that we, as a pediatric critical care community, are still learning to understand the importance of delirium on our population. Just as with pain, sedation, and withdrawal, delirium is amenable to being screened for and we recommend routine screening of EVERY PICU patient at least once a day for delirium using a validated screening tool. At this time, the only validated delirium screening tools available to us in the PICU are either the preschool or pediatric Confusion Assessment Methods for the ICU (PCAM-ICU) and the Cornell Assessment for Pediatric Delirium (CAPD).

KATE: Dr. Berkenbosch: What are some strategies PANDEM recommends to decrease ICU delirium?

As with many adverse ICU outcomes, the first steps in delirium management are to limit modifiable risk factors such as treating the underlying medical disease such as infection/sepsis, hypoxemia, and hypotension, reducing sedative exposure, especially benzodiazepine exposure as the evidence that this is linked to delirium development is quite strong, and promoting a PICU environment as conducive to sleep as possible.

KATE: Any pharmacological strategies if patients are refractory?

One of the concerns we had as a task force was a perception that typical and atypical antipsychotics have become somewhat widely used for a lot of PICU patients with delirium and are used in some settings without working on the steps just discussed. The literature available simply does not support the use of these agents routinely – they do not prevent delirium development and they do not reduce the duration of delirium when used like this. Rather, we suggest that the use of these agents be restricted to that patients with refractory delirium or with severe delirium manifestations which put them at risk for self-injury. If used, due to possible adverse cardiovascular effects, a baseline electrocardiogram should be obtained and be followed by routine electrolyte and QTc interval monitoring.

ICU delirium is defined as acute brain dysfunction with cardinal features of inattention and acute or fluctuating mental status. Predisposing factors include Younger age, developmental delay, cyanotic heart disease, MV, sedative depth and choice are predisposing/precipitating factors. Delirium prolongs ICU/hospital stay and increases the cost of care. A non-pharmacological approach especially with a focus on prevention, optimizing sleep hygiene, family engagement on rounds, and family involvement with direct-patient care is recommended. Routine use of haloperidol or antipsychotics for the prevention or decrease in duration of delirium in critically ill pediatric patients can be used on a case by case basis.

KATE: Especially for delirium, I believe that optimizing the pediatric ICU environment is essential in preventing delirium. Can you comment on what you mean by optimizing the PICU environment?

This is a great portion of our summary table, the optimization of the environment not only focuses on the child’s comfort but also addresses family decision-making and the importance of the multidisciplinary team. One of the conditional recommendations was a suggestion to use a standardized early mobility protocol that outlines readiness criteria, contraindications, and developmentally appropriate mobility activities. Other, More day to day centric Environment recommendations include the use of noise-reducing devices such as earplugs or headphones to reduce the impact of non-modifiable ambient noise.

The overall goal is to focus on the triad of patient, care team, and family in order to optimize outcomes and increased the level of satisfaction with care. Understanding the patient’s developmental status and functional state is essential as we integrate an optimal pediatric ICU environment with regard to sedation and mobility.

RAHUL Dr. Berkenbosch, thank you for your expertise on the PANDEM Guidelines and we greatly appreciate your time as a guest on PICUDOC on-call podcast.

This concludes our episode on Pain, Agitation, Neuromuscular Blockade, and Delirium in critically ill pediatric patients with consideration of the PICU Environment and Early Mobility (PANDEM) Guidelines. We thank Dr Berkenbosch for being the guest expert on our podcast. We hope you found value in our short, case-based podcast. We welcome you to share your feedback, subscribe & place a review on our podcast! Please visit our website picudoconcall.org which showcases our episodes as well as our Doc on Call management cards. PICU Doc on Call is co-hosted by myself Dr. Pradip Kamat, Dr. Kate Phelps, and Dr. Rahul Damania. Stay tuned for our next episode! Thank you!

More information can be found

Smith, Heidi A. B. MD, MSCI (Chair), et. al. Society of Critical Care Medicine Clinical Practice Guidelines on Prevention and Management of Pain, Agitation, Neuromuscular Blockade, and Delirium in Critically Ill Pediatric Patients With Consideration of the ICU Environment and Early Mobility, Pediatric Critical Care Medicine: February 2022 – Volume 23 – Issue 2 – p e74-e110 doi: 10.1097/PCC.0000000000002873

Fuhrman & Zimmerman – Textbook of Pediatric Critical Care Chapters:

Sedation and Analgesia Chapter 1583: Heard CM et al. Page 1583-1610

Neuromuscular Blocking Agents Chapter 1567: Tobias J. Page 1567-1582

Tolerance, Dependency, and Withdrawal Chapter 1611. Tobias J. Pages 1611-1616

Pediatric Delirium Chapter 1617. Traube C et al. Pages 1617-1628

Acute rehabilitation and early mobility in the pediatric intensive care unit. Chapter 69. Lenker H et al. Pages 845-854