A recent review (DS Fishman, DB Andropoulos, JR Lightdale. JPGN 2019; 69: 3-5) discusses the topic of sedation and an FDA warning from 2016 that should be familiar to pediatric GI physicians. Related blog post (2017): FDA Warning Anesthesia and Developing Brains
The medications which induce an ‘anesthetic state’ may cause cell death and may be “causing some degree of irreversible cellular injury –at least in developing brains, which are particularly vulnerable to apoptosis… [which leads to the] sobering thought that …sedatives could be associated with long-term neurological effects.” At the same time, the authors caution of the potential for the warnings to cause “a delay in the care of the patient.” The authors advocate the following talking points:
- “A single short exposure (~60 minutes) does not appear to cause adverse neurodevelopmental outcomes”
- “There is some evidence that longer (>3 hours) or repeated exposure could have negative effects on behavior or learning.”
Websites for physicians and families:
My take: These FDA warnings need to be taken seriously and low yield/low value endoscopy needs to be avoided.
Park Guell, Barcelona
BG Feagan et al. Gastroenterol 2018; 154: 61-4. In this study of GED-0301 (Mongersen), an antisense oligodeoxynucleotide affecting Smad7, was randomly assigned to 63 patients with Crohn’s disease (160 mg/day). Endoscopic improvement was observed in 37% at week 12. Clinical remission (CDAI<150) was noted in 32% (4 weeks of Rx), 35% (8 weeks of Rx) and 48% (12 weeks of Rx). No new safety signals were noted.
Related blog posts:
PJ Pasricha et al. Gastroenterol 2018; 154: 65-76. First of all, I have to say that I like the visual abstracts in many Gastro studies. In this randomized, double-masked “APRON” study of 126 patients with chronic nausea or gastroparesis receiving Aprepitant, a neurokinin-1 receptor antagonist, or placebo, the key findings were the following:
- Aprepitant did not reduce symptoms of nausea significantly compared to placebo
- Apreptiant-treated patients had improvements in secondary outcomes of symptom severity for nausea (1.8 vs 1.0, P=.005 on Gastroparesis Clinical Symptom Index) and overall symptoms (1.3 vs. 0.7, P=.001)
Related blog post:
B Bielawska et al. Gastroenterol 2018; 154: 77-85. Using data (administrative databases) and propensity matching from more than 3 million outpatient colonoscopies (2005-2012), the authors noted that the use of anesthesia assistance (AA) was associated with an increased risk of aspiration pneumonia (OR 1.63) but not perforation (OR 0.99). Though this study is limited by its retrospective design and reliance on administrative data, the authors state “the potential for residual confounding by indication for AA [is] extremely unlikely, especially because AA use in Ontario appears to be driven by institutional policy or business model rather than by patient factors.”
Related blog posts:
Bright Angel Trail
A good review on the issue of anesthesia and the developing brain: DB Andropoulos, MF Greene. NEJM 2017; 376: 905-7.
The authors from Texas Children’s Hospital comment on the prior studies and how their approach has changed since the FDA on December 14, 2016 issued a “Drug Safety Communication” (www.fda.gov/Drugs/DrugSafety/ucm532356.htm). The FDa warning targets anesthesia in children less than 3 yrs of age and pregnant women in the 3rd trimester who undergo anesthesia for >3 hrs.
At Texas Children’s, the authors state that the FDA warning is now discussed with parents of all children younger than 3 yrs receiving an anesthetic. The authors, however, worry that the “FDA warning will cause delays for necessary surgical and diagnostic procedures.”
A new study provides some reassurance that anesthesia at a young age is unlikely to cause harm (little to no effect) in most children.
Full text: P Glatz et al. JAMA Pediatrics, Published online November 7, 2016. doi:10.1001/jamapediatrics.2016.3470: Association of Anesthesia and Surgery During Childhood with Long-Term Academic Performance
Findings In this cohort study among 33 514 exposed children, exposure to surgery with anesthesia before age 4 years was associated with 0.41% lower school grades and 0.97% lower IQ test scores, with no difference in school grades with regard to age. The overall difference was markedly less than the differences associated with sex, maternal educational level, or month of birth during the same year.
Comment: Despite efforts to control for indications which of themselves could impact the results, it is quite possible that the small changes detected in this study are a result of confounding factors rather than due to the anesthetic itself.
My take (from the authors): “Exposure to anesthesia and surgery before age 4 years is associated with a small difference in academic performance or cognitive performance in adolescence on a population level. The magnitude of this association should be interpreted in light of potential adverse effects of postponing surgery.”
Related blog post: More evidence of anesthetic neurotoxicity
One of the more troubling commentaries that I read recently (Rappaport BA et al NEJM 2015; 372: 796-97) provides additional insight into the issue of anesthetic neurotoxicity.
The possibility that anesthetic agents could result in learning disabilities and other neurologic impairments is not new (Pediatrics 2011); however, the data has become more concerning.
- “Compelling evidence from animal models is supported by a small number of observational studies in children who underwent anesthesia early in life.” Exposure to multiple (but not single) episodes of anesthesia and surgery were associated with increased risk of learning disabilities.
- Anesthetics which have been implicated include propofol, ketamine, sevoflurane, etomidate, desflurane, and isoflurane. Histologic changes, in animal models, have included apoptosis and cell death, changes in neuronal morphology, and decreased number of synapses.
- “In June 2014, SmartTots convened a meeting…the participants concluded that the current data from animal studies are now sufficiently convincing that large-scale clinical studies are warranted.” SmartTots Consensus Statement
- “Care providers should be made aware of the potential risks that anesthetics pose to the developing brain…and parents should consider how urgently surgery is needed, particularly in children under 3 years of age.”
Take-home message: While recognizing that confounding variables make it difficult to be certain, it appears that anesthetics (particularly prolonged or repeated courses) can result in neurologic changes. There is enough information available to recommend avoiding truly elective procedures which require anesthetics in young children.
According to a recent study highlighted in Gastroenterology & Endoscopy News, gum chewing immediately prior to anesthesia is probably safe.
Here’s an excerpt:
Patients who are fasting before upper endoscopy can safely chew gum up until the time of the procedure, researchers have found…
The prospective randomized controlled study evaluated the effect of gum chewing on volume and pH of gastric contents in 67 patients scheduled to receive IV conscious sedation for upper endoscopy. The night before the procedure, patients were randomly assigned to chew gum until the start of sedation…—or to not chew gum, with no limit on the number of pieces or how long they could chew.
The median volume suctioned from the gum chewers was 13 mL, compared with 6 mL for non-gum chewers. Similarly, gastric fluid also was greater for gum chewers—0.35 versus 0.11 mL/kg for patients who did not chew gum. “The 0.35 mL/kg is still under 0.4 mL/kg, which is where the risk for aspiration comes into effect,” he noted…The pH also did not change.
Take-home message: While this study provides some reassurance, I suspect that asking families to give nothing before an endoscopy will be easier than trying to explain the nuances and risks for aspiration. For those who have only had gum, though, it may not be necessary to cancel their case.
From Atul Gawande’s Twitter Feed
A New Yorker article by Atul Gawande highlights the importance of spending time and talking about good ideas on a person-to-person basis as the best way to help innovations take hold. Specific innovations that are discussed include the introduction of anesthesia, the control of germs/Lister’s theories of sepsis, adoption of oral rehydration solutions, and preventing hypothermia in newborns. The link to the article and a brief video review on the Colbert report:
Quite possibly (J Pediatr 2012; 160: 409-14).
There have been recent reports that surgery in preterm and even term infants can affect neurodevelopmental outcomes. This report, which looked at infants born at <30 weeks or birth weight of <1250 g, adds more information in this area. The surgery group (n=30) had more white matter injury on MRI and lower developmental scores at 2 years than the nonsurgical group (n=178). Infants requiring bowel surgery had the worst outcomes. The exact reasons for these outcomes and the significance are unclear, in part due to the small number of infants with bowel surgery. Potential factors include inflammatory mediators/cytokines, and anesthesia effects.
The article notes that the FDA has issued warnings regarding anesthetic use in neonates and young children. These agents may cause abnormalities in the developing brain, particularly in the thalamus.
This study has a number of limitations including the lack of preoperative comparative imaging studies. Nevertheless, despite unresolved issues regarding causality, it is clear that infants who have necrotizing enterocolitis remain at high risk for poor neurodevelopmental outcomes.
- -Anesth Analg 2007; 104: 509-20. Anesthetics in neonates and young children.
- -J Pediatr 2008; 153: 170-5. Adverse neurodevelopmental outcomes in infants with sepsis or NEC.