Sedatives and Tranquilizers

In adult horses, reliable, fast acting sedation is necessary to improve handling and the quality of anesthesia. However, with neonatal foals, many of the commonly used sedatives can have detrimental effects on an immature cardiovascular system. The most commonly used classes of sedative in horses are alpha‐2 agonists and phenothiazines.

The alpha‐2 agonists, xylazine, detomidine, and romifidine, are favored in adult horses because of their reliable, quick acting sedation and analgesia (Sanchez and Robertson 2014; Moorman et al. 2019). However, drugs in this category can have profound effects through alpha‐receptor agonism. In healthy foals up to 28 days of age, xylazine administration can result in bradycardia, hypertension and then hypotension, upper airway obstruction, ventilatory stridor, decreased minute ventilation, marked ataxia, and recumbency (Carter et al. 1990). A reduction in cardiac output associated with alpha‐2 agonist use is well known and likely to be more profound in foals as their cardiac output is more heart rate dependent than mature horse. Alpha‐2 agonists in horses may negatively affect gastrointestinal motility and perfusion and increase post‐glomerular diuresis that may be detrimental to fluid and electrolyte balance, particularly in compromised patients (Rutkowski et al. 1991; Sutton et al. 2002; Nuñez et al. 2004; Zullian et al. 2011). Due to the immature cardiovascular status of neonatal foals and the likelihood of clinically relevant disease, minimizing the use of alpha‐2 agonist drugs, whenever possible, is recommended.

Acepromazine, a phenothiazine, is a centrally acting dopamine receptor antagonist that is useful as a tranquilizer in horses. Onset of action is up to approximately 20 minutes and has a dose‐dependent duration of action of 1–2.5 hours in horses (Marroum et al. 1994). Additionally, packed cell volume is reduced by up to 20% and blood pressure significantly decreases (Marroum et al. 1994). Due to its long duration of action, lack of a reversal agent, and actions on the circulatory system, acepromazine has not gained wide popularity for sedation in neonatal foals.

Benzodiazepines have centrally acting muscle relaxation and sedative effects through enhancing the effects of the inhibitory neurotransmitter γ aminobutyric acid (GABA) on chloride and other ion channels. Benzodiazepines have minimal clinically relevant effects on cardiovascular or ventilatory performance. Additionally, drugs in this class have potent anticonvulsive activity which may be helpful in foals with neonatal asphyxia (Johne et al. 2021). Traditionally, benzodiazepines such as midazolam and diazepam are combined with ketamine for their muscle relaxant properties during induction of anesthesia in horses. In adult horses, benzodiazepines provide little to no sedation but can produce ataxia, anxious, agitated, or aggressive behavior and are not recommended as a single therapy (Muir 2009; Fischer and Clark‐Price 2015). However, in foals less than two to four weeks of age, benzodiazepines can produce profound sedation, relaxation, and recumbency (Fischer and Clark‐Price 2015). Midazolam may be preferred over diazepam due to formulation differences. Diazepam is not water‐soluble and is therefore found with propylene glycol as a carrier agent. At high doses, propylene glycol can be tissue irritating and cause necrosis, hemolysis, and cardiac arrhythmias (Lim et al. 2014). Midazolam gives the benefit of being water‐soluble and thus formulations are made without propylene glycol. Midazolam can be administered intramuscularly if intravenous access is limited. Additionally, intranasal midazolam is reported to be effective for seizure control in dogs (Charalambous et al. 2017) and though not published, anecdotal reports suggest similar anti‐seizure and sedative effects when administered intranasal in foals. The pharmacokinetics of midazolam have been well described in adult horses at dosages of 0.05 and 0.1 mg/kg (Hubbell et al. 2013). However, the pharmacokinetics have not been described in juvenile or neonatal horses. Neonatal foals presenting for anesthesia frequently have disease that may have an immunological component (i.e. failure of passive transfer, sepsis). Midazolam has been shown to suppress phagocytosis and oxidative burst, essential functions of the innate immune system, in equine neutrophils, and macrophages; however, it is unknown if this has any clinical implications (Massoco and Palermo‐Neto 2003).

Opioid Analgesics

It is important to recognize that, at birth, animals have a developing nociceptive system. Although not completely mature, neonatal animals are able to process and interpret pain sensations. In fact, the ability to “feel” pain occurs early in the second half of gestation (Bellieni 2020). The central nervous system is quite plastic at birth, and structural and functional “fine‐tuning” of the nociceptive system continues as the animal develops. The spinal circuitry is activity dependent and therefore there can be long‐term detrimental consequences to untreated pain (van den Hoogen et al. 2019). Untreated pain can lead to neurotoxicity, alterations in spinal neuronal circuits, and apoptosis of developing neuronal brain cells (van den Hoogen et al. 2019). Questions continue to surround the use of opioids as analgesics in horses with behavioral changes (aggression, sedation), gastrointestinal stasis, and respiratory depression during anesthesia being main points of contention. Butorphanol, a κ agonist – μ antagonist, is the most commonly used opioid in horses. Butorphanol has been evaluated in healthy neonatal foals at 0.05 mg/kg and although the pharmacokinetics are different from adult horses (greater volume of distribution and faster clearance in neonates), it appears to be well tolerated with minimal effects on vital parameters (Arguedas et al. 2008). Clinical signs of sedation and increased nursing behaviors can be expected to occur. Of the numerous μ agonist opioids available for clinical use, there is little published data in neonatal foals. Anecdotal use of morphine suggests that it provides clinically relevant sedation when combination with midazolam as a premedication prior to surgery. Fentanyl, a μ agonist opioid, is considered 100 times more potent than morphine and is used commonly as an infusion during anesthesia for surgery in small animal patients. Fentanyl has been studied in healthy foals in a dose escalation manner (Knych et al. 2015). At dosages greater than 4 μg/kg, foals develop ataxia, muscle rigidity, and may head press. Foals become heavily sedated and recumbent at 32 μg/kg. It is important to note that efficacy studies with opioids have not been performed in neonatal foals and clinical use is frequently based on clinical experience and extrapolation from adult horses and other species. Local use of opioids, particularly intra‐articular use of preservative free morphine, may allow for a reduced dosage and minimizing systemic effects while still benefiting from the analgesic properties. In the authors’ opinion, μ agonist opioids should be considered for routine use in anesthetized neonatal foals that are undergoing invasive, painful procedures as the negative effects of pain outweigh the potential negative effects of opioid use.

Induction Agents

Ketamine continues to be the induction agent used most commonly in adult horses as it provides rapid unconsciousness, can be administered in a reasonable volume, and provides for a smooth and controlled induction. However, in neonatal foals, the concern about controlling a large body mass during induction is not as problematic as an adult horse and therefore allows for more options for induction.

When inducting a neonatal foal for anesthesia, quick control of the airway is essential to provide oxygen and ventilatory support as hypoxemia can rapidly occur. In human infants, hypoxemia during anesthesia is recognized as a critical factor that increases morbidity and mortality (Disma et al. 2021). Intubation can be quickly accomplished with the use of inhalants, ketamine, propofol, or alfaxalone in neonatal foals.

Inhalant anesthetics has been used for induction of anesthesia in foals (Steffey et al. 1991). A facemask with an airtight seal can be applied over the nose of a foal for induction, but in depressed or gently restrained foals, nasotracheal intubation can be performed in the awake animal. This requires use of a long, straight, silicone endotracheal tube with an internal diameter of 6–14 mm depending on the size of the foal (Figure 13.1). Soaking the endotracheal tube in warm water to soften and applying water‐based lubricant to the outer surface will facilitate insertion. Additionally, desensitizing the nasal mucosa with lidocaine may improve compliance from the foal. Once placed, the endotracheal tube can be attached to a breathing circuit on an anesthesia machine, and oxygen and inhalant anesthetic can be administered for induction. Inhalant anesthetics cause dose‐dependent vasodilation and decreased cardiac output through reduced stroke volume in adult horses and similar changes should be expected in foals (Steffey and Howland 1980; Steffey et al. 2005). Careful titration of the dose of inhalant anesthetic during induction and maintenance of anesthesia while minimizing side effects can be achieved through attentive physiologic parameter monitoring of the foal.

Maintenance Agents

For short procedures (<30 minutes), maintenance of anesthesia may be provided with additional doses of injectable anesthetics such as propofol or alfaxalone. Oxygen/ventilatory support may be necessary due to the respiratory depressant effects of the drugs combined with the foal’s physiologic immaturity. For major surgical procedures or the need for prolonged anesthesia (>30 minutes), inhalant anesthetics isoflurane and sevoflurane are the mainstay. This requires tracheal intubation and the use of an anesthesia machine. Many of the large animal anesthesia machines that are commonly used for adult horses are not suitable for anesthesia of foals weighing less than 330 lbs. (150 kg). The large volume of the breathing circuit in these machines makes quick adjustment of anesthetic vapor concentration nearly impossible and the larger one‐way valves may result in clinically relevant resistance to breathing. Additionally, for foals that require mechanical ventilation, large animal anesthesia machine bellows may not safely accommodate smaller tidal volumes, flow rates, and pressures necessary to prevent lung injury. Standard small animal anesthesia machines and mechanical ventilators can be utilized for safe delivery of anesthetic. More recently, an electronic large animal anesthesia machine with a precision motor piston driven ventilator became available on the veterinary market (Tafonius, Hallowell Engineering and Manufacturing Corporation). With the use of a “foal circuit,” very precise ventilation utilizing various modes of ventilation can be applied for use in foals. The minimum alveolar concentration (MAC), common use, and side effects of isoflurane (MAC = 1.31) and sevoflurane (MAC = 2.84) have been well described in adult horses (Steffey et al. 1977, 2005; Brosnan 2013). MAC values of isoflurane and sevoflurane in foals have not been reported. However, MAC values of inhalant anesthetics are decreased in human term neonates less than one month of age and even further decreased in human pre‐term neonates (LeDez and Lerman 1987). Thus, neonatal foals likely require lower concentrations of isoflurane and sevoflurane similarly and practitioners are advised to adjust vaporizers downward in neonatal foals during anesthesia to minimize excessive anesthetic depth. Previously mentioned, cardiovascular side effects of vasodilation and decreased stroke volume can be problematic and techniques (use of supplemental analgesic drugs) that allow for a reduced concentration of inhalant to be administered should be considered. Ventilatory changes can also be expected to occur in neonatal foals during inhalant anesthesia. Hypoventilation progressing to apnea should be expected as inhalant dose increases. The neonatal brain has an altered response to elevations in carbon dioxide resulting in irregular breathing patterns (Neumann and von Ungern‐Sternberg 2014). Further blunted by inhalant anesthetics, a weak respiratory drive frequently results in the need for assisted or mechanical ventilation of foals.

In 2016, the United States Food and Drug Administration issued a warning that repeated or lengthy (>3 hours) general anesthesia in children less than three years of age may affect the development of the child’s brain (Olutoye et al. 2018). This statement was made due to mounting evidence of anesthetic toxicity in the developing brains of research animals. Drugs in two classes of sedative/anesthetic agents were implicated: GABA agonists (e.g. inhalant anesthetics, benzodiazepines, and propofol) and N‐methyl‐D‐aspartate (NMDA) antagonists (e.g. ketamine). Neuronal anesthetic toxicity can lead to structural, functional, and compensatory changes in sensory and learning systems (Aksenov et al. 2020). Neurotoxicity of inhalant anesthetics appears to be through enhancement of apoptosis in various parts of the brain that can lead to cognitive deficits (Jevtovic‐Todorovic et al. 2003). This phenomenon appears to occur only in developing brains, as inhalants do not have similar effects in mature brains (Stratmann et al. 2010). To date, there is no information on the effect of anesthetic drugs on the development of the equine brain. However, in light of the recommendations in human neonates, it seems prudent that practitioners should limit the duration and number of anesthetic episodes and the dosages of sedative and anesthetic drugs used in foals as much as possible.

Cardiovascular Monitoring and Support

The goal of cardiovascular monitoring is assessing the adequacy of circulation and tissue perfusion. Heart rate and rhythm (ECG), mucous membrane color and capillary refill time, peripheral temperature, arterial blood pressure, and blood lactate concentration are useful tools for assessment. Dark mucous membranes, prolonged capillary refill times, cool extremities, and elevated lactate concentrations can all suggest poor perfusion and indicate the need for intervention. Likewise, decreases in heart rate and blood pressure can indicate depressed pump function. Resting values for heart rate and blood pressure change during the first few weeks of a foal’s life as physiologic growth and maturity progress. Foals can be expected to have higher heart rates and lower blood pressure in the first week as compared to the second week, and younger foals have a decreased corrective response to anesthetic‐induced hypotension (O’Connor et al. 2005). Vital signs should be interpreted based on the foal’s age, and more aggressive therapies to combat hypotension may be necessary in younger foal. Arterial blood pressure can be measured via indirect methods with an appropriately sized cuff placed around the base of the tail. However, similar to other species, indirect blood pressure measurement is likely not suitable for decision making after a single measurement and only useful for detecting trends over time. However, as the cardiovascular status of anesthetized foals can change quickly, the authors recommend direct blood pressure measurement from an arterial catheter for systemically ill foals or any foal undergoing general anesthesia for more than 30 minutes. Arterial catheters can be placed in the transverse facial, lateral metatarsal, lingual, or femoral arteries (Figure 13.2) (Fischer and Clark‐Price 2015). In adult horses, a target value for mean arterial blood pressure of 70 mmHg or greater has been associated with a decrease in morbidity and mortality, particularly associated with equine peri‐anesthetic myopathy (Schauvliege and Gasthuys 2013). Neonatal foals likely do not need to maintain mean arterial blood pressures of 70 mmHg or greater. Cardiovascular studies in foals for recommendation of arterial blood pressure are not available. However, in anesthetized human neonates, a 20% reduction in systolic blood pressure compared to awake baseline resulted in a less than 10% chance of cerebral desaturation (Michelet et al. 2015). When awake neonatal foal blood pressure is considered, the human study suggests that mean arterial blood pressure of >50 mmHg may be acceptable in anesthetized foals.

Cardiac output monitoring is not routinely performed in clinical veterinary patients. However, more recently, an ultrasound dilution (UDCO) method has been developed for human infants that utilizes a peripheral venous and arterial catheter. Invasive heart catheterization or loss of blood that is necessary for other methods is not needed for UDCO. This method has been validated for use in foals to assess cardiac function and has the advantage of being useful in awake and anesthetized foals (Shih et al. 2009; Fries et al. 2020). For critically ill foals, measurement of cardiac function with UDCO before, during, and after anesthesia may help detect cardiac performance changes early and guide goal‐directed therapy.

Hypotension during anesthesia may be related to vasodilation, hypovolemia, bradycardia, and/or decreased contractility (decreased stroke volume). Treatment aimed at hypotension should be directed at an identified underlying cause and not “shot gun” therapy aimed at improving a number on a vital signs monitor. As previously stated, foals have minimal cardiovascular reserve and thus heavy‐handed administration of corrective therapies may result in further worsening of cardiovascular function and patient health status. Hypotension may be simply related to the anesthetic agents used, and decreasing the plane of anesthesia may allow for acceptable correction of parameters. Hemodynamic instability related to shock may be observed in any anesthetized foal as most anesthetic episodes are related to correction of diseases that have systemic impact. Shock in neonates is most commonly diagnosed only after the onset of the hypotensive phase which indicates serious disease progression. Early identification and intervention is key to successful management (Singh et al. 2018). Ideally, identification of potential or the onset of shock occurs early on and the foal is stabilized prior to anesthesia (see sepsis in the following text). Once meaningful hypotension is identified, a systematic examination for cause should be performed. A combination of physical parameters (anesthetic depth, capillary refill time, mucous membrane color, extremity temperature), vital sign monitor parameters (heart rate and rhythm, pulse oximetry, end‐tidal CO₂) and clinical pathology findings (blood gas, electrolyte, lactate, and hematocrit) should be utilized for determining course of action. While anticholinergic drugs (atropine, glycopyrrolate) have traditionally been avoided for use in adult horses due to concerns surrounding gastrointestinal stasis, use to accelerate heart rate in foals may be sufficient to counter anesthetic‐induced bradycardia. Hypovolemia should be corrected with intravenous fluid therapy to correct losses. However, overaggressive use of fluids may result in fluid overload and hypernatremia (Fielding and Magdesian 2015). Fluid boluses of 20 ml/kg have been suggested and should be repeated up to three times (Fielding and Magdesian 2015). Goals for fluid therapy are a blood lactate concentration less than 4 mmol/l, normalization of perfusion parameters, and urine production. If hypotension persists after fluid therapy, infusion of inotropic and/or vasopressors should be instituted. Dobutamine is used for inotropic support, and norepinephrine is used for vasopressor support (Hollis et al. 2006; Valverde et al. 2006; Fielding and Magdesian 2015). The combined use of dobutamine and norepinephrine in foals has been described and has been used by the authors for cardiovascular support in severely ill foals that did not have adequate response to single therapy (Hollis et al. 2006). Vasopressin increases vascular resistance and blood pressure in anesthetized foals; however, splanchnic circulation is decreased resulting in a potential decrease in gastric mucosal perfusion (Valverde et al. 2006).

Ventilatory Monitoring and Support

The unique respiratory physiology of the neonatal foal and the depressant effects of sedative, analgesic, and anesthetic drugs, often necessitate the use of assisted or mechanical ventilation during anesthesia. Adequacy of ventilation in the anesthetized foal can be assessed with a combination of pulse oximetry, end‐tidal gas determination, and arterial blood gas analysis. Hypercapnia (PaCO₂ > 55 mmHg, pH ≤ 7.25) is usually an indicator of hypoventilation while hypoxemia is usually an indicator of a reduced gas diffusion across the alveolar‐capillary barrier. Some indications for mechanical ventilation during general anesthesia in the neonatal foal include persistence of hypoxemia and/or hypercapnia, use of neuromuscular blocking agents, thoracic procedures or imaging studies, irregular ventilator pattern that impedes uptake and maintenance of inhalant anesthetic, and spontaneous movements of the thoracic wall or abdomen that impedes a surgical procedure.

Due to the immaturity of a foal’s lungs, lung‐protective strategies that minimize VILI should be considered. VILI can result from excessively high tidal volume (volutrauma), higher pressures during ventilation (barotrauma), shear forces damaging lung that is insufficiently opened (atelectotrauma), subsequent release of pro‐inflammatory cytokines, and high levels of oxygen resulting in oxidative stress (oxygen toxicity) (Neumann and von Ungern‐Sternberg 2014). Lung‐protective ventilation strategies that avoid high tidal volume and airway pressure, use of recruitment maneuvers, and preventing repetitive opening and closing of alveoli through use of positive end‐expiratory pressure are recommended (Table 13.3).

Fluid and Electrolyte Monitoring and Therapy

Fluid, electrolyte, and acid–base status is monitored via analysis of blood samples. Shifts in parameters can happen rapidly and frequent sampling can allow for identification and initiation of therapies aimed at correction and balance. Derangements in sodium, chloride, and potassium are common in sick foals and fluid and electrolyte balance may vary depending on the disease (see below for treatment recommendations for specific diseases and conditions). Correction of fluid deficits and electrolyte imbalance should take place prior to inducing anesthesia whenever possible. While foals have a higher percentage of total body water than adult horses (10%), foals have a lower colloidal oncotic pressure, that, when accompanied with excessive exogenously administered fluids, can result in rapid development of edema (Magdesian 2013). Therefore, high volumes of fluids (other than fluid boluses needed for hypotension) should not be administered during anesthesia. If daily maintenance fluids are being administered as part of a treatment plan, those can be continued at a similar rate, or if maintenance fluids are not being administered, fluid rates of 2–5 ml/kg/h can be administered during anesthesia. While initial replacement fluids should utilize isotonic fluids such as lactate Ringer’s solution, maintenance fluids before and during anesthesia should be comprised of hypotonic fluid solutions. Hypotonic fluids with supplementation of potassium (based on serum potassium concentrations) and dextrose (based on serum glucose concentrations) are thought to be more appropriate than isotonic fluids (Dathan and Sundaram 2021; Fielding and Magdesian 2015). Daily sodium requirements are quickly met with oral and intravenous fluid therapy in foals; thus, the use of isotonic fluids results in sodium retention secondary to a foal’s inability to excrete large amounts of sodium quickly. Commercial maintenance fluids are hypotonic (approximately 110 mOsmol/l) and can be utilized or standard isotonic crystalloid fluids (approximately 295 mOsmol/l) can be diluted with sterile water to make a hypotonic solution similar to commercial products. If potassium supplementation is required, potassium phosphate may be used to supplement the maintenance fluids instead of potassium chloride to minimize hyperchloremia. For older healthy foals (>2 weeks), standard isotonic solutions can be utilized.

Dextrose support will likely be needed during anesthesia of neonatal foals, as glycogen storage is not sufficient to maintain appropriate blood glucose levels. Blood glucose should be checked at regular intervals (30–60 minutes) during anesthesia and adjustments made to intravenous fluid dextrose concentrations to maintain blood glucose concentrations between 150 and 250 mg/dl during anesthesia. Blood glucose in awake foals should be maintained at approximately 150 mg/dl. Dextrose can be added to the intravenous fluids to achieve a concentration of 1–5%. Solutions greater than 5% can be hyperosmolar and result in hyperglycemia, lysis of red blood cells, and osmotic diuresis, and should be avoided.

Plasma can be utilized for foals with a low oncotic pressure and/or hypoalbuminemia. In adult horses, plasma can be cost prohibitive for colloidal support but in foals, 20–40 ml/kg of fresh frozen plasma may be feasible. In cases of failure of passive transfer, hyperimmune plasma may be used for immunoglobulin replacement and immune therapy. However, failure of passive transfer should be corrected well before anesthesia and surgery is considered as these foals are at high risk for infections and sepsis.

Body Temperature Monitoring and Thermal Support

Inadvertent peri‐anesthetic hypothermia (IPH) is one of the more common adverse events associated with general anesthesia. IPH is associated with delayed recovery, poor wound healing, increased risk of infection, altered coagulation, and hypotension (Clark‐Price 2015). Neonatal foals have a larger surface area to body mass ration than older horses and have less skeletal muscle mass, thus they lose body heat more rapidly and have less capacity to generate heat. Additionally, hypothermia is further exacerbated by the impairment of thermoregulatory centers in the brain stem (Sessler 2015). Monitoring the body temperature of foals is therefore an essential part of an anesthetic plan. Aggressive heat support is necessary throughout the anesthetic period and during recovery. During anesthesia, use of active warming techniques (circulating warm water pads, force warm air blankets, resistive polymer electric blankets) that cover as much of the foal as possible can help reduce the temperature gradient from the foal to the environment and minimize hypothermia. Similarly in recovery, use of active warming as well as covering the foal in prewarmed blankets can be used to reduce recovery time and complication.