Reducing induction stress in the Australian feedlot sector

Induction stress and subsequent adverse health impacts are well documented in the beef cattle feedlot sector. Despite the best efforts of feedlot managers, stress and associated health problems remain as a major economic cost in the industry. Bovine respiratory disease is the most common animal health problem in the feedlot environment, costing the Australian beef feedlot industry
approximately 40 million dollars per annum. Increased levels of stress during transition into the feedlot have been associated with an increased likelihood of the disease. Despite management strategies including backgrounding, low-stress handling, transition diets, and vaccination schedules, the prevalence of bovine respiratory disease remains a significant problem in Australian feedlots.
Bromide has been recognised in recent years as a potential therapeutic agent for ruminant livestock systems, with international patents awarded for its use as a therapeutic agent for tremorergic intoxications and for stress.
Bromide, as a known anxiolytic and pan-neuronal inhibitor, has been demonstrated to have GABAergic activity and to reduce activity in the central amygdala; both important mechanisms for mitigation of the stress response. Additionally, a long elimination phase and wide therapeutic window make bromide a suitable candidate for minimising stress during and after many management and husbandry practices on farms and feedlots, and in transport settings.

Previous research has investigated the use of bromide as a sedative in cattle (Genicot et al. 1991), and it has been widely used as a calmative agent in horses (Ho et al. 2010). Our research has previously focussed on its use in sheep, with pharmacokinetic and efficacy studies being undertaken, outcomes of which have supported the use of bromide in other ruminant livestock systems (Quast et
al. 2015b; Combs et al. 2019). Although both species are ruminants, pharmacokinetic profiles are expected to differ between sheep and cattle, as is the case between sheep and horses (Raidal and Edwards 2008), and similar to other pharmacological agents frequently used in production livestock such as lidocaine and macrocyclic lactones. For this reason establishing the pharmacokinetic parameters of bromide in cattle is required before further applied research can be undertaken. Serum concentrations of
bromide have previously been reported in cattle at varying dietary bromide inclusion rates (Knight and Costner 1977), but many pharmacokinetic parameters of importance were omitted. The long elimination phase of bromide makes it a potential candidate for use in feedlots where induction
stress is high, but interventions are kept to a minimum. It was anticipated that stress amelioration during feedlot induction and the transition phase will reduce the likelihood of morbidity and mortality in feedlot cattle and therefore increase productivity as an indirect measure of effect. Also, as production measures are rarely applicable for product registration purposes, impacts on mortality
and incidence of disease were investigated as the necessary measures for registration of a pharmaceutical product, particularly in Australia and the United States.

To investigate the efficacy of use of bromide to mitigate feedlot induction stress in cattle, the following project objectives were determined:
1. To define the regulatory landscape for bromide in animal production industries;
2. To determine the pharmacokinetic profile, including quantitation of residues, for bromide in cattle; and,
3. To identify health and production outcomes for cattle treated with bromide at feedlot induction.

To determine the pharmacokinetic profiles of bromide, twenty-one steers were randomly assigned to the treatment groups and given as an oral dose containing 100 mg/kg, 300 mg/kg, or 500 mg/kg LW of bromide as the potassium salt. Serial blood sampling was undertaken at 15 time points, 0–72
hours after treatment. Serum bromide concentrations were determined by colourimetric spectrophotometry. Three steers were assigned to a control group to observe baseline (endogenous) serum and tissue bromide concentrations. Steers were euthanased at 7, 21, or 42 days, and tissue
bromide concentrations were determined by ion chromatography. In this trial, bromide exhibited first order pharmacokinetics, with a terminal elimination half-life (t1/2) in serum of 7.75, 7.06 and 6.52 days for 100, 300 and 500 mg/kg doses, respectively. After oral dosing with bromide, return to
baseline was approximately 28, 34 and 42 days for 100, 300 and 500 mg/kg dose rates respectively. Tissue concentrations of bromide after oral administration were measured at days 7, 21 and 42 in fat, kidney, liver and muscle tissues. Return to baseline values for bromide in tissues was dependent on dose and varied between 7–42 days.

An applied study was undertaken in an Australian feedlot to determine the merit of bromide as a therapeutic agent for stress mitigation on feedlot induction, measuring health and production outcomes. Cattle (n = 1936) were recruited in August and September 2019 as part of the feedlot’s normal intake. All animals were placed on 120 day feeding regimens and underwent typical husbandry during their time on feed. Recruited cattle were drafted into six sets of replicates that comprised of one treatment pen and one control pen. Cattle were allocated to treatment or control pens by order of presentation at the induction chute. Treatment cattle were given a low dose of bromide orally and both cohorts was followed to slaughter.

Bromide salts are highly soluble in water (the notable exception being silver bromide) and are therefore fully disassociated in solution. Consequently, the pharmacokinetics and pharmacodynamics of the bromide anion (Br-
, referred to as Br or bromide in this report) are independent of the salt counter-cation. As such, the Australian Pesticides and Veterinary Medicines Authority (APVMA) approved a research permit for a feedlot efficacy study using bromide, based on the pharmacokinetics and residue depletion data.

Major findings
An in-house review identified an opportunity to register bromide salts in multiple countries. Although both a production claim and therapeutic claim are feasible, determining the desired indication will be critical for regulatory approval. Both human food safety and target animal safety will require various studies but no major issues are anticipated.

This study identified that oral treatment with bromide at a low variable dose rate weight (LW) at feedlot entry did not have a significant effect on animal performance (P = 0.09; ‘deads and salvage culls in’ average daily gain) when all animals were considered across the full duration of time on feed (120 days). No difference was observed at slaughter in meat quality scores. Statistical significance was not reached due to the relatively low number of deaths experienced during the study, there was, however, evidence that treatment with bromide reduced mortality with untreated animals found to be 2.8 times more likely to be registered as notifiable deaths (mortalities and salvage culls) than their untreated counterparts. Also, treatment with bromide showed a trend towards reduced mortalities by up to 50% (P = 0.081). When hospitalisations within the first 28 days on feed were considered, the active therapeutic
window, a greater number of control cattle were hospitalised for BRD-related illness compared to P.PSH.0805 – Reducing induction stress in the Australian feedlot system their untreated counterparts (P = 0.014). This data suggests that bromide may assist in mitigating BRD-related presentations in the first 28 days in the feedlot commensurate with the time of effect after a single oral dose at induction. Specifically, calculated odds ratios suggested that control group
cattle were twice as likely to be treated for suspected respiratory disease in the first 28 days on feed compared to treated cattle. This represents a significant disease reduction in bromide treated steers in this study during the early phase on feed.

Together, the outcomes of this project support bromide as a potential candidate as an anxiolytic agent with a pharmacokinetic profile that suits use in intensive beef operations. This was further indicated by the results of the applied trial in which differences were observed for mortality, morbidity for the first 28 days on feed, and without adverse effects on meat quality.

Recommendations
Opportunities for the registration of bromide as a therapeutic agent for management of stress-related disorders in feedlot cattle should be pursued for the benefit of Australian intensive beef production systems.