Significance of the critical limits for patient outcomes
For many analytes (e.g. troponins, CRP, D-dimer) there is no definitive concentration that constitutes a significant acute health risk, and in such cases the clinical picture will be more of a deciding factor than the actual analytical result. In the case of other analyses (e.g. electrolytes) patients may have very abnormal or life-threatening values without there being any clear clinical symptoms. For such analyses there may be documentation for when a concentration is associated with a serious condition requiring treatment.
With chronic hyponatraemia, symptoms do not usually occur at serum sodium concentrations of over 120 mmol/l (11) – (13), while if there is a rapid fall (less than 24 hours), nausea and faintness occur already at concentrations of less than 125 – 130 mmol/l. If the sodium concentration in the blood falls further (below 115 – 120 mol/l), life-threatening complications may arise (11, 14) – (17). Serious symptoms of hypernatraemia usually do not occur before the sodium concentration in the plasma/serum exceeds 158 mmol/l. Studies have shown that clinics rapidly react and take action if sodium concentrations of less than 120 or more than 155 mmol/l are found (18).
In cases of severe hypokalaemia (defined as potassium < 2.5 mmol/l (19)) patients may experience muscular weakness and muscular cramps, in addition to ECG changes and cardiac arrhythmias (20). However, cardiac arrhythmias are rare in patients without known comorbid heart disease (19). Severe hypokalaemia may result in rhabdomyolysis and paralysis (21). Hyperkalaemia may result in muscular weakness, paralysis, severe cardiac arrhythmias and death. The risk of arrhythmia is higher for potassium values greater than 6.0 mmol/l, but is particularly high when potassium is > 6.5 mmol/l (22). There is evidence that patients with renal failure and chronic hyperkalaemia are less susceptible to fatal arrhythmias than patients who develop acute hyperkalaemia (23).
Phosphate deficiency can cause symptoms stemming from the central nervous system, musculature and heart (24). Serious symptoms do not usually develop before the serum phosphate concentration is less than 0.3 mmol/l (25, 26).
There is no clear correlation between calcium concentration and symptoms. The degree of seriousness is determined primarily by how rapidly the hypo- or hypercalcaemia develops. (27). Tetany seldom occurs before total calcium falls below 1.9 mmol/l (28) and in rare cases low total calcium may result in serious arrhythmias (28). Chronic moderate hypercalcaemia with calcium values of 3.0 – 3.5 mmol/l may be tolerated relatively well, while the patient may become serious ill, possibly with clouded consciousness, if the hypercalcaemia develops rapidly. Patients with total calcium of over 3.5 mmol/l must be hospitalised immediately and treated, irrespective of what symptoms they might have (29). In rare cases, severe hypercalcaemia may increase the risk of both supraventricular and ventricular cardiac arrhythmias (30).
Severe hypomagnesaemia is defined as magnesium of less than 0.5 mmol/l (31) and is associated with ventricular arrhythmias, particularly in myocardial infarction patients (32). In contrast to hypomagnesaemia, hypermagnesaemia is rare (33). Typical symptoms are neuromuscular (34) – (38), cardiovascular (34, 36, 38) and metabolic (34, 39, 40). The first, mild symptoms of hypermagnesaemia can be observed with magnesium concentrations in the plasma/serum of over 2.0 mmol/l, while magnesium concentrations of over 3.0 mmol/l may extend the atrioventricular conduction time and concentrations of over 5 mmol/l may cause paralysis and cardiac and respiratory arrest (36, 41).
Diabetic ketoacidosis and hyperosmolar, non-ketotic hyperglycaemia may by definition occur at glucose values of 13.9 and 33.3 mmol/l respectively (42). One study shows that the average serum glucose level of adults with diabetic ketoacidosis is 25.7 mmol/l (SD 0.9), while the corresponding value in children is 28.0 mmol/l (SD 1.4) (43).
It is difficult to find documented risk of infection associated with a low leukocyte concentration in isolation. When about 1100 samples with a neutrophil granulocyte concentration of from 0.4 to 0.6·10⁹/l were tested, the leukocyte concentration varied from 0.5 to 5.5 · 10⁹/l. In 90 % of these samples, the leukocyte concentration was < 3.0·10⁹/l. Thus the leukocyte count can vary very considerably with neutropaenia, so the quantity of neutrophil granulocytes should be studied in this situation. The acute health risk represented by a high leukocyte count alone is associated with the risk of leukostasis, tumour lysis syndrome and disseminated intravascular coagulation (DIC) in connection with malignant blood diseases (44). These conditions are rare with leukocytes < 100· 10⁹/l.
The risk of infection with a low concentration of neutrophil granulocytes in the blood depends largely on what reserves the patient has in the bone marrow. There is little correlation between risk of infection and granulocyte concentration in patients with leukopaenia and otherwise normal bone marrow (45). In cancer patients with therapy-induced bone marrow depression, the risk of infection increases when the granulocyte count falls below 1.5·10⁹/l. At concentrations of < 0.5·10⁹/l the risk of infection increases substantially and isolation is called for (46).
There is no evidence of any acute risk of major bleeding in cases of thrombocytopaenia before the thrombocyte concentration is < 15 ·10⁹/l (47, 48). Thrombocytosis (> 500 ·10⁹/l) results in a somewhat higher risk of thromboembolic episodes (49). Values > 1000 ·10⁹/l imply a somewhat increased risk of acquired von Willebrand syndrome and of bleeding (50). Thus there is little acute health risk associated with thrombocytosis.
The risk of bleeding complications increases with rising PT-INR values. Studies have shown that the relative risk (number of incidents divided by the total number exposed compared for two cohorts) of major bleeding events increases by about 1.4 per unit increase in the PT-INR (51). For INR values of over 4.5, the relative risk of bleeding complications thus increases to about six (52). Another study shows that the odds ratio (number of patients with events/number of patients without bleeding events compared for two cohorts) for intracranial haemorrhage first increases when the PT-INR exceeds 4.0, and at a PT-INR of about 5, the odds ratio can be estimated at approximately five (53).