@phdthesis{01JX25F3ZCD9A20FNXZGZKR9QT,
  abstract     = {{Summary
Gamma-hydroxybutyric acid (GHB) has been widely used in human medicine for its sedative
and sleep-enhancing properties, with additional research in animals highlighting its tissue-
protective effects. Recent trends in veterinary anaesthesia, particularly the shift towards total
intravenous anaesthesia and a lower reliance on volatile anaesthetics, have increased the
demand for safe, effective alternatives that support stable sedation or anaesthesia with minimal
cardiorespiratory impact. Revisiting older drugs like GHB, which has well-documented effects
in humans, may offer new opportunities to meet these evolving needs.
Despite its established utility in human medicine, GHB has seen limited exploration in
veterinary contexts. Previous studies in animals have suggested that large doses may be
required for sedation, and certain species exhibit seizure-like effects, which may have
discouraged further research. However, critical knowledge gaps remain for livestock species
such as pigs and calves, which have yet to be studied. This thesis provides a foundational
exploration of GHB in pigs and calves, focusing on its pharmacokinetics (PK), sedative
efficacy, and safety. Understanding GHB’s PK, safety, and efficacy in these animals is
particularly relevant given the frequent need for sedation or anaesthesia in research and clinical
settings and may lay the base for considering its use for broader indications.
Chapter I provides an introduction and overview of GHB’s biochemical, neurophysiological,
and pharmacological properties, as well as its historical and clinical uses in human medicine.
The chapter highlights its unique features, including minimal effects on respiratory and
cardiovascular function, its ability to enhance sleep depth, and its tissue-protective qualities.
Additionally, the mechanisms of GHB’s action, such as its interaction with GABA-B and
specific GHB receptors, are discussed, as are its nonlinear PK profiles observed in previous
studies. While research is available on some of these aspects in small animals, the chapter
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underscores the significant gaps in understanding GHB’s PK and sedative efficacy in large
animal species, particularly livestock.
Chapter II outlines the primary aim of this thesis: to address these knowledge gaps by
investigating the PK, efficacy, and safety of GHB in pigs and calves. This research is intended
to lay the groundwork for assessing GHB’s feasibility as a sedative in veterinary medicine,
with a specific focus on its potential application in TIVA protocols for clinical and research
purposes.
Chapter III examines the PK of GHB in pigs following intravenous and oral administration.
Building on findings from previous pilot studies, a crossover study involving six pigs was
conducted, where SOGHB was administered at doses of 500 mg/kg IV and 500 mg/kg and 750
mg/kg orally. Oral GHB demonstrated poor bioavailability (45%), likely due to significant
first-pass metabolism and limited absorption, with peak whole blood concentrations reached
approximately 1.5 hours post-administration. No indications of nonlinear PK were observed,
suggesting the metabolism was not saturable. However, more extensive research is needed to
confirm this finding.
Following IV administration of 500 mg/kg, only one animal displayed signs of deep sleep,
which was somewhat unexpected based on the pilot study results. Other animals exhibited
agitation, restlessness, and ataxia. This apparent inter-individual variability left the study
unable to fully evaluate the quality of sedation, underscoring the challenges of achieving
consistent sedative effects in pigs and highlighting the need for further investigations to refine
GHB's application in this species.
Chapter IV investigates the cardiorespiratory effects of GHB in pigs during isoflurane
anaesthesia, focusing on its safety and compatibility with volatile anaesthetics. Building on the
findings of Chapter III, where inconsistent sedation and agitation hindered the assessment of
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vital parameters, this study was conducted in a controlled environment under general
anaesthesia to gain deeper insights into the physiological effects of GHB and to evaluate its
safety when combined with volatile anaesthetics.
In a crossover design, six pigs were administered 250 mg/kg GHB intravenously as a bolus
over 5 minutes, with saline serving as the control. GHB administration resulted in a mild but
significant increase in mean arterial pressure (MAP), indicating its potential to counteract
anaesthesia-induced hypotension. Arterial oxygen levels decreased slightly, and carbon
dioxide levels showed a modest increase, suggesting minor respiratory depression.
These findings suggest that GHB can be safely combined with a standard anaesthetic protocol
for inhalant anaesthesia in pigs, providing haemodynamic benefits and demonstrating its
compatibility with general anaesthesia. However, the results also highlight the need for careful
monitoring during spontaneous ventilation to ensure safety.
Chapter V explores the sedative efficacy of GHB in calves, shifting the focus from pigs to a
species with distinct clinical potential. A dose-escalation study assessed the effects of
intravenous GHB at doses of 100, 150, and 200 mg/kg in Holstein-Friesian calves. The results
demonstrated predictable and dose-dependent sedation at 150 and 200 mg/kg, with calves
achieving lateral recumbency within 8–10 minutes and remaining sedated for 189 ± 41 and 283
± 29 minutes, respectively. However, the sedation was insufficient for clinical handling, as
responses to noxious stimuli were only partially diminished, and occasional strong motor
reactions, including myoclonic jerks, were observed, posing possible safety challenges during
clinical or experimental procedures.
Pharmacokinetic analysis revealed that GHB in calves had a longer elimination half-life (~4.2
hours) and slower clearance (~106 mL/kg·h) compared to pigs, potentially contributing to more
sustained sedation. The cardiorespiratory effects were overall mild, with MAP, HR, and PaCO₂
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remaining within acceptable ranges. However, mild respiratory depression suggested that
supplemental oxygen or ventilatory support might be prudent during prolonged recumbency
when using GHB.
This chapter demonstrated the potential of GHB as a sedative in calves while highlighting its
limitations as a standalone agent, particularly due to incomplete analgesia and the occurrence
of erratic motor responses. Further research into combining GHB with other sedatives or
analgesics is recommended to improve its safety and effectiveness in veterinary clinical
applications.
In general, the findings of this thesis provide valuable insights into the potential of GHB as a
veterinary sedative, highlighting both its promise and the challenges associated with its use.
While GHB demonstrated significant interspecies differences, its unique properties—such as
haemodynamic stability and prolonged sedative effects—offer avenues for further exploration,
particularly in species where sedation is currently limited by the drawbacks of existing agents.
In pigs, GHB exhibited challenges such as inconsistent sedation and low oral bioavailability,
suggesting that alternative dosing strategies, such as continuous rate infusion (CRI), might be
necessary to achieve reliable effects. Conversely, in calves, sedation was more predictable and
dose-dependent, with prolonged durations. However, the lack of analgesia and occasional
motor responses limit its use as a standalone agent, particularly for invasive procedures. These
interspecies differences were further underscored by PK variations, with calves showing longer
drug persistence, likely contributing to their more consistent sedative response compared to
pigs.
The haemodynamic stability observed in both species positions GHB as a promising adjunct in
anaesthetic protocols, particularly in mitigating anaesthesia-induced hypotension. However,
respiratory effects, including mild respiratory depression, warrant closer monitoring. Further
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studies comparing GHB with other commonly used sedatives, as well as exploring its use in
combination protocols, are essential to evaluate its relative safety and efficacy. Integrating
GHB into multimodal protocols, potentially alongside agents like midazolam, phenothiazines,
or opioids, could enhance sedation quality, reduce excitatory responses, and address its
limitations.
Conclusion
This research highlights that GHB’s potential in veterinary medicine has likely been
underestimated. While it is unlikely to replace mainstream anaesthetics, its unique
pharmacological profile offers targeted applications, particularly in species like calves, where
sedation was both predictable and prolonged. However, challenges such as inconsistent effects
in pigs, lack of analgesia, and mild respiratory depression underscore the need for refinement
before broader application.
By revisiting this underutilised drug with updated protocols, including combination approaches
and alternative dosing strategies, GHB could play a valuable role in advancing veterinary
anaesthesia practices. This thesis provides a foundation for further research into GHB’s
feasibility as a component of TIVA protocols, contributing to the broader goal of improving
safety, sustainability, and efficacy in veterinary anaesthesia. Future studies should aim to refine
its use, explore its broader therapeutic potential, and ultimately establish its place within modern veterinary practice.}},
  author       = {{Cuypers, Charlotte}},
  language     = {{eng}},
  pages        = {{204}},
  publisher    = {{Ghent University. Faculty of Veterinary Medicine}},
  school       = {{Ghent University}},
  title        = {{Gamma-hydroxybutyric acid : are we sleeping on it?}},
  year         = {{2025}},
}