Tuesday, October 27, 2015

Just a Little Prick: IV versus SQ Insulin for DKA

October represents pharmacists’ month and we’ve just concluded pharmacy week. This time honored tradition of free hospital pens and PHARMA sponsored lunches gives us time to indulge our narcissistic tendencies as a profession.  At the same time, it serves as a rally call for continued efforts in our daily professional lives. These efforts, at least for hospital based pharmacists and particularly clinical pharmacists, are simultaneously our performance measures as well as justification for continued existence.  Proving we matter takes a lot of effort, initiatives and can be a slippery slope to becoming “drug police.” However, working alongside our peers, doing that Steven Covey thing of ‘seeking first to understand, then be understood,’ is tremendously helpful in the process.  Changing the culture of insulin drips in DKA is one example.

Insulin regular infusions for the treatment of DKA dates back to the 1970’s where it was superior to subcutaneous regular insulin for initial glucose control and prevented hypoglycemia.[1] As usual with emergency medicine literature, this study as a basis for a standard therapy is fraught with limitations and modern approaches to DKA treatment are aimed at resolution of acidosis, volume replacement and correction of electrolytes.  Furthermore, for certain patients with mild to moderate DKA who are being admitted to an ICU solely as a result of their insulin continuous infusion is unnecessary and an inappropriate use of hospital resources. 


Mild DKA
Moderate DKA
Severe DKA
HHNKS
Plasma glucose (mg/dL)
>250
>250
>250
>600
Arterial pH
7.25 – 7.30
7.00 – 7.24
< 7.00
> 7.30
Serum bicarbonate (mEq/L)
15 – 18
10 to < 15
< 10
> 15
Urine ketones
Positive
Positive
Positive
Small
Serum ketones
Positive
Positive
Positive
Small
Beta-hydroxybutyrate
High
High
High
Normal or elevated
Effective serum osmolarity (mOsm/kg)
Variable
Variable
Variable
> 320
Anion gap
> 10
> 12
> 12
Variable
Mental status
Alert
Alert/drowsy
Stupor/coma
Stupor/coma


While many avenues to solve this issue exist (ie, allowing non-ICU floors to take patients on insulin drips), one strategy is to use subcutaneous insulin rather than a drip for mild to moderate DKA patients.  Given the advancement of insulin products over the past 45 years, rapid (aspart, lispro) and ultra rapid (glulisine) insulin products exist that obviate the need for IV administration (as long as that SQ tissue is perfused, otherwise IM is an option, or just IV will do).  Although the evidence of SQ vs IV insulin is not iron clad, it’s as good as the evidence backing IV therapy.

Ref
Bolus
Maintenance
Titration
N
Outcomes
2
Aspart: O.3 U/Kg sq
0.1 U/Kg sq q1h
0.05 U/kg sq q1h
45 (15, 15, 15)
No difference LOS, Duration of DKA
Aspart: O.3 U/Kg sq
0.2 U/Kg sq q1h
0.1 U/kg sq q1h
Regular: 0.1 U/Kg IV
0.1 U/kg/hr IV
0.05 U/kg/hr IV
3
Aspart: O.3 U/Kg sq
0.1 U/Kg sq q1h
0.05 U/kg sq q1h
40 (20, 20)
No difference LOS, Duration of DKA
Regular: 0.1 U/Kg IV
0.1 U/kg/hr IV
0.05 U/kg/hr IV
4
None
Lispro: 0.15 U/kg sq q2h
0.15 u/kg sq q4h
60 occurrences from 46 patients
Similar decreases in glucose, total insulin admin
None
Regular: 0.1 U/kg/hr IV
0.15 U/kg sq q4h
5
Lispro: 0.15 U/kg IV
0.075 U/kg sq q1h
None
20 (10, 10)
No difference duration of DKA, total insulin admin
Regular: 0.15 U/Kg IV
“standard” IV infusion
N/A
6
Lispro: O.3 U/Kg sq
0.2 U/Kg sq q2h
0.1 U/kg sq q2h
50 (25, 25)
No difference duration of DKA, total insulin admin
Regular: 0.1 U/Kg IV
0.1 U/kg/hr IV
0.05 U/kg/hr IV
7
Regular: 0.1 U/Kg IV
Plus
Glargine: 0.3 u/kg sq x 1
R: 0.1 U/kg/hr IV
R: 0.05 U/kg/hr IV
40 (20, 20)
No difference in time to AG close, similar LOS
Regular: 0.1 U/Kg IV
0.1 U/kg/hr IV
0.05 U/kg/hr IV

It’s not that easy however. Considering the above research, while the ICU may be avoided, the amount of nursing workload increase will be a large obstacle. Most of the available protocols compared IV to q1h administrations of insulin and q1-2 hour glucose checks. But taking our knowledge of the PK/PD profiles of insulin, using a combined approach of rapidly titrating from SQ rapid to SQ long acting (such as glargine, see ref #7) may reduce this load and make it feasible for these patients to be cared for on a general medical ward.


Theoretical insulin regimen for research purposes
Aspart/Lispro
Bolus: 0.3 U/kg SQ x1
Aspart "Sliding Scale" (ie, something nurses are familiar with)
Plus
Detemir/Glargine
0.3 U/kg Sq x1


The evidence is by no means a slam dunk. It is however, sufficient to continue to pursue in research purposes and in certain circumstances, attempt in anecdotal cases.  As pharmacists, it’s a productive effort to continue to prove continued existence without sinking to switching everyone from IV to PO Protonix.
 References:
1) Fisher JN, et al. Diabetic ketoacidosis low dose insulin therapy by various routes. N Engl J Med, 1970;297:238-41.
2) Umpierrez GE, et al. Treatment of diabetic ketoacidosis with subcutaneous insulin aspart. Diabetes care 2004;27:1873.
3) Umpierrez GE, et al. Efficacy of subcutaneous insulin lispro versus continuous intravenous regular insulin for the treatment of patients with diabetic ketoacidosis. Am J Med 2004; 117:291-6.
4) DellaManna T, et al. Subcutaneous lispro and intravenous regular insulin treatments are equally effective and safe for the treatment of mild and moderate diabetic ketoacidosis in adult patients. Int J Clin Pract 2006;60:429-33.
5) Karoli R, et al. Managing diabetic ketoacidosis in non-intensive care unit setting: Role of insulin analogs. Indian J Pharmacol 2011;43:398-401.
6) Doshi P, et al. Prospective randomized trial of insulin glargine in acute management of diabetic ketoacidosis in the emergency department: A  pilot study. Academic emergency medicine, 2015; 22:658-662.
7) Cohn BG, et al. Does management of diabetic ketoacidosis with subcutaneous rapid-acting insulin reduce the need for intensive care unit admission.  Journal of emergency medicine, 2015;49(4):530-538.

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