Wednesday, March 24, 2021

It’s a chemo week for me, and I’m tired. So, I’ll take this opportunity to re-run one of the earliest PAADs that you probably haven’t seen, when I had just 3 subscribers, and they were all from my own family. See you again tomorrow for another exciting Throwback Thursday with Guest Reviewer Myron Yaster.

Ing C, et al. Prospectively assessed neurodevelopmental outcomes in studies of anaesthetic neurotoxicity in children: a systematic review and meta-analysis. Br J Anaesth. 2021 Feb;126(2):433-444.

In the February 2021 issue of BJA, Ing et al. chip away at the mystery of neonatal anesthetic induced neurotoxicity. They performed a systematic review and meta-analysis of published prospective studies to determine whether exposure to a single general anesthetic in early childhood (i.e., less than 3 years of age) is associated with long-term neurodevelopmental problems. The meta-analysis included randomized controlled trials as well as non-randomized studies with prospectively collected neurodevelopmental outcomes. After evaluating over 5,000 potential studies, the authors settled on 3 that met the inclusion criteria and used similar outcome scores. They include the PANDA study, the MASK study, and the GAS study. Although none of these individual studies demonstrated differences in neurocognitive or neurobehavioral outcomes in infants exposed to one short general anesthetic compared with controls, the meta-analysis that combined the data from all three (total of about 800 infants) revealed significant differences in the Full-scale Intelligence Quotient and the Child Behavior Checklist, such that infants exposed to the general anesthetic had higher scores (i.e., worse outcomes).

At first glance, this appears to be a significant contribution to the canon of studies that further our understanding of this enigmatic problem, but it’s not that simple. First of all, meta-analyses are notoriously difficult to perform, let alone understand (as a frequent reviewer for the major journals, meta-analyses represented a relatively large proportion of the studies submitted, and very few were eventually accepted for publication). This one suffers from the same kinds of shortcomings as others - disparate methodologies in each of the studies included for analysis. Furthermore, the lower the number of studies included, the more unreliable the results because bias is relatively high, whereas, differences in methodology from a larger number of studies might “wash out” and improve external validity.

But, despite studies such as this, there are more important overarching questions that interfere with our eventual understanding of the neurotoxicity problem, and will influence how we anesthetize small children to minimize neurotoxicity:

1.     Within what age range is the brain vulnerable to damage from exposure to anesthetic agents?

2.     Which anesthetic agents are responsible for brain damage? Is there a dose-related relationship? Are any anesthetics relatively safer than any others?

3.     What is the duration of exposure that increases the risk of brain damage?

4.     Are multiple exposures riskier than a single exposure?

5.     Does the nature of the surgical intervention make a difference?

6.     What are additional predisposing factors? For example, what role is played by comorbidities that require the child to require surgical intervention in the first place?

7.     What is the role of other anesthetic-related physiological perturbations such as alterations in blood pressure, temperature, glucose, carbon dioxide, prematurity, socioeconomic status, body temperature, or even head position, to name just a few?

8.     What are the specific neurocognitive deficits that are related to anesthetic exposure?

9.     Are there any medications that can be administered or substituted in the perioperative period that will mitigate these adverse effects?

After nearly 20 years of intensive study, definitive answers to all of these questions are still lacking.

In the face of this current uncertainty, anesthesia providers should follow these commonsense recommendations:

1.     Do not perform elective surgery on children of any age. Strictly speaking, there are no purely elective surgeries that we perform in children younger than adolescence. But there are a number of radiological procedures, especially MRI, that on the surface, appear to have no evidenced-based indication. Young children who are scheduled for MRI with sedation or general anesthesia should be carefully screened with input from the child’s pediatrician or neurologist to clarify the true importance for the scan to be performed during early infancy or childhood.

2.     Minimize the duration of exposure to general anesthesia in any one procedure. We all know instances in which the anesthetic exposure time was unnecessarily prolonged when the attending surgeon is finishing a case in another room, or the medical student is taught how to close a wound, or when an inexperienced anesthesia resident is allowed multiple attempts at intubation or IV insertion. That’s not to say that trainees shouldn’t learn on children, but these should be closely monitored and of appropriate duration and attempts. Surgical wait times should be minimized by meticulous planning and organization of multiple procedures by different surgeons. Waiting for the surgeon to finish another child’s procedure in a nearby operating room (or building!) is never appropriate.

3.     Use regional anesthesia whenever possible. There aren’t many surgical procedures performed in young infants that are not amenable to using local anesthesia to reduce intraoperative anesthetic requirements. When feasible, local anesthesia should be used from the outset of the procedure, not just for the purpose of reducing postoperative pain. In an off-shoot of the GAS study, McCann et al. demonstrated that spinal anesthesia for hernia repair resulted in less hypotension when compared with general anesthesia.

4.     Keep all physiologic parameters well within “normal” ranges. Yes, of course I understand that everyone’s definition of “normal” may differ, but in general, be conservative with expectations for indices such as the lowest acceptable intraoperative blood pressure, hemoglobin, glucose level, temperature, and end-tidal CO2 values.

5.     Keep the child’s head in a neutral position. There is evidence that lateral head rotation may diminish blood flow in the jugular veins or carotid arteries. There’s no clinical reason why this can’t be accomplished during a surgical procedure that doesn’t involve one side of the head or neck.