Diabetic Ketoacidosis Summaries – Journal Club

Humans –

bi-directional some studies shown that patients with DM are more likely to develop pancreatitis with 92% of people more likely to develop acute pancreatitis compared with controls . However most commonly pancreatitis precedes DM and is believed to be implicated in the pathogenesis of DM . Typically results due to chronic pancreatitis – increase disease duration is an important risk factor for the development of DM in chronic pancreatitis . Therefore continuous inflammation of the pancreas is necessary in most cases for the development of DM

The increased conc of inflammatory cytokines within the pancreatic parenchyma leads to beta cell dysfunction and subsequent loss

In more advanced cases – fibrosis that eventually impairs endocrine pancreatitis function

Cats

DM and pancreatitis often co-exist

31-83% of cats with DM were found to have clinical evidence of pancreatitis based on fPLi and or US – similar findings were also found in non diabetic cats . Most cats were asymptomatic

Necropsy studies – histo evidence of pancreatitis was found in 51-57% of cats with DM in one study but in another study histo evidence of pancreatitis was not more common in diabetic cats compared with control cats (many limitations to this study)

Most cases where DM and pancreatitis coexist it is impossible to determine which disease came first

As in humas it is likely a bi-directional association exists with pancreatitis both occurring as a result of DM and having a causal effect on DM

Experimental hyperglycaemia has been shown to induce pancreatic inflammation in cats – extension of inflammation from the exocrine to the endocrine pancreas can leaf to progressive destruction of the islets of Langerhans , impaired beta cell function and subsequently DM . Peripheral insulin resistance is also likely to occur

As in humans chronic pancreatitis is believed to be more commonly related to the development of DM in cats . However acute exacerbations of chronic pancreatitis commonly occur and there many cats present with DM and acute pancreatitis

Dx DM – persistent hyperglycemia and glucosuria in conjunction with csx Pu/pd polyphagia and wt loss

Dx – pancreatitis – challenging – combination of findings from the history and clinical presentation, pancreatic markers or imaging . CSx – mild and non specific such as anorexia and depression

fPLI – immunoassay – chronic can be normal

colorimetric lipase activity assays such as 1,2-o-dilauryl-rac-glycero-3-glutaric acid-[6’-methylresorufin] ester [DGGR] assay – have shown better performance than traditional catalytic assays but results are conflicting

US – modality of choice – normal pancreas on U/S doesn’t rule out – esp chronic or mild but also in acute cases . High specificity , sensitivity ranges between 11 and 67% . Repeat ultrasound in 2-4 days may help dx

In the case of symptomatic hypoglycaemia an insulin dose reduction of 25-50% is recommended

Glucose variability

refers to glycaemic excursions, including episodes of hypoglycaemia and hyperglycaemia during a single date or at the same time on different days. In DM cats treated with insulin blood glucose conc may vary substantially from day to day and within the same day. These variations can be particularly marked in cats with DM and a concurrent disorder.

Use of glargine and detemir are preferred

Some cats the addition of the extended release glucagon-like-peptide-1 (GLP-1) analogue exenatide may be helpful in reducing glycaemic variability and improving glycaemic control

If high glycaemic variability cant be improved in any way , insulin dose reduction should be considered to avoid risk of hypoglycaemia

Remission

Cats previously diagnosed with DM that cease to receive exogenous insulin therapy and show no evidence of DM after 4 weeks are considered to be in diabetic remission

Reported remission rate is 17->54% with data from many studies

One study showed that 2 months after 30 cats were admitted with newly diagnosed DM and no clinical signs of pancreatitis the serum spec fPL conc were significantly higher in those that did not achieve remission than those that achieved remission

These findings may suggest that cats with pancreatitis have a reduced chance of achieving diabetic remission

Most cats with concurrent DM and acute pancreatitis have already been diagnosed with DM and recievign insulin

These cats are generally anorectic which can make insulin management challenging and hosp is required – may need IV insulin

Like for acute pancreatitis diets formulated for diabetes eg high protein , moderte fat and low CHO should be suitable for cats with chronic pancreatitis

However some cats with chronic pancreatitis do not tolerate diets with a relatively high fat content – use a gi diet with lower fat content but may affect dm control

Prospective block-randomised study was to compare the basal bolus glargine regimen with a regular IV insulin protocol and to demonstrate its utility in the treatment of feline DKA

Case selection

Cats with history of DM (PU/PD with or without polyphagia or wt loss), at least 2 clinical signs consistent with DKA (mentation score >1, vomiting or anorexia ), blood glucose conc above the renal threshold , beta hydroxybutyrate conc >2.55 mmol/L and a metabolic high anion gap (AG) acidosis pH <7.27 and AG >20.6 mmol/L

Exclusion IRIS >3 stage , CHF , mentation score 4 and if clinician did not adhere to the prescribed protocol

Magnesium was measured in case of refractory hypokalaemia and supplemented with 0.75mmol/kg/24hr

All cats received standard care for DKA including IV 0.9% NaCl, potassium and phosp (if <0.49 mmol/L

Bicarb when <11 mmol/L and mandatory at a pH <6.9 if administered was required to be discontinued at pCo2 (venous) conc >0.51 kPa (38mmHg) to avoid paradoxical cerebral acidosis

For insulin treatment cats were randomly assigned to treatment grps – CRI grp or glargine grp intermittent Sc/Im glargine

CRI grp

1. units per Kg body weight of regular insulin was added to 250ml bag of 0.9% saline and the first 50ml was drained out to allow for insulin absorption by the plastic tubing. This was iniitated 2 hours after starting rehydration with a CRI of 10ml/h and adjusted every 2 hours as required to achieve a decrease in glucose conc of 2 to 3 mmol/L/h

Glargine

All cats received a bolus of 2 SC units of insulin glargine irrespective of body wight concurrently with starting rehydration and 1 IM unit /cat 2 hours thereafter

IM inj 1 unit per cat were subsequently repeated every 4 hours if glucose was >13.9 mmo/L and Sc glargine was continued every 12 hours with 0.25units/kg based on estimated bwt rounded to the next half or whole unit

The primary aim in both protocols was to achieve a blood glucose conc <13.9 mmol/L. At that point , intensive insulin therapy was continued at 10ml/k but IV F were changed to 2.5-5% glucose containing solution and adjusted to keep BG between 10-13.9 mmol/L

Insulin admin was only decreased to 5ml/hr or stopped in cats with glucose <4.4 mmol/L despite 5% glucose infusions at the calculated infusion rate

In cats with inappetence for more that 3 days a NE tube was placed and the cats were fed 4 times per day

When cats were appropriately hydrated started to eat spontaneously and beta OHB <2.25mmol/L were changed to an exclusively sc insulin regimen ( glargine q12hr with 0.25-0.5 units/kg)

Compare time to plasma beta OHB conc <2.55 mmol/L between the insulin grps

Time 0 – time IV catheter was placed and infusion therapy was started

Secondary outcome measures were time (h) to improvement of hyperglycaemia and ketonemia a, glucose <13.9, resolution of acidosis pH <7.27, consumption of first meal and discharge from hospital

Measure adverse events – hypoglycemia , severe phyophosphatemia , severe hypokalemia , hyperchloridemia, hypernatremia , severe of moderate hypothermia and bradycardia

Cats were discharged when there was no vomiting and the cars was eating and beta OHB was <2.55 mmol/L and the cats condition was assessed by the clinician das suitable for discharge to the owners

Presence of acidosis did not preclude the cat being discharged if it was caused by concurrent disease eg renal failure

20 cats met all the criteria for inclusion were block randomised to 1 of 2 grps (10 cats per group)

Demographic characteristics including age, sex, weight , body condition score and baseline variables were not significantly different between the grps

17 cats survived to discharge 8 CRI grp and 9 in glargine grp

The time until beta hydroxybutyrate decreased to <2.55 mmol/L was comparable between grps

The glargine-group had significantly shorter median times until first improvement of hyperglycaemia , defined as >1.6 % decrease from baseline and until discharge from hospital

No difference were observed in any other parameter under observation

Non of the cats exhibited Csx of hypoglycaemia

The change of HCT from baseline to discharge was moderately correlated with the lowest phosphorus conc determined during treatment \

The choice of insulin protocol has no influence on changed of HCT , TP ALT , crea , wt

In addition to the first IM insulin injection in the glargine grp a median of 3 (0-11) additional Im glargine injections were administered

Findings of this study corroborate the findings of Marshall et al who showed that the basal bolus administration of glargine insulin is a safe and effective alternative to regular insulin CRI protocol currently

As shown by Gallagher et al the application of this basal bolus protocol decreased time of improvement of hyperglycemia and to discharge without affecting survival rate or incidence of adverse events

It has been demonstrated in cats with DKA that despite significant decreases of BG conc >120% within the first 72 hours of conventional therapy , sodium the major determinant of serum tonicity increases and the effective osmolality stats relatively constant minimizing large osmotic shifts

Glargine protocol decreased time to discharge by 1.5 days , shorter time to first meal and quicker resolution of indicators of DKA

Beta hydroxy butyrate measurements are a useful adjunct from monitoring response to therapy and eliminate the need for frequent blood gas analysis which are not specific for ketones

Additionally beta hydroxybutyrate measure facilitate rapid revaluation of diagnosis in cats with low ketone concentrations but ongoing metabolic acidosis

The primary endpoint of treatment in our study was the resolution of ketonemia consistent with the definition of DKA which is a beta hydroxybutyrate conc <2.55 mmol/L

In the absence of comorbidities, conc below this cut off are rarely associated with metabolic acidosis in cats and DKA was not diagnosed at values <3.8 mmol/L

With the resolution of ketonemia to <2.55 mmol/L most of the cats in our study began to eat spontaneously and were transitioned to SC glargine alone

the median time for resolution of ketonemia in our CRI grp was 42 hours compared to 62 and 68 hours in 2 previous studies – possible explanation is the use of a different protocol for adjustment of insulin and glucose administration

In contrast to previous studies insulin infusion was not decreased at glucose conc <16.8 mmo/L or 13.9 mmol/L but insulin admin rate was kept constant until target beta hydroxybutyrate conc were reached

To allow for intensive insulin treatment 5% glucose solution were administered when glucose conc fell below 10mmol/L . This is inline with the latest treatment guidelines in decompensated diabetic children in which a decrease of insulin dose of <0.05 to 0.1 unit/kg/hr is only recommended after DKA has resolved or hypoglycaemia is impending despite the use of 10% or even 12.5% glucose solutions

The early reduction of the CRI insulin dose in the cited studies possibly delayed the resolution of ketonemia and could explain why more key indications were significantly different between the 2 protocols in Gallagher et al

Two retrospective studies compared outcome in cats treated with either 0.05or 0.1 units/kg/h.4,9Whereas the higher insulin dose reduced the odds of poor outcome defined as deaths in the first study,4no differences were found in the second.9Neither of the studies compared time until resolution of ketoacidosis or ketonemia.

A topic of debate in human medicine is whether to routinely start SC administration of a long-acting basal insulin (eg, glargine insulin)at the onset of DKA management. The rationale is to provide stable background insulin concentration and to avoid reoccurrence of hyperglycaemia during the transition time to SC insulin.18,48A common concern raised with SC insulin administration in dehydrated patients is SC insulin accumulation and sudden release after rehydration.49Ameta-analysis of 4 studies in human patients suggests that this concern is likely unwarranted. The addition of SC glargine insulin to standard protocols using IV infusion of regular insulin significantly decreased the time to resolution of DKA, without increasing the risk of adverseevents.50Interestingly, Shankar et al51proposed that the positive effects are caused by yet to be described mechanisms, other than just increased total daily insulin dose. Based on evidence in human and feline patients, some veterinary specialists are combining IV regular insulin infusions with twice- daily SC glargine insulin injections.37Prospective randomized studies are required to more conclusively estimate the benefit of adding SC insulin glargine to DKA protocols for cats

To avoid adverse events associated with hypophosphatemia such as haemolytic anaemia, IV phosphorus supplementation (potassium-phosphate) was a fixed part of our treatment protocol. Severe depletion of phosphorus may lead to ATP depletion in erythrocytes, causing failure of actin and myosin fibres in the cell membranes to maintain normal biconcave structure and deformability.27In our protocol, phosphorus was preventatively administered by providing 25% of potassium as potassium-phosphate. Consequently, hypophosphatemia was observed in only 50% of the cats, compared to 80%,867%,1and 65%4in previous studies, in which phosphorus was administered exclusively to hypophosphatemia patients. Consistent with the expected effects of phosphorus depletion on erythrocyte stability, lower phosphorus concentrations were associated with a greater decrease of HCT from baseline to discharge

Note 4 cats with severe anaemia all had moderate to severe hepatic lipidosis – possible refeeding syndrome which has been associated with hepatic lipidosis and characterised by the developed of severe hypophosphatemia

In conclusion, although the study was underpowered to detect differences in time until resolution of ketonemia, the results suggest that the basal-bolus administration of insulin glargine is a useful alter-native to the current standard CRI-protocol for the management of DKA in cats. It is simple and associated with a shorter time to first improvement of hyperglycaemia and decreased hospitalization time. Additionally,?-OHB measurements using hand-held ketone meters area useful adjunct for monitoring response to therapy and eliminate the need for frequent blood gas analyses. Further studies are required to evaluate the benefits and disadvantages of IM bolus vs CRI proto-cols and to compare choices of fluid therapy in management of feline DKA

• Timing for instituting short acting insulin therapy is unclear
• Justification for delaying insulin administration stems predominantly from the idea that blood glucose conc decrease somewhat with fluid therapy alone combined with the concern about the development of metabolic complications form insulin therapy
• Fluid therapy decreased BG because fluids reduced inulin resistance by decreasing conc of counter regulatory hormones , increase insulin availability to peripheral tissues , dilate the BG and increase GFR , thereby increase urinary glucose loss
• This reduction in BG has historically been through to cause a significant decrease in effective osmolality , theoretically leading to dangerous complications such as cerebral oedema CE
• Studies have demonstrated that decline in BG bears little consequence on the development of CE
• Instead studies have shown that inadequate normalization of serum sodium conc with declining BG bears greater impact on effective osmolality and potential for neurological complications
• Recent studies in veterinary medicine have demonstrated that measured serum osmolality does not correlate with BG in dogs and cats with DK and DKA and is more closely associated with changes in serum sodium conc , suggesting that the concern over rate of BG normalization is unwarranted
• Clinically significant electrolyte disturbances are also common during DK and DKA and these derangements can be exacerbated by insulin therapy
• Therefore in order t min complications, it has been recommended to delay insulin therapy until patients are volume resuscitated and clinically significant electrolyte derangements are corrected
• BUT insulin is required to stop ketogenesis , increase ketone body metabolism , decrease gluconeogenesis and promote glucose utilization
• Hypothesis – that earlier administration of insulin therapy in dogs and cats would be associated with more rapid resolution of DK/DKA status and shorter hospital stays
• Additionally hypothesise that there would be no difference in complications associated with insulin administration between early and late initiation of insulin therapy
• Final hypothesis that more severe ketonuria at presentation would be associated with slower resolution of DK/DKA

• 10 year study
• DK or DKA inclusion
• Dx hyperglycaemia BG >13.9 mmol/L or was euglycemic on admission with a history of DM being treated with long acting insulin and had ketonuria based on detection with nitroprusside strips
• Acidemia was not a requirement for inclusion
• Tx with either IV or CRI or IM or SQ short acting insulin was also an inclusion criteria
• Animals with multiple visits – each visit counting as separate case
• Excluded – died or euth prior to admin of insulin , had long acting insulin initiated prior to the resolution of DK/DKA , had ketonemia alone within concurrent ketonuria ( because resolution of ketonuria was used as criterion for resolution of animals DK or DKA status
• Retrospective data collection – (signalment, whether they had pre-existing diagnosis of DM being treated with long acting insulin , PEX, BP )
• Hypothermia defined as <37.9 in dogs and <38.1 C in cats
• Hypotension – SABP <90mmHg or MAP <60 mmHg – Doppler or oscillometer technique
• Presentation pH , BE and BG , urine KB conc
• Animals were classified as having mild moderate or severe ketonuria based on the results of urine test strips
• BG assessed every 2 hr during hospitalization using glucometer or blood gas analyser
• Time to resolution of DK/DKA status after initiation of short acting insulin was recorded as the earliest time at which urine test strips showed no KBs
• Outcome measures recorded included time to resolution of Dk/DKA status from the time of initiation of short acting insulin administration and length or hospitalization
• Complications recorded included include the development of worsening of hypokalaemia(<3.8 in cats and dogs lab , blood gas 3.9 in dogs and 3.3 in cats)) , hypophosphatemia (0.9mmol/L D and C lab or POC 0.8mmol/L dogs and <1 mmol/L in cats) )or hypomagnesaemia(0.7mmol/L POC cats <0.75mmol/L) , hypoglycaemia (3.3mmol/L dogs and 3.5 mmol/L cats) and the presence of declining mentation or seizures
• Patients divided into 2 groups – patients receiving short acting insulin <6 hours after admission were assigned to the early group and those receiving short acting insulin > 6hrs after admission were assigned the late group
• The groups were compared for differences in each of the outcome measures as well as rates of complications as described above.
• The association between severity of ketonuria at the admission and time to resolution of DK/DKA was also evaluated

• 90 medical records comprising 112 total cases
• 27 cases excluded due euth , discharge against medical advice , KB in serum only , starting on long acting insulin prior to resolution of DK/DKA , missing medical records , died prior to therapy , transfer to primary vet
• 60 cases in total 49 individual patients 37 dogs and 12 cats
• 44 cases included in the early insulin group with a median of 4 hours to initiation of short acting insulin (range 0-6hr) and 16 cases were included in the late insulin therapy group a median of 8.25 hours to initiation of short acting insulin (range 7-21hr)
• There were no statistically significant differences in any of the baseline characteristics examined between the early and late insulin therapy
• 8 cases were euthanized 7 (16%) in early insulin grp and 1 (6.3%) in the late insulin grp
• Ketonuria resolved more rapidly in early insulin therapy grp
• Ketonuria resolved more rapidly in cases with less severe ketonuria at presentation
• Multiple linear regression analysis showed that of pH and early vs late insulin grp only early vs late insulin therapy was associated with time to resolution of DK/DKA
• Suggesting that on average resolution of Dk/DKA status occurred approx. 19 hours earlier in patients in the early insulin grp
• Incidence of hypokalaemia , hypophosphatemia , hypomagnesemia and hypoglycaemia – no diff in the incidence of complications between the early and late grp
• Neurological signs were not observed in any case
• Length of hospitalization was not associated with time of short acting insulin admin
• Average length of hospitalization in the early insulin admin grp was 4.9+/- 2.4 d and in late grp 5.7 +/- 2.2 days

• Early administration of short acting isnulin was associated with more rapid resolution of DK/DKA without an increase in complication rates
• Insulin is required in the DK/DKA patient to halt ketogenesis and enhance KB metabolism
• Ketonuria at the time of admission to the hospital rather than at the time of institution of insulin therapy was assessed as the baseline value and it is possible that urine ketone conc may have remained higher in the late grp due to continued production on the absence of insulin therapy , thereby taking longer to resolve. It is also possible that urine ketone conc may have been lower by the time of insulin administration in the late group due to further dilution from fluid therapy
• Complication rates were similar between the animals in the early and late grps
• Based on these findings delay of insulin administration was not associated with a protective effect against complications, suggesting that avoidance of electrolyte , hypoglycaemic or neurological complications may not provide a sound rationale for delaying insulin therapy
• The mechanism of hypokalaemia , hypophosphatemia , hypomagnesemia due to insulin therapy should be independent of the timing of insulin administration though derangements may be less likely or less severe in patients receiving supplementation for a longer period before starting insulin
• All hypokalaemia or normokalaemia patients received supplemental potassium immediately after initial volume resuscitation and phosphorous and magnesium were monitored at least daily and supplemented as needed
• Therefore it is not surprising that the incidence of electrolyte derangement was similar between the early and late insulin grps
• This findings is similar to the study by Claus et al comparing different insulin in cats with Dk/DKA which showed on difference in electrolyte derangements between treatment grps
• Development of CS in tx of Dk/DKA can occur due to hyperosmolality and should be normalised gradually and recommended to delay insulin administration until after initial volume expansion and initiation of rehydration
• Recent studies in veterinary med have demonstrated that despite significant decrease in BG conc with conventional therapy serum tonicity or effective osmolality remains relatively unchanged due to increases in serum sodium conc , because sodium is the major determinant of serum tonicity
• This minimal change represents a likely reason for the low incidence of osmotic mediated neurological complications during the treatment of DK/DKA in general and absence of more complications in the early insulin admin grp
• Finding that earlier administration of short acting insulin was not associated with a shorter length of was unexpected.
• This differed from the hosp findings of Bull et al who documented shorter lengths of hosp with a protocolized approach including admin of short acting insulin in the management of DKA in people
• Iti is likely that treatment for comorbid conditions contributed to length of hosp potentially explaining the similarity in length of hosp between treatment grps

• Retrospective study with small patient population , no standardization for case allocation based on baseline characteristics , severity of illness , hydration or prelim clinical data
• Additionally there was no standardization for insulin administration or for the monitoring of complications
• Time for resolution was not standardized testing was performed on urine when animals voided or if indwelling cath in place but not all urine samples were tested
• Advantages to assessing serum KB in conjunction with urinary KBs -not routinely permed and thus limited the ability to include this data
• Due to differences in types if KB detected by different methodologies and the normal metabolism of KB’s it has been recommended that beta hydroxy butyrate monitoring replace urinary monitoring in people with Dk/DKA thus it is possible that or assessment of KB resolution was inaccurate in some cases

• early administration of insulin therapy in patients with DK/DKA is associated with a more rapid resolution of DK/DKA without a significant difference in complication rates. Although this did not lead to a reduction in the length of hospitalization, more rapid resolution of metabolic derangements is desirable, and our data support early initiation of insulin therapy. Future prospective studies are needed to assess the optimal timing of insulin administration in the treatment of critically ill diabetic patients

When administered IV in human patients glargine and regular insulin are almost identical in their effect on blood glucose (BG) conc and duration of action for both insulins is approximately 2 hours.

Aim

describe the treatment and outcome of administering glargine IM with or without SC glargine during initial stabilization of DKA in cats

Retrospective case series of primary accession and referred cases presented to an exclusively feline vet clinic

Included cases has a diagnosis of DKA and were initially stabilized with IM glargine

Cases diagnosed with DKA and treated with IM glargine with ot without concurrent SC glargine between NOV 2005 and NOV 2008

Materials and Methods

Dx DKA when BG conc was >16 mmol/L and signs of systemic illness significant glycosuria (+3 or +4) , ketosis (ketonuria or ketonemia; beta-hydroxybutyrate >0.6 mmol/L and acidosis were evident (serum bicarb <12mmol/L

The protocol for insulin therapy using glargine was adapted from published protocols using regular insulin IM for managing DKA in cats and DKA in dogs but substituting glargine for regular insulin

Initial IM doses of glargine were to a large extent calculated on a per cat basis rather than per kilogram with 14 to 15 cats receiving 1 IU IM and the remaining cat received 2 IU IM

The degree of hyperglycaemia did not influence the initial IM dose

The initial SC doses, when used also tended to be calculated on a per cat basis rather than per Kg and ranged from 1 to 3 IU

BG was assessed every 2-4 hours and subsequent glargine dose adjusted aiming to lower BG conc by 2-3 mmol/L/hr until reaching a conc of 10-14 mmol/L

A prescribed protocol was not strictly adhered to with repeated 0.5-1 IU IM injections given as required between 2 and 22 hr and SC inj administered every 12 hours or longer to maintain BG conc between 10-14 mmol/L

The timing of insulin dosing and the dose administered varied considerably as it was also influenced by the time of day and the frequency of monitoring

IV glucose was administered if BG conc fell below 10mmol/L

Where owner finances restricted overnight patient monitoring the evening insulin dose was conservative or withheld and IVF were changed to a 2.5% glucose containing solution overnight to reduce the chance of life threatening hypoglycaemia occurring while there was limited or no monitoring

Cats were managed with SC glargine alone once appetite returned and dehydration had resolved

Cats were discharged from hospital after determining an appropriate SC dose of glargine based on serial BG measurements every 3-4 hours

The outcome of using glargine IM in the initial stabilisation of DKA cats was considered successful if ketosis resolved , appetite returned and the cat was discharged from hospital on SC glargine and survived >2 weeks without the requirement of readmission to hospital for management of DKA or related complications

Results

100% were depressed and dehydrated

33% were moribund or recumbent

73% anorexia

73% first diagnosed with DM at time of presentation of DKA

A history of previous glucocorticoid admin in the previous 3 months was present in 20% of cats consisting of long acting depot inj or topical ear prep for 10 days duration

Of the 4 cats previously diagnosed with diabetes one cat was receiving 2 U lente insulin SID , one cat receiving 1.5 IU glargine BID , one cat not receiving insulin for 11 days while the owner was away and one cat had had no insulin therapy for 12 days following diagnosis

All 15 cats were initially treated with intermittent IM glargine and most of the cats 12/15 also SC glargine

Median combined insulin dose (IM and SC) administered to all 15 cats during the first 12 hours of therapy (0-12hr) was 3 U/cat (range 2-7 U/cat) or 1.4 U/kg/d

The median combined insulin dose for the following 12 hour period (12-24 hr) was 2 U/cat (range 0-4 U/cat) or 0.96 U/kg/d and for the following 12 hours (24-36hr) was 2 U/cat (range 1.5-4 U/cat) or 1.4 U/kg/d

The median time until second insulin was 4 hours (range 2-6hr) in cats (3/12) treated with IM glargine alone and 14 hours (range 2-22hr) in cats (12/15) treated with IM and SC glargine

The median time for all 15 cats to be managed with SC glargine as their sole insulin therapy was 24 hours (range 18-72hr) and of the 12 cats treated with intermittent IM and Sc glargine from the outset , half (6/12) were managed with SC glargine alone within 18 hours of initiating treatment

No cat developed clinical hypoglycaemia from insulin therapy during the stabilization period and minority of cats 2/15 13% had biochemical hypoglycaemia <3mmol/L

Hypoglycaemia was managed with IV glucose supplementation or reducing insulin dose or increasing the time interval between injections

All cats were hypokalaemia at some point during stabilisation and 93% of cats were supplemented with IV potassium

Most cats 80% developed hypophosphatemia and 42% of these cats received IV phosphorus supplementation

2 hypophosphatemia cats had haemolysis at 24 and 36 hours after initiating therapy and both received typed blood transfusion

All cats survived and were discharged after median of 4 days (range 2-5d)

1/3 of cats surviving to discharge subsequently achieved remission , median time to remission was 20 days (range 15-29d)

Median duration of remission of 16 months

4 of the 5 cats achieving remission were Burmese and 2 of these were receiving glucocorticoids at the time of diagnosis

Glucocorticoid administration was discontinued in all 3 cats receiving glucocorticoids at the time of diagnosis and 2 of the 3 cats (67%) achieved remission

Discussion

Treatment with IM glargine combined with or without Sc glargine was effective in the management of feline DKA

In cats with DKA a similar protocol to ours using SC glargine combined with regular insulin IM also resulted in faster resolution of metabolic acidosis compared with a CRI of regular insulin

No pharmacodynamic or pharmacokinetic studies that demonstrate that with dehydration SC is slower in insulin absorption than IM

Historically achieving remission has not been a commonly recognized treatment outcome for DKA cats but a recent study has reported a remission rate of 58% of cats with DKA JVIM 2008 22 (6) :1326-1332

Current recommendation for the majority of DKA cats is that glargine be administered Sc (1-2 /cat/q12hr) starting immediately and concurrent IM glargine (0.5-1 IU/cat) several hours after fluid resuscitation

Repeated doses of IM glargine (0.5-I IU/cat) can be given as often as every 4 hours to achieve the above glycaemic effect , with most cats receiving a total of 1-3 doses of IM glargine before being managed with SC glargine alone.

Pathophysiology

• Glucose is necc fuel that drives the production of energy in the form of adenosine triphosphate (ATP), by the mitochondria within the cells i
• In all organs other than in the brain , insulin is needed to move glucose from the blood into the cells where it is used to make ATP or is converted and stored as glycogen ( in the liver and muscles) or triglycerides (in adipocytes)
• Insulin also moves electrolytes such as potassium from the plasma into the cells and limits the oxidation of fat
• DM is a syndrome caused by insulin insufficiency , insulin receptor dysfunction , insulin receptor downregulation or some combination that results in lack of transport of glucose int the cell, hyperglycaemia and cellular starvation
• Pancreatic islet cell destruction and concurrent disorders that affect insulin receptors sensitivity (eg pancreatitis , chronic inflammatory disease, obesity , endocrinopathies) are conditions that are most commonly associated with feline DM
• Hyperglycaemia that exceeds the renal threshold for glucose reabsorption results in glucosuria , increased urine osmolality and urine production as well as increased plasma osmolarity and thirst
• Cellular starvation stimulates an increase in appetite , mobilatation of free fatty acids an increase in plasma aa and wt loss
• Oxidation of FFas leads to hepatic production of ketone bodies (acetoacetate, beta-hydroxybutyrate and acetone) which are used as an alternative energy source in the peripheral tissues and liver
• Acquired DM can be tolerated for a period of time
• As long as there is adequate , albeit reduced circulating insulin , hyperglycaemia does not lead to acute illness . However when there is an increased metabolic rate and energy requirement due to concurrent illness , the release of glucose counter-regulatory hormones (adrenaline, noradrenaline, cortisol, glucagon and growth hormone ) is stimulated
• These stress hormones increase insulin receptor resistance , lipolysis and FFA release and promote ketogenesis
• Significant ketonemia related to DM overwhelms the plasma buffering system , and results in a metabolic acidosis that can alter normal cellular metabolism
• Similar to glucose molecules , ketones are osmotically active
• Increased filtration of ketones by the kidney exacerbates osmotic diuresis , electrolyte imbalances and water loss, manifesting in hypovolemia and interstitial dehydration
• Untreated DKA can cause severe illness and death

Treatment

• Resuscitation from hypotension always involves the sue of an isotonic crystalloid solution
• Some clinicians prefer to use 0.9% sodium chloride (308 mOsm/l) to provide the least degree of transcellular osmolar shift when severe hyperglycaemia is present and avoid the sue to lactated Ringer’s solution to reduce competition for hepatic conversion of lactate and ketones
• But 0.9% sodium chloride is an acidic fluid and may not correct an acidemia as effectively as a balanced buffered isotonic solution such as Plasma-Lyte A pH 7.4 or Normosol-R pH 7.4 (295 mOsm/l) which contain acetate and glucose buffers that are metabolised by skeletal muscle
• It is not uncommon for hyponatremia to also be present and some clinicians might also choose to infuse 0.9% sodium chloride to correct this
• But hyponatremia may be spurious finding when hypertriglyceridemia exists and or it can be due to shift or water intravascularly in response to increased plasma osmolality caused by hyperglycaemia
• Ketostix reagent strips use a colorimetric method that measures a nitroprusside reaction for detecting acetoacetate in blood or urine , blood measurements are more precise than urine measurements are more precise than urine measurements . doesn’t measure beta-hydroxybutyrate (which can be present before detectable levels of acetoacetic acid ) making it insensitive for monitoring the severity of ketoacidosis
• Ketone testing using the Precision Xtra or Optium systems (Abbott) will measure beta-hydroxybutyrate

Insulin therapy and protocols

• insulin infusion is started after perfusion has been restored
• there is a misconception that insulin should not be initiated until dehydration has been corrected , to mitigate the impact of dilution and increased GFR which risk rapidly decreasing the effective osmolality and also potentially causing cerebral oedema
• however a retrospective study showed that a delay to insulin therapy of >6 hr significantly delayed resolution of ketonemia (by 19hr, on average) and no difference in complications was observed
• AIM to eliminate ketosis and correct acidosis without causing hypoglycaemia
• Intermittent admin of regular insulin
• Initial dosage of 0.1U/kg IM followed by 0.05U/kg Im admin hrly until the BG level is <250 mg/dl
• Glargine
• IM glargine (which has a short half life) with or without SC glargine (which has a long half life)
• Initial dse of – U per cat was administered IM with 1-3 U SC followed by 1-2 U IM IM as needed (q2hr or less frequently ) and 1-2 U Sc q12hr until regulated
• Recommended that 1-2 U SC glargine q12hr with 0.5-1 U IM up to 4 hr to achieve a BG conc of 180-252 mg/dl
• CRI of regular insulin
• More regulated decline in serum glucose levels and plasma osmolality because adjustments in infusion rates can be made 1.1 U/kg of regular insulin in a 250ml bag of 0.9% saline , drain out 50ml of solution to allow for insulin adsorption by the plastic tubing and administer the mixture at a rate of 10ml/hr
• A higher dose of insulin infusion 2.2 U/kg q24hr may be more effective at reducing hyperglycaemia in the cat and is associated with a better outcome than lower dose Claus MA et al JVECC 2010 20: 509-517
• There does not appear to be a relationship between osmolality at presentation , administered insulin dose and mentation changes
• A pilot study involving 29 cats with DKA compared the concurrent use of regular insulin IM (1 U up to 6hr) and SC glargine (0.25 U/kg q12hr) with a continuous infusion of regular insulin (1U/kg q24hr) in cats with DKA . The latera regime produced more rapid resolution of ketosis , hyperglycaemia and acidemia and an associated reduction in the length of hospital stay

Patient monitoring and additional treatment

• The ideal blood glucose level is between 150mg/dl and 250 mg/dl
• Regular insulin CRI therapy may be adjusted according to glucose levels
• Traditionally the recommendation has been to supplement dextrose when the blood sugar is <250mg/dl but this can become costly when frequent changes in supplementation (including electrolytes) necessitate additional fluid bags ,
• Broad spectrum antibiotics may be indicated when there is a left shift , a fever , severe gastrointestinal signs or overt signs of a bacterial infection
• NE tube feeding with or without partial parental nutrition is necessary to preserve electrolyte function , reverse protein catabolism and promote hepatic function until the patient is eating voluntarily
• Assisted feeding also limits the development of food aversion and the cephalic and gastric phases of digestion that can promote vomiting in cats with nausea.

Additional evaluation

• Ketoacidosis by itself , has not been associated with a poor outcome in the diabetic cat
• However coexisting conditions may affect the prognosis and outcome and should be identified and addressed
• Although not predictive of mortality elevations in serum creatinine , BUN , magnesium and total bilirubin are associated with a worse outcome in the cat with DKA

Discharge

• Insulin CRI is disconnected at least 4 hr prior to starting long acting insulin injections , unless the cat is already receiving insulin glargine
• If serum glucose is <150mg/dl insulin is not administered
• Glucose >250mg/dl 0.5-1 U glargine or protamine zinc insulin q12hr SC is administered
• This dose is recommended in the previously diagnosed diabetic as well as newly diagnosed cases , since insulin requirements may have altered
• The goal is to have a 12hr curve in hospital with nadir not les than 150mg/dl , rather than try to determine the ideal dose for long term management