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Literature Reviews:
The effects of dexmedetomidine
on cardiac
electrophysiology
in children.

Hammer GB, Drover DR, Cao H, Jackson E, Williams GD, Ramamoorthy C, Van Hare GF, Niksch A, Dubin AM.
Anesth Analg. 2008 Jan;106(1):79-83

Dexmedetomidine for sedation during electroencephalographic analysis in children with autism, pervasive developmental disorders, and seizure disorders
Ray T, Tobias JD.
J Clin Anesth. 20 (5) 364-8, 2008

Clinical uses of dexmedetomidine in pediatric patients
Phan H, Nahata MC, Clinical uses of dexmedetomidine in pediatric patients.
Pediatric Drugs
10(1) 49-69 2008

Pediatric procedural sedation with ketamine: time to discharge after intramuscular versus intravenous administration.
Ramaswamy P, Babi RE, Deasy C, Sharwood LN.
Academic Emergency Medicine
2009 16:101-7.

 

 

 

 

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Literature Reviews

Paper #1

Dexmedetomidine (DEX) use is increasing for procedural sedation of children.  In the collected literature concerning its use in pediatric sedation, DEX appears to be effective and relatively safe for this purpose.  Debate continues as to the importance of some of the side effects that are noted with the use of this agent – notably bradycardia and some hyper/hypo-tension.

For this edition of the newsletter, we are once again reviewing the use and some of the possible side effects of dexmedetomidine when applied in children for procedural sedation.  The first article tries to shed some light on the often noticed tendency for DEX to decrease heart rate in sedated children:

Hammer GB, Drover DR, Cao H, Jackson E, Williams GD, Ramamoorthy C, Van Hare GF, Niksch A, Dubin AM. The effects of dexmedetomidine on cardiac electrophysiology in children. Anesth Analg. 2008 Jan;106(1):79-83

Abstract Exerpted:

Introduction: The authors begin with a description of dexmedetomidine (DEX) as an alpha2-adrenergic agonist that is approved by the Food and Drug Administration for short-term (<24 h) sedation in adults. They note that at the time of this publication it had not been approved for use in children. In spite of this fact they point out that the use of DEX for sedation and anesthesia in infants and children appears to be increasing. They note that there have been some concerns regarding the hemodynamic effects of the drug, including bradycardia, hypertension, and hypotension. While some reports of the bradycardia present with DEX sedation are available, there is really no data specifically regarding the effects of DEX on the cardiac conduction system. They aimed to characterize the effects of DEX on cardiac conduction in pediatric patients.

Methods: Twelve children between the ages of 5 and 17 yr undergoing electrophysiology study and ablation of supraventricular accessory pathways had hemodynamic and cardiac electrophysiologic variables measured before and during administration of DEX (1 mcg/kg IV over 10 min followed by a 10-min continuous infusion of 0.7 mcg x kg(-1) x h(-1)).

Resuts: Heart rate decreased while arterial blood pressure increased significantly after DEX administration. Sinus node function was significantly affected, as evidenced by an increase in sinus cycle length and sinus node recovery time. Atrioventricular nodal function was also depressed, as evidenced by Wenckeback cycle length prolongation and prolongation of PR interval.

Conclusion: DEX significantly depressed sinus and atrioventricular nodal function in pediatric patients. Heart rate decreased and arterial blood pressure increased during administration of DEX. The use of DEX may not be desirable during electrophysiology study and may be associated with adverse effects in patients at risk for bradycardia or atrioventricular nodal block.

Commentary: 

Really nothing earth shattering or new here.  Slowing of heart rates has been noted in a number of studies in children taking DEX (1).  This is particularly true if the drug is given to children who are on digoxin. The unique part of this paper is the detail in which the authors are able to describe the electrophysiological changes.  There appears to be effects both on the SA node and the AV conduction system. Some tendency toward hypertension is similarly not surprising and has been previously reported.  This is thought to be due to peripheral agonism of the alpha one receptors.  Over time this effect is overcome by the effect of agonism at the alpha two receptors centrally.  Higher dose regimens are well known to cause more significant bradycardia in a small but not insignificant percentage of patients and hypotension is also noted – although generally not severe. (2) Most often no specific therapy is needed in these cases.

Unfortunately the most interesting question regarding the electrophysiological effects of DEX remain to be answered.  Should we worry about bradycardia when it occurs in the setting of a drug known to slow heart rates vs. episodes of severe illness or hypoxia? Future work should focus on the measures of general well being that could be measured during induced bradycaria – such as blood gases, blood flow, cerebral oxygenation etc.  that could better help us to understand the impact of bradycardia on patients.  While we wait for these studies it would seem very prudent to avoid DEX in patients where bradycardia is a risk – such as those patients with any degree of heart block or those on medications that could predispose to bradycardia such as digoxin.

References:

  1. Berkenbosch JW, Tobias JD. Development of bradycardia during sedation with dexmedetomidine in an infant concurrently receiving digoxin. Pediatr Crit Care Med 2003;4:203-5.

  2. Mason KP, Zgleszewski SE, Prescilla R, Fontaine PJ, Zurakowski D. Hemodynamic effects of dexmedetomidine sedation for CT imaging studies. Paediatr Anaesth 2008;18:393-402.

Paper #2

EEG's have proven to be a particularly difficult procedure for which to design appropriate sedation.  In 2008 we saw some indication that DEX may offer some help in this regard.

Ray T, Tobias JD. Dexmedetomidine for sedation during electroencephalographic analysis in children with autism, pervasive developmental disorders, and seizure disorders. J Clin Anesth. 20 (5) 364-8, 2008

Abstract Excerpted:

Introduction: The authors sought to assess the efficacy of dexmedetomidine in providing sedation during electroencephalographic (EEG) analysis in children with autism, seizure disorders, or pervasive developmental disorders (PDDs).

Methodology: The charts of 42 children, aged two to 11 years, who received dexmedetomidine for sedation during EEG analysis, were studied. Information collected included route of administration of dexmedetomidine (oral and/or intravenous [i.v.]), loading dose, and infusion rate. Heart rate, blood pressure, respiratory rate, and level of sedation were monitored every 5 minutes, and oxygen saturation was monitored continuously during the procedure. Interventions (administration of fluid or use of an anticholinergic agent) for hypotension or bradycardia were identified.

Results: 18 children received oral dexmedetomidine (range, 2.9-4.4 microg/kg) before placement of an i.v.. Forty patients received an i.v. loading dose of dexmedetomidine (2.1 +/- 0.8 microg/kg), which was given in increments of 0.5 to one microg/kg every three to 5 minutes until a sedation score of 3 to 4 was achieved. Effective sedation was eventually achieved in all patients. An i.v. infusion of dexmedetomidine was started (1.5 +/- 0.2 microg kg(-1) hr(-1)) in all patients. During performance of the EEG, adjustments in the infusion rate (increase or decrease) or additional bolus doses were necessary in 25 patients. No significant hemodynamic or respiratory effects were noted.

Conclusions: Dexmedetomidine provides effective sedation during EEG analysis in children with autism or PDD.

 Commentary:

There is no question this paper suffers from all of the issues that a retrospective analysis will suffer.  There is no control group and we are unsure that this methodology will work for all providers. Despite all of its limitations, we appreciate reports and discussion of sedation for autistic children – a subgroup of our patient population that offers extreme challenges and receives little specific attention in most sedation studies.

It is important to note that DEX appears not to interfere with EEG reading. Readers should note the wide variety of doses used to achieve sedation and the relatively large doses of IV DEX required to induce sedation.  In this case the authors titrated the induction dose to achieve desired sedation.  The recommended time for the bolus of DEX is 10 minutes – these authors describe bolus doses given every 3-5 minutes with a max dose of almost 3 mcg/kg (total).  These bolus doses were the same whether or not an oral dose of the medication was given prior to IV placement. It is interesting to note that the manner in which this drug is given and the total dose that is given are clearly evolving as we encounter more and more of the reports of its usage.  Clearly larger doses than those generally used in adults are required to achieve adequate sedation in many children.  It is also important to note that the time frames involved in achieving sedation are at times as long as 70 minutes in this review – a fact that must be taken into account if one is trying to run an efficient sedation service.  The sedation system must be built with longer (and variable) times to sedation appreciated – especially for this patient population.


Paper # 3

For those looking for a fairly extensive review of the literature and uses of DEX, I would refer you to the excellent article by Phan and Nahata.

Phan H, Nahata MC, Clinical uses of dexmedetomidine in pediatric patients. Pediatric Drugs 10(1) 49-69 2008

Commentary:  This review article has something for almost everyone.  It begins with a nice review of many of the drugs that are commonly used for procedural sedation in pediatrics. The authors then review the pharmacology of Dexmedetomidine as well as the best known data on pharmacokinetics.  There is a balanced presentation of the advantages (lack of respiratory depression, favorable onset and recovery time) and the potential issues related to cardiovascular changes such as bradycardia, hypertension/hypotension. The paper is then divided into several sections, beginning with use of the drugs in an intensive care unit including situations such as burn care and cardiothoracic care. There is an extensive section on the use of DEX for radiological studies including the relatively few that have compared the drug with other sedatives such as midazolam and propofol. This is followed by a section on the use of DEX as a sedative for pre-anesthetic sedation – this allows some discussion of the use of oral DEX.  There is also a discussion of the use of DEX for invasive procedures. Finally, there is some review of the literature concerning the use of DEX during anesthesia to decrease emergence agitation and shivering in the postoperative period.

Unfortunately, the literature on DEX is evolving at a rate that makes this review somewhat out of date even now, just months after its publication.  Still, this is a worthwhile review that includes an extensive review of the literature concerning DEX use in children. It also presents the information in a balanced manner that allows the reader to interpret the appropriate use of the drug for him/herself.


Paper #4

We end with a switch away from our DEX articles to some new information on the usage of ketamine for pedatric sedation. There has been relatively little information on the relative efficiency and effectiveness of IV vs. IM Ketamine for procedural sedation in children.  A recent paper has compared these methodologies with results that are fairly consistent with the little previous data that has been published.

Ramaswamy P, Babi RE, Deasy C, Sharwood LN.  Pediatric procedural sedation with ketamine: time to discharge after intramuscular versus intravenous administration. Academic Emergency Medicine 2009 16:101-7.

Abstract Excerpted:

Objectives: The authors propose that there is limited data comparing intramuscular (IM) vs intravenous (IV) ketamine.  Their objective with this study was to determine which mode of delivery resulted in a quicker time to discharge from the emergency department when the drug was used for procedural sedation in this setting.

Methods: The authors reviewed the records on all patients who had received Ketamine IM or IV at their tertiary care children’s hospital ED during the period from 2004-2007.  Prospective sedation registry data, retrospective medical records, and administrative data were reviewed for drug dosages, use of additional agents, time of drug administration to discharge, total ED time and adverse events.  A subgroup of patients who received only a few stitches was also identified to see how the drugs performed for very minor procedures.

Results: 229 patients were enrolled with a median age of 2.8 years (1.8-4.3 years) and median weight of 15.7kg. Ketamine was most frequently used for laceration suture (80%), and foreign body removal (9%).  In this analysis, 48% received IM Ketamine and 52% received IV ketamine.  Multivariate linear regression analysis determined time from drug administration to patient discharge was 21 minutes shorter with IV Ketamine administration. Total time in the ED was not significantly different.  In the short suture subgroup, time discharge from administration was also shorter in the IV group (p,.001) but total time in the ED was once again not significantly different.  Overall adverse events were noted in 35% of the IM group and 20% of the IV group. Only one patient required brief bag-mask ventilation. 

Conclusions: Time to drug injection to discharge was shorter in the IV compared to IM Ketamine groups – for standard procedures and short procedures.  Overall time in the ED was similar.

Commentary:

As always, we applaud the effort that these sedation investigators are making in their attempt to explore the details of efficiency and safety of their sedation practice. However, several pitfalls should be taken into consideration when considering the conclusions of this study.

1) Some of the data collection in this study was prospective – a significant portion of the outcome data was retrospectively collected and the study does suffer from all of the difficulties in accuracy that this type of study invariably presents.  Hopefully, this bias is spread equally across groups.  In addition, this was not a randomly assigned group of patients. Once again, it is not clear if decisions as to what route of administration were chosen could have been biased by the condition of the patient. 

2) There is also the issue of subsequent doses of medication – the route of which and the criteria for which was left completely up to the sedation provider.  In fact, most of the patients who received IM Ketamine had additional doses given by the IV route.  This was not a pure IV vs. IM comparison.

3) The sedation was considered adequate if the “procedure could be completed”.  As we have noted previously in this newsletter, while this endpoint is certainly the easiest we know of to define, it leaves a lot of doubt as to exactly how well the sedation met the goals of the proceduralist.  Was the child screaming and crying during the procedure or was the child quiet and holding still?  We plead with sedation investigators to use more specific measures of sedation outcome than were presented here.

4) “Adverse events” is used to describe any event from oxygen desaturation below 90% to laryngospasm to vomiting post procedure.  We would propose that these adverse events are not created equal. It would be nice to separate out the REALLY concerning outcomes from the less concerning issues in order to understand which of the delivery methods raises the most concern.  We note once again the relatively high rate of emesis (approximately 15%) in the combined study population.

5) The issue of “total time in the ED” is difficult to completely evaluate.  While patients were discharged more quickly after IV delivery, they spent the same amount of time in the ED in total.  This implies that there was a greater time from admission to the ED to receiving Ketamine.  Was this delay due entirely to difficulty in obtaining IV access, or to the fact that issues regarding flow and protocol in this ED did not allow efficient IV access for children?  This brings up the larger issue of “appropriate outcomes” in studies such as this.  Clearly there are many ED’s that use IM routes of administration strictly because they prefer not to attempt to start IV’s on small children if they do not absolutely need to. We are not sure if this measure (total time in ED) helps to differentiate the two methods of ketamine delivery as much as it merely tells us the manner in which this ED handles patients.  A prospective study that standardized this process would be helpful in this area. 

Having pointed out these issues, it is reassuring that the findings of this study concur with previous relatively small prospective randomized studies that found a faster time to discharge after IV ketamine delivery when compared to IM dosing.

Thanks and we look forward to your feedback.

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Editors:
Joseph Cravero MD
George Blike MD

Departments of Anesthesiology
and Pediatrics,
Children’s Hospital
at Dartmouth
,
Dartmouth Hitchcock
Medical Center,
Lebanon, NH

Circulation
4610 estimated

 


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