staging.vettimes.com

Tag: Hyperparathyroidism

  • Ionised hypocalcaemia, pt 4: controversies and prognostic indications

    Ionised hypocalcaemia, pt 4: controversies and prognostic indications

    Ionised hypocalcaemia (iHCa) is a well-known electrolyte abnormality in critical human patients, which is also beginning to be recognised in our critical feline and canine patients.

    The exact mechanism for the development of iHCa is still unknown – making prevention difficult, if at all possible. Controversy also exists as to whether treating iHCa is of any benefit, especially in non-clinical cases.

    Despite these issues, serum concentration is proving to be an accurate prognostic indicator for the morbidity and mortality rates of some of the more critical patients.

    Research

    Over the past 30 years, significant resources have been put into trying to demystify the pathophysiological causes of iHCa in critically ill people; however, the exact mechanisms are still to be determined.

    Some proposed mechanisms include:

    • abnormal parathyroid hormone secretion or function
    • abnormal vitamin D synthesis or function
    • hypomagnesaemia
    • calcium chelation
    • alkalaemia
    • calcium sequestration in tissue or cells
    • an increase in calcitonin precursors (procalcitonin)

    In a canine study where endotoxaemia was induced, it was found hypovitaminosis D was associated with iHCa (Holowaychuk et al, 2012).

    Veterinary studies

    The true incidence of iHCa in critically ill canine and feline patients is yet to come to a consensus, due to the limited veterinary studies.

    In one retrospective study, 90% of 55 cats with septic peritonitis was reported to have iHCa (Kellett-Gregory et al, 2010), while only 24% of septic dogs (n=58) was reported to have iHCa (Luschini et al, 2010).

    Regardless of the true incidence, the commonness of this change questions whether a need exists to treat iHCa, especially cases in the mild or non-clinical categories.

    No consensus

    At this stage, no consensus exists to either support or prohibit the treatment of hypocalcaemia in critically ill patients.

    Well-designed prospective studies are scarce in human literature and non-existent in the veterinary field; no evidence-based guidelines are available for treatment.

    Based on logic, arguments for the administration of calcium to critically ill patients include:

    • iHCa during hospitalisation is a negative predictor for morbidity and mortality of patients.
    • Hypocalcaemia can cause decreased myocardial contractility.
    • In hypotensive patients dependent on vasopressors or inotropic agents, the supplementation of calcium may be beneficial.

    Arguments against calcium supplementation include:

    • Calcium accumulation within cells predisposes to hypoxia and ischaemia-reperfusion injury.
    • Increased mortality in experimental models of sepsis when calcium is supplemented, on top of the lack of evidence to support this act.

    Prognostic use

    Serum calcium concentrations – or, rather, the trend of it in hospital – appears to be of valuable prognostic indicators.

    Kellett-Gregory et al (2010) found although no direct associations existed between the presence or severity of iHCa at the time of patient admission, a positive correlation existed between the lowest iCa post-hospitalisation, and the length of hospitalisation and duration of intensive care stay.

    Of the cats that had iHCa, those that failed to return to a normal ionised calcium (iCa) during hospitalisation had a significantly lower rate of survival to discharge. Interestingly, iHCa was not associated with the status of hypotension, coagulopathy or arrhythmias, so cannot be used to predict the occurrence of these.

    These findings were echoed by Luschini et al (2010), where low mean ionised calcium and lowest documented ionised calcium concentrations were found to be associated with a poor outcome. The severity and duration of iHCa appears to be important in determining prognosis in these patients.

    Conclusion

    Controversy exists regarding whether treatment of mild iHCa in critically ill patients is recommended; however, one thing we now know is serum iCa concentration is a reliable predictor of mortality and morbidity in canine and feline patients.

    References

  • Ionised hypocalcaemia, pt 2: eclampsia

    Ionised hypocalcaemia, pt 2: eclampsia

    As discussed in part one of this blog series, a myriad of disease processes can lead to ionised hypocalcaemia (iHCa).

    Despite this, only hypocalcaemia caused by eclampsia and hypoparathyroidism (primary or iatrogenic – post-surgical parathyroidectomy) are severe enough to demand immediate parenteral calcium administration.

    Hypoparathyroidism is quite rare, so this blog will not explore the detailed pathophysiology behind this syndrome. However, it is worthwhile mentioning – aside from primary hypoparathyroidism – no other disease state requires long-term calcium supplementation.

    Eclampsia, on the other hand, is the most common cause of clinical hypocalcaemia in dogs and cats. Multiple factors can predispose animals to the development of this phenomenon, so understanding the pathophysiology behind this potentially fatal disease will not only help with future diagnosis and treatment, but also help prevent this issue.

    Periparturient occurrence

    Eclampsia – also known as puerperal tetany or periparturient hypocalcaemia – occurs in the periparturient period anywhere from the final few weeks of gestation to four weeks postpartum, with the latter being the more common time frame of manifestation.

    The serum concentration of ionised calcium (iCa) is often less than 0.9mmol/L in bitches or less than 0.8mmol/L in queens. It presents as muscle fasciculation and tetany, but not usually in seizure since most patients maintain consciousness. Exceptions occur when these patients are left untreated – these patients may develop refractory seizures, cerebral oedema and death.

    The increased muscle activity generates a lot of heat and uses a significant amount of glucose; therefore, hyperthermia and hypoglycaemia are common sequelae in patients with delayed presentations.

    Reduced iCa

    Eclampsia occurs as a result of reduced iCa in the extracellular compartment. In lactation-associated hypocalcaemia, it is the result of the body’s inability to maintain serum iCa through increased osteolytic activity and gastrointestinal calcium absorption, and reduced renal calcium excretion to compensate for the loss of calcium through milk production.

    Other factors often predispose animals to developing eclampsia. These can include poor periparturient nutrition, excessive calcium supplementation and large litter size.

    Excessive calcium supplementation in the prenatal period causes parathyroid gland atrophy, preventing parathyroid hormone release – resulting in reduced gastrointestinal calcium absorption and osteoclastic activity, and increased kidney calcium loss.

    Clinical signs

    Clinical signs can progress rapidly and become fatal if left untreated.

    In the early phases, non-specific signs can present as:

    • facial pruritus
    • hyperaesthesia
    • panting
    • tremors
    • muscle fasciculations
    • paresis
    • ataxia

    Within a few hours, these clinical signs rapidly progress to rigidity, and tonic and clonic spasms with opisthotonos. By this stage, animals will develop severe tachycardia, tachypnoea and hyperthermia. Without treatment, a high mortality rate exists.

    kitten
    “Early supplementation of puppies and kittens with commercial milk formula will significantly reduce the lactation demand on the dam.” Image © Dobroslav / Adobe Stock

    Patients presenting with eclampsia require immediate medical intervention, as well as concurrent supportive therapy. The acute management of clinical iHCa is the same, regardless of the cause, and will be discussed in detail in part three.

    Supportive therapies required to manage and prevent a patient relapsing in eclampsia often include active cooling and glucose supplementation. In cases that seizure, anti-seizure medications – such as diazepam and barbiturates – and mannitol for cerebral oedema may be required.

    Prevention

    Even before getting to the stage where an animal requires treatment, all effort must be taken to prevent a dam from developing hypocalcaemia. This can be easily achieved by improving the calcium content of the food during the perinatal period, as well as reducing the milk demand by early weaning kittens or puppies. This is likely particularly helpful for those with a history of eclampsia or with large litters.

    From the second half of gestation, it is recommended a commercial formulation of puppy/kitten food (1% to 1.8% calcium and 0.8% to 1.6% phosphorus) is to be fed to the dam without any additional minerals or vitamin supplementation.

    Postpartum calcium is similar to the second half of gestation, requiring a diet containing at least 1.4% calcium with a 1:1 ratio with phosphorus (most balanced growth formula for puppies and kittens).

    Less demand

    Early supplementation of puppies and kittens with commercial milk formula will significantly reduce the lactation demand on the dam. Together with this, starting at aged three to four weeks, solids can be introduced at this time. These techniques will be particularly helpful to those with a history of previous eclampsia or those with large litter sizes.

    Aside from the parenteral calcium supplementation required, other supportive therapy – such as active cooling, IV fluid therapy and glucose supplementation – may be required.

    Long term, the dam’s nutritional content of calcium must be optimal from the second half of gestation. All additional calcium or other vitamins and mineral supplementations should not occur prior to parturition.

    In the postpartum dam with a history of eclampsia or that is at risk, changing to a nutritionally balanced commercial food aim for growing puppies and kittens is ideal. Early weaning – or abrupt weaning if hypocalcaemia is severe – may be required in severe cases or those with a high risk of relapse/development.

  • Ionised hypocalcaemia, pt 1: introduction

    Ionised hypocalcaemia, pt 1: introduction

    Low ionised calcium (iCa) is a widely recognised electrolyte disturbance in critically ill human patients who have undergone surgery, are septic, have pancreatitis, or have sustained severe trauma or burns.

    Similar changes occur in our critical canine and feline patients, though less well documented.

    Calcium plays a vital role in a myriad of physiological processes in the body, so any deviation from the very narrowly controlled range is associated with severe repercussions.

    Low iCa has many causes; however, this three-part blog will only focus on the more common and peracute to acute causes. It will also discuss the treatment of low iCa and the controversy behind treatment of iCa in critically ill patients.

    Forms

    Calcium in the serum or plasma exists in three forms:

    • ionised or free calcium
    • protein-bound calcium
    • complexed or chelated calcium (bound to phosphate, bicarbonate, sulfate, citrate and lactate)

    iCa is the biologically active fraction of calcium and is not to be confused with total calcium (tCa). A lack of concordance exists between the two. Adjustment formulas are inaccurate, even with the correction of the tCa to serum total protein or albumin concentration, and should not be used to predict iCa.

    The normal reference range for iCa in dogs is 1.2mmol/L to 1.5mmol/L; in cats, it is 1.1mmol/L to 1.4mmol/L.

    Function

    An example of low ionised calcium.
    An example of low ionised calcium.

    Calcium is essential in maintaining normal physiological processes in the body. iCa regulates:

    • vascular tone
    • myocardial contraction
    • homeostasis

    In addition, it is needed for:

    • enzymatic reactions
    • nerve conductions
    • neuromuscular transmission
    • muscle contraction
    • hormone release
    • bone formation
    • resorption

    In critical patients, particularly those with severe trauma or sepsis, vascular tone and coagulation is particularly important. For this reason, iCa is tightly kept in a narrow range and regulated by the interactive feedback loop that involves iCa, phosphorous, parathyroid hormone, calcitriol and calcitonin.

    Diseases and causes

    Diseases commonly associated with low iCa in dogs and cats include:

    • acute kidney failure
    • acute pancreatitis
    • diabetic ketoacidosis
    • eclampsia
    • ethylene glycol intoxication
    • protein-losing enteropathies
    • sepsis
    • trauma
    • urethral obstruction
    • parathyroid diseases
    • tumour lysis syndrome

    Situations altering the fraction of extracellular calcium seen on a regular basis include:

    • acid-base disturbances
    • lactic acidosis
    • protein loss or gain
    • increased free fatty acids

    Iatrogenic causes include:

    • citrate (anticoagulant) administration during blood transfusions
    • phosphate
    • bicarbonate
    • sulfate administration

    Low iCa can also develop during cardiopulmonary resuscitation, quickly declining with increased duration.

    • Part two will go into more depth regarding the most common causes of low iCa that require acute treatment, the treatment involved, controversies surrounding treatment of non-clinical low iCa, and prognostic indications.
  • Handling an Addisonian crisis – part 1

    Handling an Addisonian crisis – part 1

    Addison’s disease (hypoadrenocorticism) is one of those annoying diseases that does not always play by the rules.

    One of the main reasons is the clinical signs of Addison’s disease can be frustratingly non-specific and we don’t often see the classic “low sodium, high potassium” electrolyte changes we are attuned to noticing. Therefore, it is important to recognise the early signs, or have a set of clinical signs, history and biochemistry changes that trigger the Addison’s disease alarm bells.

    Once diagnosed, we can look at the approach to stabilising a patient in an Addisonian crisis.

    Clinical signs

    The clinical signs of Addison’s disease can be vague and non-specific, these include:

    • anorexia
    • lethargy
    • weakness
    • gastrointestinal signs
    • polyuria and polydipsia

    A history of chronic intermittent vomiting and/or diarrhoea that resolves with symptomatic management would be one of the triggers.

    Another trigger is the subtle changes in blood tests. These include:

    • the absence of a stress hyperglycaemia in a sick patient (normal glucose or even a low blood glucose, for example)
    • hypercalaemia (ionised) of any degree
    • absence of stress leukogram

    These changes are often seen in isolation, so don’t expect them to all be there at the same time. We see patients all the time with inappropriately normal or low blood glucoses with gastrointestinal signs that we later diagnose with Addison’s.

    Hypercalcaemia – what’s the big deal?

    Why hype up and down about normal or low blood glucoses? Because low blood glucoses are rarely caused by inappetence or gastroenteritis alone, and the body is pretty good at maintaining glucose within normal levels (except, maybe, for very young patients and some toy breeds). Any low glucose Addison’s should be considered, and a stress hyperglycaemia is so common in ill patients that its absence makes me concerned.

    What is the big deal about hypercalcaemia? It is so tightly regulated that any elevation Addison’s is on the differential list. How does Addision’s cause these changes? Corticosteroids are released during stress or ill states, which result in a stress hyperglycaemia. They also play a role in the excretion of calcium in the urine, so preventing a hypercalcaemia.

    What about the electrolyte changes, the hyponatraemia and hyperkalaemia? When these changes are present they make diagnosis much easier, but they are not always present, such as with “atypical hypoadrenocorticism”, so the absence of that classic change does not rule out Addison’s.

    Next, we will cover the management of the Addisonian crisis.

  • SNAP cortisol test

    SNAP cortisol test

    While hyperadrenocorticism is not an uncommon incidental finding in patients presenting to our emergency clinic, hypoadrenocorticism is a lot less common. Or, possibly, more frequently underdiagnosed.

    Textbook clinical presentations combined with haematology and biochemicial changes can make diagnosis straightforward, but not all patients will present with all the classic signs.

    SNAP cortisol test
    The SNAP cortisol test is a quantitative ELISA test that measures the level of serum cortisol in dogs.

    To complicate things further, hypoadrenocorticism is the great mimicker of diseases; it is often impossible to arrive at a definitive diagnosis without knowing the cortisol levels.

    The SNAP cortisol test allows clinicians to determine cortisol levels in-house – a blessing to those of us who work out-of-hours – but is not without its limitations.

    Suspicious signs

    Patients with hypoadrenocorticism often present with vague and non-specific clinical signs, but certain clinicopathological changes help raise the suspicion:

    • a decrease in sodium-to-potassium ratio (below 1:27)
    • azotaemia
    • an inappropriately low urinary specific gravity, despite evidence of dehydration or hypovolaemia
    • a leukogram unfitting to the degree of illness of the patient (a “reverse stress leukogram”- neutropenia, lymphocytosis, eosinophilia)
    • anaemia
    • hypoglycaemia
    • hypercalcaemia

    Although most Addisonian patients will not present with all these signs – especially those in the early stages of disease or those with atypical Addisonian disease (glucocorticoid insufficiency only) – any patients showing any of these haematology and biochemicial changes should have hypoadrenocorticism ruled out as part of the diagnostic plan.

    Imperfect ELISA

    The SNAP cortisol test has been advertised as an in-house assay to aid the diagnosis, treatment and management of both hyperadrenocorticism and hypoadrenocorticism, although the quality of the result is not perfect. This quantitative ELISA test measures the level of serum cortisol in dogs.

    In one study1, the SNAP cortisol test appears to have a good correlation with an external laboratory chemiluminescent assay test; however, in 12.8% of cases (5 of 39 patients), the SNAP test result could have led to a different clinical decision regarding the management of the patient.

    Since long-term Cushing’s management relies on reliable, repeatable cortisol level detection, this high level of discrepancy is unacceptable, especially when more accurate alternatives are available at external laboratories.

    Still useful

    Despite this, it is still very useful helping to assess for the presence or absence of hypoadrenocorticism, especially in an emergency setting.

    I use the SNAP cortisol to measure the resting cortisol level. If it is below 2ug/dL or in inconclusive range (between 2ug/L and 6ug/L), but the clinical picture suggests hypoadrenocorticism, I would perform an adrenocorticotropic hormone (ACTH) stimulation test and send samples to an external laboratory. If it is well above the inconclusive range, I would not perform an ACTH stimulation test.

    In summary, I think the SNAP cortisol test can be useful in helping assess for hypoadrenocorticism, but would still recommend performing an ACTH stimulation test and running the samples externally.

    However, use it with caution for hyperadrenocorticism diagnosis and its long-term management – especially when more accurate and economical alternatives are available.