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doi: 10.1097/01.anes.0000296717.85521.b5
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Paradoxical Effects of Midazolam in the Very Young

Tobin, Joseph R. M.D.

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MIDAZOLAM is a ubiquitously used benzodiazepine in hospital settings. It is an effective premedicant producing anxiolysis and anterograde amnesia. Although used in infants and children widely, new scientific understanding of the developing central nervous system prompts reevaluation of use of midazolam in the very young. This month’s Anesthesiology highlights ongoing work examining the response of the developing brain to midazolam. In contrast to the well-described effects of midazolam in the adult, Koch et al.1 report that “midazolam dose-dependently decreased mechanical thresholds and increased mechanical and thermal reflex magnitudes” in neonatal rats. The experimental design permitted the conclusion that the differences seen in neonatal rats were mediated supraspinally, and very young rats demonstrated no sedation to midazolam as assessed by latency of the righting reflex.
In their article, Koch et al. examined the effect of midazolam (a positive allosteric modulator of the γ-aminobutyric acid type A [GABAA] receptor) administered to rats in a wide dose range and over an age range from immediate newborn to postnatal day 40, the equivalent in age of an adolescent human. The animals were tested for mechanical withdrawal thresholds, mechanical and thermal reflex threshold size, and level of sedation. In the youngest animals, midazolam elicited a reduced mechanical threshold (greater sensitivity to touch and possibly pain). In the older animals, midazolam had no effect on withdrawal thresholds. The investigators also tested animals using the righting reflex to evaluate the sedative properties of midazolam. The youngest animals (postnatal day 3) were able to right themselves as quickly after midazolam as they did before treatment; however, older animals demonstrated an increased latency to right themselves after midazolam. The youngest animals were not sedated, whereas older animals were as expected.
The current article raises our level of understanding regarding the use of a common sedative (midazolam) in very young rodents. These animals demonstrated either insensitivity or paradoxical effects of midazolam in the youngest animals. These are not common observations (but have been anecdotally reported) in the clinical arena working with human infants. We routinely do see a sedative effect of midazolam even in young children. However, the doses prescribed to sedate a young child might be equal to or greater than what we routinely use in adults as a premedicant to anesthesia. Tolerance also seems to develop rapidly in young children, and dose escalations are common when used as continuous intravenous infusions in intensive care units. The current scientific report may help to explain these observations, which are not in our literature to any great degree.
The developing brain experiences significant and rapid growth and synaptogenesis in the first years of life. The balance of neurotransmitters in the developing brain is not similar to the more mature central nervous system. This period of increased central nervous system activity is associated with a higher propensity of seizure activity and of adaptive neuroplasticity after injury. The effect of any centrally acting drug in developing systems cannot necessarily be predicted by observations in the adult. Recently demonstrated developmental shift in the regulation of the chloride transporters in the rat central nervous system has been suggested to explain the excitatory effects of GABA and GABA-mimetic agents in early life.2
Parallel observations of differing age-associated sensitivity to the volatile anesthetics have been made. In children, minimum alveolar concentration of volatile anesthetics is consistently higher than reported values in adults. Although the volatile agents do not necessarily work by a uniform mechanism of action, the GABAA receptor is likely involved. Is the observation of reduced sensitivity to volatile agents also due to developmental differences in the brain with excitatory activity of GABAA receptors? Is synaptogenesis so robust, or is there a lack of inhibitory activity in the developing brain that underscores these observations? We may now have at least one well-established target to understanding developmental differences noted in our youngest patients.
Developmental pharmacology has been an important theme of scholarship and discussion in the journal over the past many decades. Clinically, doses of midazolam used in infants and children often exceed doses (mg/kg) used in adults, sometimes by many-fold. Infants and children have higher basal metabolic rates and cardiac indices as well as differences in pharmacokinetics for many agents when compared with adults. The application of observations made in adult patients or subjects does not always translate to an anticipated therapeutic effect when prescribing pharmaceuticals to younger patients. With new investigations evaluating agents in developmental models, we are discovering paradoxical effects in contrast to previous work in adult subjects. US National Institutes of Health–funded research applications are required to address issues of developmental and sex-related differences in the proposed research.
Regulatory requirements (US Food and Drug Administration) limit the description of a pharmaceutical agent to its demonstrated “safe and effective” applications. Therefore, when an agent has not been studied in a specific population, no recommendation can be made as to whether the drug may be safely used.
There have been increasing reports of “off-label” use of new, and not so new, pharmacologic agents in children during anesthesia and sedation. These have significant implications for children with whom we work. For example, fentanyl is now used in many institutions via the intranasal route following its initial description.3 Many reports of the introduction of dexmedetomidine use in children were published in 2006. Although we take responsibility for prescribing these drugs and in reviewing the merit of clinical reports in the journal, off-label use is common but unregulated (except in clinical trials research).
The current article provides us with a well-designed trial examining multiple different effects of midazolam, including a generalized sedation evaluation, afferent sensitivity to mechanical stimulation, and integrated responses to mechanical and thermal stimulation. The rodent model poses a great opportunity for us to continue to advance our comprehension of developmental pharmacology. With recent work examining possible widespread neurodegeneration after common anesthetic exposure,4 more work is still necessary. Although clinically useful in isolated doses, should midazolam be evaluated for possibly hypersensitizing preterm and full-term newborns to stimuli? Does the magnitude of possible hypersensitivity increase with continuous use of midazolam as an intravenous sedative in intensive care units? Should midazolam be avoided in the very young? Does the rodent model predict actual responses in humans?
As we acquire new scientific information regarding our pharmaceuticals, we should expect some thoughtful introspection of our practice. Although we believe anesthesia and analgesia are meritorious in young infants, we should be willing to examine scientific information, propose new translational studies, and improve our clinical practice. Rodent and nonhuman primate models will certainly be important in developing new pharmaceuticals and identifying the possible benefits and hazards to our young population. This study is a welcome addition to our current knowledge in developmental pharmacology.
Joseph R. Tobin, M.D.
Departments of Anesthesiology and Pediatrics, Wake Forest University School of Medicine, Winston-Salem, North Carolina. jtobin@wfubmc.edu
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References

1. Koch SC, Fitzgerald M, Hathway GJ: Midazolam potentiates nociceptive behavior, sensitizes cutaneous reflexes, and is devoid of sedative action in neonatal rats. Anesthesiology 2008; 108:122–9

2. Ben-Ari Y: Excitatory actions of GABA during development: the nature of the nurture. Nat Rev Neurosci 2002; 3:728–39

3. Galinkin JL, Fazi LM, Cuy RM, Chiavacci RM, Kurth CD, Shah UK, Jacobs IN, Watcha MF: Use of intranasal fentanyl in children undergoing myringotomy and tube placement during halothane and sevoflurane anesthesia. Anesthesiology 2000; 93:1378–83

4. Jevtovic-Todorovic V, Hartman RE, Izumi Y, Benshoff ND, Dikranian K, Zorumski CF, Olney JW, Wozniak DF: Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci 2003; 23:876–82

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Current Opinion in Anesthesiology
Pediatric pharmacology in the first year of life
Sumpter, A; Anderson, BJ
Current Opinion in Anesthesiology, 22(4): 469-475.
10.1097/ACO.0b013e32832bc7ff
PDF (165) | CrossRef
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