Lisa Murphy DACVECC

Hypoadrenocorticism Refresher

By Lisa Murphy DACVECC

Primary hypoadrenocorticism (HA) is an uncommon disease in dogs and rare in cats.

Adrenal gland physiology

First, we’ll go over some basic adrenal gland physiology.

The adrenal cortex is primarily responsible for secreting several important hormones including cortisol and aldosterone. Cortisol has several functions including carbohydrate, lipid and protein metabolism, immune system modulation and proper catecholamine function. The amount of cortisol being released is determined by a negative feedback system:

  • The hypothalamus produces corticotropin releasing hormone (CRH) which stimulates the anterior pituitary to release adrenocorticotropic hormone (ACTH).

  • ACTH stimulates the zona fasiculata and reticularis of the adrenal cortex to produce and release cortisol.

  • Increased serum cortisol inhibits the release of CRH and ACTH.

Aldosterone is also released from the cortex; however its release is stimulated by hypovolaemia which is recognised by the kidney. In times of hypovolaemia.

  • Angiotensin II is released via a hormonal cascade and stimulates the zona glomerulosa to release aldosterone.

  • Aldosterone stimulates cells in the renal collecting duct to resorb sodium (leading to secondary water retention and restoration of the effective circulating volume) and excrete potassium.

Causes of HA

Primary HA is caused by adrenal gland dysfunction. Although much more rare, secondary HA can also occur; this is caused by hypothalamic or pituitary dysfunction. Most cases of primary HA involve concurrent cortisol and aldosterone deficiency although atypical HA can also occur where only cortisol is deficient.

The typical signalment for HA is young-to-middle aged dogs with females more likely to be affected. Average age of onset is 4 years old.

The most commonly affected breeds include Portuguese water dogs, Great Danes, Westies, Standard Poodle, Wheaton Terrier and Rottweilers.

In cats there is no known sex or breed predisposition.

The exact cause of primary HA is unknown but is believed to be immune-mediated destruction of the adrenal cortex. Less common causes of primary HA include trauma, infiltrative disease or iatrogenic destruction due to mitotane or trilostane therapy for hyperadrenocorticism. In one study evaluating 156 dogs on chronic trilostane treatment for hyperadrenocorticism, the relative risk of developing HA was 15% at 2 years and 26% by 4 years.

Clinical presentation

The clinical presentation of typical HA can be vague and non-specific. We will focus on the emergent Addisonian crisis:

Common clinical signs of a crisis include lethargy or collapse, hypothermia, hypovolaemic shock and bradycardia. Much of these signs occur secondary to the electrolyte changes induced by this disease (mainly hyperkalaemia and hyponatraemia).

On blood work, common findings include hyponatraemia, hyperkalaemia, azotaemia with a concurrent inappropriately low urine specific gravity (typically < 1.030) and possible lack of a stress leucogram.

Most of these patients (> 90% in some studies) will also have a low sodium/potassium ratio, typically less than 28. Other differentials of this include any disease which leads to severe dehydration including renal failure, severe gastrointestinal disease, and body cavity effusions among others.

Other less common blood work findings include hypoglycaemia and hypercalcaemia. Cortisol promotes gluconeogenesis and glucogenolysis and calciuresis leading to these respective electrolyte derangements.

In cases of severe hyperkalaemia, patients can experience significant bradycardia and/or dysrhythmias. Common ECG changes noted include:

  • Bradycardia

  • Diminished/absent P waves

  • Tented T waves

  • Wide/bizarre QRS complexes

  • Ventricular tachycardia/fibrillation

Diagnosis

There are several ways to evaluate if a dog may have HA:

1. A screening test evaluating the resting cortisol can be performed initially with values less than 1 mcg/dl having excellent sensitivity (100%) and good specificity (98%) for HA in dogs.

Values < 2 mcg/dl were also 100% sensitive but only 78% specific for HA.

Dogs with values > 2 mcg/dl are very unlikely to have HA

2. A confirmatory ACTH stimulation test should be performed in all cases of suspected HA. This test is considered the gold standard.

The drug used in this test (cortisyn) is very expensive and recent studies have shown that the low dose ACTH (5 mcg/kg) stimulation test is as effective as the standard dose (using a 250 mcg vial in a dog or 125 mcg vial in a cat).

3. In cases where primary vs. secondary HA needs to be differentiated or to diagnose atypical HA, endogenous ACTH levels can be measured.

Animals with atypical HA (cortisol deficiency without concurrent aldosterone deficiency), should have normal electrolyte values and an elevated endogenous ACTH level.

4. Evaluation of a dog’s cortisol/ACTH ratio: in one study, all dogs with HA had ratios < 0.17 vs. healthy dogs who had values > 0.79 (reference range 1-1.26).

5. Urine sodium levels: in a recent study dogs with HA had significantly higher urine sodium levels when compared to dogs with non-adrenal illness

While there are several tests that may increase suspicion for HA, the ACTH stimulation is the gold standard confirmatory test.

It is important to note that most exogenous glucocorticoids can interfere with adrenal function tests; therefore tests should be delayed if the patient has recently received steroids. Of all types of glucocorticoids dexamethasone has the least effect on testing. In a true Addisonian crisis, fluid resuscitation is the most important first step so delaying steroid administration until after the ACTH stimulation test likely does not have a significant impact on survival.

Treatment

Volume resuscitation:

Intravenous fluids are the mainstay of therapy in a crisis. Despite their potassium content, a balanced electrolyte solution is recommended over 0.9% sodium chloride solution. This is because the latter could increase the patient’s blood sodium levels too quickly which can cause neurological complications. Once the effective circulating volume is restored, kidney function and GFR will increase leading to kaliuresis; this negates the risk of using fluids with low potassium levels in a hyperkalaemic patient.

Hyperkalaemia:

Patients who have life-threatening hyperkalaemia require rapid intervention.

In animals that are experiencing significant cardiotoxic effects, calcium gluconate can be administered. This will not lower potassium levels and its cardioprotectant effects last approximately 15-20 minutes so more definitive treatments need to be instituted following calcium administration.

Treatments to lower plasma potassium levels include fluid resuscitation as well as administration of substances which shift potassium from the extracellular compartment into the intracellular compartment:

  • The most commonly used is 50% glucose solution and regular (neutral, soluble) insulin (0.1 u/kg with concurrent glucose supplementation to avoid hypoglycaemia)

  • Sodium bicarbonate is used less commonly as this drug carries significant risks due to several possible side effects and should only be considered a last resort.

Following adrenal function testing, patients with typical HA can be started on mineralocorticoid and glucocorticoid supplementation:

  • Mineralocorticoids can be given daily in tablet form or as an injection given approximately every 25-30 days.

  • Glucocorticoids are typically administered intravenously to begin with and then per os. They are usually weaned off over time.

  • The timeline for clinical recovery is different for every patient although it can be anywhere from hours following supplementation to 3-5 days.

  • Animals with atypical HA (singular glucocorticoid deficiency) only require glucocorticoid supplementation.

  • Cats typically take longer to respond than dogs.

The prognosis for this disease is quite good, especially in those who survive the initial crisis. However they do require lifelong monitoring and treatment. This is typically long-term mineralocorticoid administration with intermittent glucocorticoid administration at times of physiological stress or illness.

Drowning Refresher

By Lisa Murphy DACVECC

Pathophysiology

Once the airway is below the surface of a liquid voluntary breath-holding occurs. This is then followed by involuntary laryngospasm as liquid enters the oropharynx and larynx. During both of these periods, the victim is not breathing gas and develops hypercapnia, hypoxaemia and acidosis. Once the arterial oxygen partial pressure drops sufficiently, laryngospasm stops and liquid is then actively aspirated. It is the hypoxaemia which leads to unconsciousness and apnea. 

Once aspirated, water leads to several severe side effects:

  • One of the most significant is surfactant dysfunction and washout which reduces lung compliance and leads to atelectasis.
  • Water also interferes with the normal osmotic gradient in the alveolar-capillary membrane thus directly injuring the pulmonary epithelium. Damage to these cells has several effects including the release of inflammatory mediators and increased membrane permeability worsening fluid accumulation in the lung parenchyma.

It was once believed that the type of water (salt versus fresh water) was a more important determinant of outcome than the volume aspirated, however, more recent studies have found this to be untrue. This is because it’s the volume of water which affects surfactant function regardless of the type aspirated. Pool water is interesting because it typically contains agents to limit bacterial growth so secondary pneumonia is uncommon with this type of aspiration. 

The temperature of the water aspirated can also play a role in survival. Cold water is associated with higher rates of survival. This is because it reduces cellular metabolism (and thus oxygen consumption) and activates the diving reflex (leading to bradycardia, hypertension, shunting of blood to the cerebral and coronary circulations). 

Diagnosis 

The history of a drowning episode is usually known. Common tests performed in these cases include:

  • Blood gas analysis (ideally arterial) – most cases have a mixed respiratory and metabolic acidosis
  • Thoracic radiography:
    • Pulmonary oedema is likely
    • In some cases, where the volume of water aspirated wasn’t large but they suffered a choking-like episode, non-cardiogenic pulmonary oedema (NCPO) may be identified. This is suspected where the pulmonary oedema is predominantly in the caudodorsal lung field.
    • In cases which don’t go on to develop pneumonia, there is usually radiographic resolution of oedema within 7-10 days.

Treatment

The focus should be on controlling the patient’s hypoxaemia.
The risk of pneumonia is low (estimated at 12% in humans) so empirical antibiotics are not recommended. In general, it is much more likely for these cases to develop pneumonia if they undergo mechanical ventilation.
Steroids also have not been shown to increase survival and their use is not recommended. 

Similarly, there is little evidence supporting the use of diuretics in cases of NCPO. Diuretics are most useful for hydrostatic oedema which is associated with congestive heart failure. In cases of NCPO, the oedema is due to changes in pulmonary epithelium permeability (permeability oedema). Fluid can still leak into the parenchyma despite diuretic use. And since diuretics have systemic effects, they put patients at risk of dehydration and potential renal compromise. 

There are several criteria that we can use to help identify those patients who could benefit from mechanical ventilation. The main indications are as follows:

  • Arterial partial pressure of carbon dioxide > 60 mmHg
  • Arterial partial pressure of oxygen < 60 mmHg despite non-invasive oxygen supplementation 
  • Excessive respiratory effort with impending respiratory fatigue

Prognosis is not known in veterinary medicine. In general, animals showing more organ systems negatively affected and those requiring positive pressure ventilation have a worse prognosis. 

Seizure Refresher

By Lisa Murphy DACVECC

Seizures are one of the most common neurological emergencies seen by small animal vets both in general practice and in emergency clinics. What follows is a brief discussion of seizures and some of the more commonly used anticonvulsive medications for management of these cases.

Idiopathic Epilepsy:

  • Most dogs suffering from idiopathic epilepsy are between 1-5 years old with genetic predilection in the beagles, the Keeshond, the dachshund, the Irish wolfhound, Labrador and Golden Retrievers and the English springer spaniel.
  • They can have any type of seizure (generalized/tonic-clonic, focal) but generalised is more common.
  • Predisposing factors are not known in animals but in people include stress, sleep deprivation, missed medications and concurrent illness.
  • Idiopathic epilepsy is less common in cats although also usually occurs around 1-5 years old.
  • In studies evaluating dogs > 5 years old, 35% had no identifiable cause of epilepsy, while the remainder were divided into those with neoplasia (52%) and those with other aetiologies (inflammatory, vascular, congenital). All dogs in the 8-10 year old group and in the over 15-years old group, and 80% of dogs in the 11-13 years old group, had neoplasia as the underlying cause.
  • When comparing the neurological exam to MRI findings, of those who had an abnormal neurological exam 79% went on to have a lesion on MRI. A properly performed neurological exam is considered to have 74% sensitivity and 62% specificity for diagnosing secondary epilepsy. 

Metabolic and Toxic Causes:

Among the lesser studied causes of seizures in our patients are metabolic and toxin associated seizures, of which there are a number of potential culprits.

A retrospective study was performed on almost 100 dogs and found some very interesting findings. Intoxications were the most common cause with metaldehyde most likely (although this likely depends on geographic location). When evaluating metabolic causes alone, hypoglycaemia was most common. Interestingly, reactive seizures secondary to metabolic disorders or toxins had a 1.57x higher risk of a status epilepticus presentation as compared to idiopathic epilepsy.

Secondary Intracranial Hypertension: 

While most seizures do not tend to be life-threatening, animals which have multiple seizures in a short period may be at risk for developing intracranial hypertension (ICH). Typically, intracranial pressure (ICP) is maintained within a narrow range secondary to several physiological processes. These can be disrupted as a result of seizure activity. 

If left untreated, significant intracranial hypertension may lead to the Cushings response which is often fatal. Clinically it should be suspected in a seizuring patient with systemic hypertension and bradycardia. 

Anticonvulsive Medications

Common first line anticonvulsive medications:

Thankfully, most patients presenting with seizures do not go on to develop such life-threatening complications and typically just require acute control of their seizures.

Benzodiazepines:

  • The most common medications employed to stop seizures are benzodiazepines. Diazepam and midazolam are typically given intravenously (0.5 mg/kg) or rectally (1 mg/kg) for rapid seizure control.
  • It is important to note however that they have a very short duration of action and animals may start having seizures again within 10 minutes of their administration.
  • These drugs also need to be used cautiously in patients with seizures due to hepatic encephalopathy as the drug’s metabolism will be reduced resulting in more significant sedation.
  • In some cases, a continuous infusion or repeated bolus administration must be used while waiting for the patient to respond to medications used for longer-term seizure control. Midazolam is recommended for this as it is water soluble and causes less thrombophlebitis; however, neither drug is superior to the other for seizure control.

Ketamine/Dexmedetomidine:

  • Some patients are refractory to acute control with benzodiazepines and will continue to seizure. Recent case reports in veterinary patients have shown that ketamine and dexmedetomidine may be able to offer short-term seizure control in such cases.
  • In both cases, high doses are typically needed and patients require continuous monitoring for significant side effects.
  • Patients typically remain on an infusion until they are seizure free for at least 6-12 hours. The drug then needs to be slowly weaned over the next 6-12 hours.
  •  While the dog is on these infusions, a second medication for chronic seizure control must be started.  

Common long-term anticonvulsive medications:

Phenobarbital:

  • The most commonly used drug in veterinary patients.
  • Benefits include relatively low cost and, for most animals, being well tolerated long term.
  • Major disadvantages include the need to ‘load’ the drug as therapeutic levels can take several days to be attained during which time the animal would be at continued risk of further seizures. This involves the administration of a larger dose for the first 24 hours followed by a much lower maintenance dose. At high loading doses, most dogs will be very sedated. Their carers need to be warned that they can continue to be very sedated, and potentially ataxic, for the first few days of treatment.
  • Cats tend to show fewer side effects.
  • Phenobarbital also needs to be used cautiously in animals with an underlying hepatic disease as the drug will increase hepatic enzymes over time. 

Potassium Bromide (KBr):

  • Can also be employed in dogs
  • It requires loading to attain therapeutic levels during which time the dog can be very sedated.
  • While it can offer excellent seizure control, some dogs develop significant side-effects (e.g. gastrointestinal, megaoesophagus, dysphagia) and treatment needs to be discontinued.
  • It is important to note that bromide competes with chloride ions in the renal tubule. Vets treating animals that are on chronic KBr treatment with intravenous fluids need to recognize that concurrent use of 0.9% sodium chloride will speed up renal clearance of KBr. 

Levetiracetam:

  • Has become more widely used in recent times
  • The exact mechanism of action is unknown
  • Major benefits of this drug include minimal side effects and that it attains therapeutic levels within 60 minutes of administration
  • While levetiracetam has excellent short-term effects, its use as long-term monotherapy for seizure control is controversial. It has been used in this was for idiopathic epilepsy but, after a ‘honeymoon’ period, an additional anticonvulsive medication may be needed.

Zonisamide:

  • A synthetic sulfonamide based drug
  • Takes a few days to achieve therapeutic levels
  • Tends to be well tolerated by most dogs
  • Advantages include generic drugs now available (so less cost) and the need for only twice daily dosing (so better compliance)
  • There are sparse case reports of dogs developing immune-mediated thrombocytopenia secondary to the sulpha component within the drug so this risk, while low, should be discussed with carers.
  • One caveat to its use is that concurrent use of phenobarbital increases the renal clearance of zonisamide so the dose may need to be increased. 

Pregabalin:

There is not as much data available for the use of this drug in dogs. Studies that have been performed show that it can reduce seizure frequency by fifty per cent when used in dogs on chronic phenobarbital or potassium bromide therapy.