Test strip reading - Cats Negative Trace

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1 WHAT I LEARNED FROM MY DIABETIC CAT: DIAGNOSIS AND MONITORING Ellen N. Behrend, VMD, PhD, DACVIM Although diagnosis of diabetes mellitus (DM) is usually a no-brainer, it can sometimes be difficult, especially in cats. Overall, the same techniques we use to monitor can potentially be used for diagnosis; doing a full glucose curve is an exception. One consideration is how accurate glucose test strips are for measurement of glucosuria. The test strips only measure the presence of a reducing substance and other compounds, e.g. cephalexin and enrofloxacin 1, can cause false positive tests. In addition, the presence of ketones can decrease the sensitivity of the test. We did a small research project on the accuracy of the Bayer Multistix for measurement of glucose in canine and feline urine. On the Multistix chart, trace = 100 mg/dl glucose, 1+ = 250 mg/dl, 2+ = 500 mg/dl, 3+ = 1000 mg/dl and 4+ = > 2000 mg/dl and the sensitivity is mg/dl. Thus, based on the color chart, we assigned a negative reading = <75 mg/dl, 1+ = mg/dl, 2+ = mg/dl, and 3+ = >750 mg/dl. The Multistix are not highly accurate at least in dogs, tending to underestimate urine glucose. Actual glucose concentration (Expected reading; # cases) <75 mg/dl (Negative; n=135) mg/dl (Trace; n=89) mg/dl (1+; n=13) mg/dl (2+; n=4) >750 mg/dl (3+; n=9) Test strip reading - Dogs Negative Trace Actual glucose concentration <75 mg/dl (Negative) (n=51) mg/dl (Trace) (n=3) mg/dl (1+) (n=1) mg/dl (2+) (n=1) >750 mg/dl (3+) (n=0) Test strip reading - Cats Negative Trace To get the most accurate measurement and to ensure that glucose is really present in the urine, based on these results, it is best to have the lab measure urine glucose concentration as they would serum. Given the difficulty of using the Multistix we did a small project looking at the use of glucometers for measurement of urine glucose concentration. We used the Alphatrak as well as the Accuchek in dogs and cats. Unfortunately, the results were not promising (unpublished data). Another possible means to differentiate stress hyperglycemia and DM is measurement of glycosylated proteins, either glycosylated hemoglobin or fructosamine. Glycosylated hemoglobin (GHb)

2 is formed by non-enzymatic, irreversible binding of glucose to hemoglobin. 2 Fructosamine refers to glycosylated serum proteins, mainly albumin. 3 Both GHb and fructosamine form at a rate proportional to the average BG present, so the higher the mean BG concentration over time, the greater their concentrations should be. The levels of glycosylated proteins are also affected by the half-life of the native protein. Thus, GHb reflects glycemic control over the previous 2-3 months, while fructosamine reflects that over the previous 2-3 weeks. As with any laboratory test, care must be taken to use the correct sample handling techniques and methodology for measurement, and limitations of the test must be recognized. Cats may have lower normal GHb concentrations than dogs 4 and normal ranges vary between laboratories, so it is necessary to be sure that the laboratory has its own established normal ranges for dogs and for cats and to use those in interpreting values obtained. Anemia may lower GHb concentrations. As with GHb, ranges for serum fructosamine concentration vary between laboratories. Within the normal range, serum protein does not affect fructosamine; however when serum protein concentration is less or greater than normal, fructosamine levels may be decreased or increased, respectively. Both parameters correlate with BG and are typically not affected by stress. However, the value obtained from the laboratory must be interpreted in conjunction with all other data. Normal animals or well-controlled diabetics can have elevated concentrations of either GHb or fructosamine, and, conversely, uncontrolled diabetic animals can have normal levels of either. Fructosamine may be elevated in sick, hyperglycemic, but non-diabetic cats. A good option for monitoring urine glucose at home in cats is the Purina Glucotest. We did a study at Auburn that showed that the Glucotest tends to overestimate urine glucose concentrations in the midranges (50-300mg/dL), even when exposed to urine glucose concentrations that directly correlate with the published color chart. However, the overestimation was by one category, e.g. 50 read as 150 mg/dl and would be likely clinically irrelevant. The color change read at 8 were more accurate than the initial readings, but the change over time is not consistent with the labeled 8-hr color stability claim. Again, the change over time was typically by one category. 5 The Glucotest is designed for cats, but given the low accuracy of the Multistix, we have done a small project assessing the Glucotest for dog urine. Unfortunately, for dogs, the Glucotest do not appear to be accurate (unpublished data). One question to ask, is what are we looking for in monitoring diabetics, or, in other words, what is the goal of therapy? At all costs, hypoglycemia should be avoided. On the flip side, how high can BG go? The goal of therapy is to get rid of the clinical signs in order to provide a good quality of life for the pets and clients. The strict control aimed for in human diabetics is not practical and may not be necessary in veterinary patients. Strict control in humans is required to avoid serious diabetic complications such as nephropathy, retinopathy, vasculopathy, etc. For whatever reason, these complications are not prevalent in veterinary populations. To get rid of clinical signs, BG needs to be below the renal threshold the majority of the time, i.e. < approximately 200 mg/dl in dogs and approximately mg/dl in cats. Performance of in-hospital blood glucose curves has long been the gold standard for assessing diabetic control. To construct a curve, BG is measured in general every 2 hrs for one interval between injections, i.e. for 12 hrs if insulin is administered twice daily and for 24 hrs if insulin is given once daily. For glargine, the suggestion has been made to only measure BG every 4 hours, but I still measure BG q 2 hrs. When BG is <125 mg/dl, the concentration should be measured hourly. A normal insulin/feeding schedule must be maintained as much as possible. If a patient does not eat the normal amount of the normal food at the usual time, the serial glucose curve should probably not be performed. The patient should be fed its standard diet at the usual time and the insulin given by the owner in the hospital so the owner s injection technique can be assessed. Obtaining a fasting blood sample for measurement of BG prior to insulin injection can aid in appraisal of glycemic control, but this may not be possible if normal feeding time occurs before the hospital opens. Furthermore, feeding a dog or cat at home may ensure that the pet will eat. If the patient is fed at home, the insulin should then be given by the owner either at home or, especially if owner technique is questionable and needs to be assessed, in the hospital in front of a technician or veterinarian. Clearly, cooperation between client and veterinarian is necessary to maximize the information obtained with minimal disturbance to routine. If given a choice between obtaining a fasting BG sample or assessing owner injection technique, choose to assess the owner's technique.

3 A curve should be performed the first day insulin is given. Glucose concentrations may be lower than expected after the first 24 to 48 hours of insulin therapy, especially in cats as stress hyperglycemia resolves 6. This first curve is done solely to ensure that hypoglycemia does not occur. If hypoglycemia is found, the insulin dose should be decreased 25% and another curve done the following day with the same goal in mind to check for hypoglycemia. The insulin dose should not be increased based on the first day s curve. A patient requires 5-7 days on a dose of insulin to equilibrate and reach maximal effect. Another glucose curve should be performed 7 days after discharge. Based on assessment of the curve, the insulin dose can be increased or decreased as deemed necessary. A serial glucose curve should establish the time to peak insulin effect, duration of effect and degree of fluctuation in BG. The pattern of insulin effect should be used to determine dose, interval, and feeding schedule. Ideally, glucose concentrations should reach a nadir at 80 to 150 mg/dl. The highest glucose concentration should be close to 200 to 250 mg/dl in dogs or 300 mg/dl in cats. The actual nadir and peak concentrations in a patient will probably be lower, or higher, respectively, than measured because the exact time of nadir and peak effects of insulin are not known. Changes in the dose of insulin can usually be made without affecting the duration of effect. The glucose differential is the difference between the nadir and the BG prior to the next dose, and can be a measurement of insulin effectiveness. 7 If the curve is relatively flat, e.g. differential of mg/dl, the insulin, with the exception of glargine where such curves are expected, may not be having a desired effect. The absolute BG must also be taken into consideration. If all BG are < 200 mg/dl, the insulin is very effective. However, if all BG are between mg/dl, then the insulin is ineffective at that dose, stress hyperglycemia is present or you have caught a patient post- Somogyi (for a number of hours after a Somogyi phenomenon, insulin resistance will be present). In assessing a glucose curve, whether it is the first curve performed on a patient or the last of many, two basic questions need to be asked. First, has the insulin succeeded in lowering BG? And, second, how long has the insulin lasted? By answering these questions, logical changes in dosing regimen, if necessary, can be made. Results of a serial glucose curve should always be interpreted in light of clinical signs. Curves in dogs can vary from day to day 8 and do in cats as well. 9 Stress hyperglycemia can also falsely elevate results. If a patient is not polyphagic, polydipsic or polyuric and body weight is stable or increasing, diabetic control is likely good. The first aim in regulating a diabetic is to achieve an acceptable nadir. (Note: this is true for all insulins EXCEPT glargine. For insulin glargine, dose adjustment is made based on the pre-insulin glucose concentration.) In general, if an acceptable nadir is not achieved, the insulin dosage should be adjusted depending on the size of the animal and the degree of hyperglycemia. Usually changes of approximately 10% are appropriate. Obtainment of an acceptable glucose nadir may not be possible in some animals, however, if insulin with a short duration of activity is used. In these patients, the BG is typically quite high in the morning since there has been inadequate control for most of the previous day. Even if an insulin injection is capable of lowering BG, it does not have a long enough effective period to lower BG into an acceptable range. In other words, a glucose curve in this situation shows a noticeable but brief decrease in BG after the insulin injection. Hypoglycemia should always be avoided. No matter what other BG concentrations are during the day, if the value of the BG nadir is <80 mg/dl, a reduction in insulin dosage is indicated. Decrease the dose 25% if there are no signs of hypoglycemia and 50% if there are signs, and then do another curve to ensure hypoglycemia does not recur. Once an acceptable nadir is accomplished, duration of action, roughly defined as the time from the insulin injection through the lowest glucose and until the BG exceeds 200 to 250 mg/dl, can be determined by a glucose curve. If the dose of insulin is inadequate and the target glucose nadir has not yet been achieved, the dose must be increased until the nadir is acceptable before duration of effect of the insulin can be determined, i.e., duration and nadir cannot be assessed at the same time if one or the other is insufficient. Once control has been achieved, glucose curves should be performed to assess adequacy of glycemic control every 3 to 6 months or earlier if clinical signs suggest that control has been lost. The more precarious the control, the more frequently rechecks should be done. As during the initial curves, if the nadir is unacceptable, the insulin dose must be lowered or raised accordingly. If duration of action appears to have changed, then the same modifications as discussed above can be made. Admittedly, glucose curves are not perfect. As discussed above, they can vary from day to day. However, they serve 2 very useful purposes that other techniques do not. First, they can clearly show clinically undetectable hypoglycemia. A phenomenon exists in human diabetics referred to

4 as hypoglycemic unawareness. In this situation, the body does not respond to mild or even moderate hypoglycemia as in normal patients and clinical signs do not develop. However, when moderate to severe hypoglycemia occurs, profound clinical signs appear acutely without warning. Although unproven, I believe the same occurs in veterinary patients. I certainly have seen patients that the owners thought were doing well until they seizured. Certainly, it could be that the owners were not observant or were absent during the hours of the day when the patient was hypoglycemic, but I do not think that fits all such cases I have seen. A glucose curve will hopefully document mild hypoglycemia that can be fixed before a seizure occurs. Thus, periodic curves can be helpful even in a seemingly well controlled patient. Secondly, and more importantly, other techniques and clinical signs can suggest that control is lacking, but the only way to know how to change the therapy to gain control is by performance of a curve. Although performance of glucose curves in-hospital has been considered the gold standard, problems exist with this method as well. Owners can measure BG at home and perform other tests that can be helpful as well. Although owner observation of the presence or absence of clinical signs is very important, judgment of adequacy of control should not rely solely on owner reports. Recent emphasis has been placed on finding better monitoring methods. Glucose curves can be affected by the stress of hospitalization and deviation from normal routine. One study recently assessed day-to-day variability of serial glucose curves in diabetic dogs and found some change even on consecutive days. 8 One important point from the study was that due to the variation, predicting the timing of a diabetic s nadir on the basis of previous serial glucose curves and obtaining a single sample at that time is unlikely to give a reliable result 8, i.e. spot checking does not provide helpful information. It should also be recognized that glucose curves can vary day to day when done at home as well. 10 In order to avoid some of the problems associated with in-hospital curves, performance of glucose curves at home has taken on new importance. For home glucose curves, it is not necessary for venous blood to be collected. Capillary blood is suitable. 11 Choices of sites are the ear, gum, foot pads or elbow callus. To me, the gum and foot pads are not recommended due to associated pain. I have not tried using the elbow callus. Two types of lancing device are available. If using conventional automatic devices designed for pricking human fingertips, a device with a variable needle depth should be chosen. The appropriate depth for each patient can then be used. 12 Warming of the ear with a hair dryer or a warm, wet washcloth enclosed within a plastic bag may be necessary but not well tolerated, and it may take up to 2 minutes to obtain an adequate sample. 12 A device which creates a vacuum after lancing the skin (e.g. Microlet Vaculance, Bayer) does not require warming of the ear and generates an adequate drop of blood within approximately 30 seconds 12, but mastery may be a bit difficult and require repeated instruction. 11 A needle can be used as well, especially if the marginal ear vein is the site of blood collection. 13 Glucometers that require minimal amounts of blood as well as those that sip the blood into the strip are desirable. Training of owners to perform home glucose curves takes time. Not all owners are suited to perform such a task. A small study of 9 owners of diabetic dogs (n=7) and cats (n=2) indicated that, at least in that population, the most frequently encountered problems were the need for more than 1 puncture to obtain a blood drop, the creation of a sufficient blood drop, the need for assistance in restraining the pet and the resistance of the pet. Two dogs became more resistant over time and the owners abandoned the technique. The 2 cats become more compliant, especially as the technique was performed in a place chosen by the cat. 13 Continuous monitoring of glucose concentrations has also received attention of late. 14;15 The CGMS (Continuous glucose monitoring system, Minimed) is a device that can be strapped onto a patient and a small needle inserted into subcutaneous tissue. Interstitial glucose concentrations are sampled every 5 minutes for up to 72 hrs. Using such a device gives many more data points for evaluation and avoids the stress of multiple venipunctures or catheterization. Indeed, the device could potentially be worn by a patient at home. However, 3 BG concentrations must be measured per 24-hr period. The device has been assessed in normal and diabetic dogs and cats. Interstitial and serum glucose concentrations were highly correlated overall. 14;15 The working range of the CGMS is approximately mg/dl, i.e. BG outside the range can not be measured. In certain cases, postprandial increases in BG were not detected in the interstitial fluid. 15 Some variation existed between patients and the differences between serum and interstitial glucose concentrations were more marked in some patients than others. The greatest discrepancies occurred at higher BG 15 No irritation resulted

5 from sensor placement. 14;15 Preliminary results suggests that the data generated by the CGMS is useful for clinical management of insulin therapy, at least in diabetic dogs. 15 As discussed in the last lecture, for use of insulin glargine in cats, a protocol exists for adjustment of therapy on the basis of urine glucose concentrations. Although this is what I did for my own cat, and his DM resolved so things must have been going well, the limitations of such an approach need to be considered. First, based on the data we have so far, for cats Purina Glucotest is recommended as compared to any other technique based on accuracy as well as major convenience. Second, the significance of a negative urine glucose needs to be considered. Remember, all this means is that in the period since the last urination, the BG was below the renal threshold, i.e. <300 mg/dl in cats and <200 mg/dl in dogs. So, for example, the BG in a cat could have been 200 mg/dl or it could have been 40! The only way to know is to measure BG. If BG measurement is not an option, the risk of hypoglycemia is high. Measurement of urine glucose concentration at home can aid in monitoring. First, urine glucose levels can be determined as needed to aid in assessment of glycemic control, especially when other data are conflicting. Consistently negative readings on urine glucose may indicate that insulin dosages are either adequate or excessive. A serial glucose curve will differentiate between adequate insulin therapy and use of excessive doses that could result in hypoglycemic shock. Uniformly high urine glucose readings coupled with unresolved clinical signs indicate that the insulin dose may be inappropriate. 16 Second, urine glucose concentrations can be determined regularly (at least weekly) to help in the assessment of ongoing control. Changes in urine glucose levels may alert the owner and clinician to loss of glycemic control and a need for reevaluation. If urine can not be collected, then, for cats, use of Glucotest (Purina) may help (see above). In general, I think one of the best uses of glycosylated proteins is to evaluate trends in glycemic control if measured at each recheck. Current recommendations are not to try to normalize serum concentrations of glycosylated proteins but to aim, in general, for a concentration slightly above normal. For my own cat, his fructosamine was already normal! I did remeasure his fructosamine over time to at least make sure that it was not below normal. A fructosamine below normal indicates chronic hypoglycemia. Home monitoring of clinical signs alone has been advocated as an accurate method of diabetic assessment. 17 In one study of 53 dogs, control was judged to be good or bad based on clinical signs, physical examination findings and body weight. Then, clinical determination of good or poor control was compared with fasting BG, serial glucose curve and serum fructosamine and GHb concentrations. Although all parameters of glucose control were significantly lower in dogs with good control, considerable overlap existed between the 2 groups for all. All BG measurements, fructosamine and GHb were consistent with good glycemic control in 60% of dogs judged to have good clinical control or with poor control in only 39% of judged to have poor clinical control dogs. The initial fasting BG was mg/dl in 80% of dogs with good clinical control and in 21% of dogs with poor clinical control. The study s authors concluded that history, physical examination and body weight are sufficient for initial assessment of glycemic control and a glucose curve may not be necessary in a dog with apparent good clinical control when the initial morning BG is mg/dl. 17 Certainly, the importance of home monitoring of clinical signs cannot be over-emphasized. However, this author has some concerns with study methodology and conclusions and believes that glucose curves should be performed periodically in all diabetic patients (for aggressive animals or those who experience stress hyperglycemia in the hospital, the curves are most appropriately performed at home). References available from the author.