Washington University Emergency Medicine Journal Club -July 15, 2021
It’s another busy shift in TCC on a random weekday and all of the ICUs are filled to the brim. You get a page that a triage patient is coming to 2L, and a glance at the chart reveals a 24-year-old female with a history of type 1 diabetes whose blood sugar is 450. Her finger stick ketone level was 4.2. The patient is walked back to the room, has a steady gait, and looks quite well.
In the room, you find a well-appearing woman with normal respirations, a heart rate of 104, and a blood pressure of 114/68. She reports running out of her insulin 2 days prior and does not have insurance or the money to get more insulin. She has had some nausea, vomited once, but denies abdominal pain, fevers, chills, or urinary symptoms.
Despite her appearance, her bedside labs are concerning for diabetic ketoacidosis (DKA). You order additional labs, including a BMP and venous blood gas, and write for a liter of IV crystalloids while awaiting the results. As her fluid is finishing, her labs come back, revealing a pH of 7.2, bicarbonate level of 12, and an anion gap of 22. Her CBC is normal and HCG is negative.
The patient is clearly in DKA, though she does not appear to be in severe DKA. Your training has been to start a continuous IV insulin infusion in these cases, but you remember recently hearing about a new protocol for managing mild to moderate DKA with subcutaneous insulin, and you remember reading about the use of such protocols in pediatric patients. As these patients require less frequent blood glucose checks, they do not require ICU admission (which is good as she would otherwise be waiting hours in the ED until you “fixed” her). You open the order set, start her on the pathway, and admit her to the floor for further management. Given this huge departure from your previous training and practice, you decide to look up the evidence supporting this new pathway to see just how robust it is…
Population: Adult patients with mild to moderate DKA
Intervention: Intermittent doses of subcutaneous fast-acting insulin analog (aspart or lispro).
Comparison: Continuous infusion of intravenous regular insulin.
Outcome: Duration of therapy, time to resolution of DKA, time to resolution of hyperglycemia, ICU admission, ICU length of stay, hospital length of stay, hypoglycemia, recurrence of DKA.
You use the PubMed advanced search builder to create the following search strategy: (aspart OR lispro) AND ((diabetic ketoacidosis) OR DKA) (http://tinyurl.com/q4neutu). This identifies 71 articles, from which three randomized controlled trials and a Cochrane Reviews systematic review and meta-analysis were chosen.
Article 1: Karoli R, Fatima J, Salman T, Sandhu S, Shankar R. Managing diabetic ketoacidosis in non-intensive care unit setting: Role of insulin analogs. Indian J Pharmacol. 2011 Jul;43(4):398-401. Answer Key
Article 2: Andrade-Castellanos CA, Colunga-Lozano LE, Delgado-Figueroa N, Gonzalez-Padilla DA. Subcutaneous rapid-acting insulin analogues for diabetic ketoacidosis. Cochrane Database Syst Rev. 2016 Jan 21;(1):CD011281. Answer Key
Article 4: Umpierrez GE, Latif K, Stoever J, Cuervo R, Park L, Freire AX, E Kitabchi A. Efficacy of subcutaneous insulin lispro versus continuous intravenous regular insulin for the treatment of patients with diabetic ketoacidosis. Am J Med. 2004 Sep 1;117(5):291-6. Answer Key
DKA is a relatively common and dangerous complication of diabetes in both children and adults, affecting an average of 6.3% of patients with diabetes each year. The primary treatment is hydration, electrolyte monitoring, and insulin therapy, traditionally accomplished via IV regular insulin,. Both the American Diabetes Association (ADA) and the International Society for Pediatric and Adolescent Diabetes (ISPAD) recommend a continuous infusion of IV regular insulin as standard of care in the management of DKA. These recommendations are based primarily on studies from the 1970s (Menzel 1970, Fisher 1977) that suggested that the delayed onset and longer half-life of SC and IM regular insulin make these routes inadequate for the management of DKA. However, these studies evaluated the use of regular insulin, and pre-dated the development of fast-acting insulin analogs (aspart and lispro) which may be more efficacious in the management of DKA when administered by these alternate routes. Insulin lispro, for example, has an onset of action of 10 to 20 minutes and reaches peak concentration within 30-90 minutes when administered by SC injection (Holleman 1997).
Management of DKA with continuous IV insulin is typically accomplished in an ICU or intermediate-care setting. As the population ages, the demand for ICU beds is increasing, and availability is often limited. ICU admissions also drastically increase the cost of care. While patients in DKA are often critically ill, their care is generally algorithmic, and may not require ICU level care in those without severe DKA. Given that ICU care is often dictated by the use of a continuous IV infusion of insulin, an alternative regimen that involves intermittent SC insulin may allow admission to general medical wards or “step-down” units.
The current body of literature comparing IV and SC insulin in DKA in adults is comprised of small, randomized trials (Umpierrez 2004, Umpierrez 2004, Karoli 2011). The outcomes from these studies suggest that the use of SC fast-acting insulin is both safe and effective at treating mild to moderate DKA. No differences were observed in the duration of therapy required to resolve hyperglycemia or DKA in any of these studies. The incidence of hypoglycemia was low in the all of the studies and similar with either treatment. There were no episodes of recurrent DKA or death noted in any of the studies. An initial SC injection of 0.3 units/kg of insulin aspart or lispro can be given, followed by SC injections either hourly (0.1 units/kg) or every 2 hours (0.2 units/kg) with similar safety and efficacy to continuous IV insulin. A Cochrane systematic review and meta-analysis of this topic identified one additional study in adults (Ersöz 2006) and one study involving pediatric patients (Della Manna 2005), both of which demonstrated similar safety and efficacy.
While these regimens seems to be safe and effective, their benefit over traditional IV strategies is less clear. The primary potential benefit involves eliminating the need for ICU admission, and thereby reducing cost. Only one of these studies assessed the cost of care, and indicated a 39% reduction with subcutaneous insulin (Umpierrez 2004). However, it is quite possible that this cost difference was due to added ICU charges rather than a true difference in the intensity of care required (Haas 2004). Patients receiving SC insulin in this study had blood glucose levels checked every hour, while levels in those receiving IV insulin were only checked every 2 hours. Given the frequency of insulin administration required with a SC strategy – every 1 to 2 hours – the amount of nursing time required may actually increase with SC insulin regimens. If the use of SC insulin does not reduce ICU admissions, then there is likely no benefit, and IV regular insulin remains a logical treatment option. In a retrospective chart review of DKA patients treated with SC aspart at Rush University Medical Center in Chicago, there was still a mean ICU length of stay of 43.36 hours, indicating that such patients were still admitted to the ICU for initial management.
Perhaps, then, we should alter our question, and instead be asking whether patients with uncomplicated DKA be admitted to the ICU at all, regardless of the route of insulin administration chosen? A review of 67 cases of DKA admitted to the ICU at Truman Medical Center in Kansas City, MO found that over a third of patients did not warrant ICU treatment based on existing admission criteria. These data suggest that increased use of “step-down” or intermediate care units could reduce the need for ICU admission in uncomplicated DKA patients, whether IV or SC insulin strategies are employed. As we introduce a new pathway using SC insulin in mild to moderate DKA (the SQUID pathway) it will be important to monitor not only the efficacy of treatment, but the amount of nursing care required for implementation.