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Tag: Calcium

  • 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 3: acute treatment and management

    Ionised hypocalcaemia, pt 3: acute treatment and management

    Treatment of ionised hypocalcaemia (iHCa) is reserved for patients with supportive clinical signs, then divided into acute and chronic management.

    Since the most common cases of clinical hypocalcaemia in canine and feline patients are acute to peracute cases, this blog will focus on the acute treatment and management of hypocalcaemia.

    Clinical signs

    The severity of clinical signs of iHCa is proportional to the magnitude, as well as the rate of decline in ionised calcium (iCa) concentration.

    The normal reference range for iCa is 1.2mmol/L to 1.5mmol/L in dogs and 1.1mmol/L to 1.4mmol/L in cats. Serum iCa concentrations in younger dogs and cats are, on average, 0.025mmol/L to  0.1mmol/L higher than adults.

    Mild iHCa (0.9mmol/L to 1.1mmol/L) – as seen in critically ill dogs and cats with diabetic ketoacidosis, acute pancreatitis, protein-losing enteropathies, sepsis, trauma, tumour lysis syndrome or urethral obstructions – often has no observable clinical signs.

    Moderately (0.8mmol/L to 0.9mmol/L) to severely (lower than 0.8mmol/L) affected animals – in the case of eclampsia and those with parathyroid disease – often display severe signs.

    Early signs of iHCa are often non-specific, and include:

    • anorexia
    • rubbing of the face
    • agitation
    • restlessness
    • hypersensitivity
    • stiff and stilted gait

    As the serum iCa concentration further decreases, patients often progress to:

    • paresthesia
    • tachypnoea
    • generalised muscle fasciculations
    • cramping
    • tetany
    • seizures

    In cats, the gastrointestinal system can also be affected, presenting as anorexia and vomiting.

    Treatment

    The need for treatment of hypocalcaemia is dependent on the presence of clinical signs, rather than a specific cut-off of serum concentration of iCa itself.

    Moderate to severe iHCa should always be treated. Mild hypocalcaemia, on the other hand, may not be necessary, especially if it is well tolerated. It should be remembered the threshold for development of clinical signs is variable, and treatment may benefit critical cases with an iCa concentration of less than 1.0mmol/L.

    Treatment is divided into the acute treatment phase and chronic management.

    In the tetanic phase, IV calcium is required – 10% calcium gluconate (equivalent to 9.3mg/ml) administered at 0.5ml/kg to 1.5ml/kg dosing to effect. This should be administered slowly with concurrent ECG monitoring. Infusion of calcium needs to be stopped if bradycardia develops or if shortening of the QT interval occurs.

    Some suggest calcium gluconate (diluted 1:1 with 0.9% sodium chloride) of half or the full IV dose can be given SC and repeated every six to eight hours until the patient is stable enough to receive oral supplementation. However, be aware calcium salts SC can cause severe necrosis or skin mineralisation.

    Calcium chloride should never be given SC, as it is a severe perivascular irritant.

    Correcting iCa

    Irrespective of the chronicity of the treatment, the rule of thumb is correction of calcium should not exceed 1.1mmol/L.

    Correction of iCa to normal or hypercalcaemic concentration should always be avoided, as this will result in the desensitisation of the parathyroid response, predisposing renal mineralisation and formation of urinary calculi.

    Some of the more common calcium supplementation medications – both parenteral and oral formulas – are detailed in Table 1. Supplementation of magnesium may also benefit some patients, as it is a common concurrent finding in critically ill patients with iHCa.

    Table 1. Common calcium supplementation medications
    Drug Calcium Content Dose Comment
    Parenteral calcium
    Calcium gluconate
    (10% solution)    		 9.3mg/ml
    i) slow IV dosing to effect (0.5ml/kg to 1.5ml/kg); acute crisis, 50mg/kg to 150mg/kg over 20 to 30 minutes
    ii) 5mg/kg/hr to 15mg/kg/hr IV or 1,000mg/kg/day to 1,500mg/kg/day (or 42mg/kg/hr to 63mg/kg/hr)
    Stop if bradycardia or shortened QT interval occurs.
    Infusion to maintain normal Ca level
    SC calcium salts can cause severe skin necrosis/mineralisation.
    Calcium chloride
    (10% solution)    		 27.2mg/ml 5mg/kg/hr to 15mg/kg/hr IV Do not give SC as severe perivascular irritant
    Oral calcium
    Calcium carbonate
    (many sizes)    		 40% tablet 5mg/kg/day to 15mg/kg/day
    Calcium lactate
    (325mg, 650mg)    		 13% tablet 25mg/kg/day to 50mg/kg/day
    Calcium chloride
    (powder)    		 27.2% 25mg/kg/day to 50mg/kg/day May cause gastric irritation
    Calcium gluconate (many sizes) 10% 25mg/kg/day to 50mg/kg/day

    Next time…

    The next blog will look at the pathophysiology behind iHCa among critically ill animals. It will also look at the controversy regarding treatment of non-clinical iHCa cases and the prognostic indications of iCa concentrations.

  • 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.
  • Lipaemia – the bane of biochemistry

    Lipaemia – the bane of biochemistry

    Last week we covered haemolysed samples – this week we’re looking at lipaemic samples.

    Lipaemic samples are caused by an excess of lipoproteins in the blood, creating a milky/turbid appearance that interferes with multiple biochemical tests and can even cause haemolysis of red blood cells.

    lipaemic sample
    A severely lipaemic sample (red arrow). IMAGE: eClinPath.com (CC BY-NC-SA 4.0).

    Lipaemia can follow recent ingestion of a meal – especially one high in fat. Although not pathognomonic for any diseases, its presence can help increase the suspicion of certain diseases, including:

    • pancreatitis
    • diabetes mellitus
    • hypothyroidism
    • hyperadrenocorticism
    • primary hyperlipidaemia (in some specific breeds, such as the miniature schnauzer)

    It warrants further investigation in patients that have been ill and inappetent.

    Irksome interpretations

    Lipaemia can dramatically impact laboratory testing and is often troublesome in critically ill patients, making interpretation of biochemistry particularly difficult, if not impossible.

    Lipaemia can affect different analysers in different ways, most commonly causing:

    • Falsely increased calcium, phosphorus, bilirubin, glucose and total protein (via refractometer) and some liver parameters such as alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, haemoglobin concentration, and mean corpuscular haemoglobin concentration.
    • Falsely decreased sodium, potassium, chloride, albumin and bicarbonate.

    Tube tips

    Assessment of a centrifuged haematocrit tube before running a biochemistry panel can help reduce wasted biochemistry consumables.

    If the sample is lipaemic in the haematocrit tube then maybe try some of the following tips.

    • If blood tests are planned in advance, try fasting the patient beforehand for 12 to 24 hours.
    • Repeat sampling a couple of hours later may yield a less lipaemic sample.
    • Collecting and centrifuging a larger amount of blood (3ml to 5ml, for example) can sometimes yield enough clear sample between the lipid layer and red blood cells.
    • Refrigeration of the sample can help the separation.
    • Extract lipids using polar solvents, such as polyethylene glycol.
    • Centrifugation at higher than normal speeds (if possible) can also assist in clearing the layer.
  • PCV/total solids interpretation: serum colour

    PCV/total solids interpretation: serum colour

    When interpreting the often misinterpreted and underused PCV and total solids test, it is important to take note of the serum colour as this may give clues into the diagnosis.

    PCV tubes
    Normal serum colour (left) compared to a patient with immune-mediated haemolytic anaemia. The serum is haemolysed and anaemia is present.

    The most common abnormalities seen in clinic are icteric, haemolysed and lipaemic serum.

    Clear serum can also be of importance – especially when you interpret it with blood counts and urine colour.

    Haemolysis

    The most common abnormality of serum colour changes is haemolysis. In my experience, the most common cause is suboptimal collection technique. To confirm this, simply collect another sample and repeat.

    If it is repeatable, and concurrent anaemia or pigmenturia is present, it warrants further investigation.

    Intravascular haemolysis can be caused by:

    • immune-mediated haemolytic anaemia
    • blood transfusion reactions
    • infectious diseases such as Mycoplasma haemofelis, Babesia canis, Ehrlichia canis, FeLV and others
    • Heinz bodies from the ingestion of heavy metal, onions or paracetamol
    • hypophosphataemia
    • macroangiopathic disease (neoplasia, for example)
    • envenomation – typically, snake bites

    Testing issues

    Haemolysis can also affect other laboratory testing. It can lead to an artefactual increase in glucose, phosphorus, bilirubin, total protein, fructosamine and triglycerides, and a decrease in sodium (pseudohyponatraemia), cholesterol, calcium, potassium and albumin.

    Extravascular haemolysis often does not cause haemolysed serum as it is generally slower and the body is able to clear the haemoglobin before it can lead to discolouration of the serum.