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
Plasma glucose (mg/dL)
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
Serum ketones
Normal or elevated
Effective serum osmolarity (mOsm/kg)
> 320
Anion gap
> 10
> 12
> 12
Mental status

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.

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
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
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
Regular: 0.1 U/kg/hr IV
0.15 U/kg sq q4h
Lispro: 0.15 U/kg IV
0.075 U/kg sq q1h
20 (10, 10)
No difference duration of DKA, total insulin admin
Regular: 0.15 U/Kg IV
“standard” IV infusion
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
Regular: 0.1 U/Kg IV
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
Bolus: 0.3 U/kg SQ x1
Aspart "Sliding Scale" (ie, something nurses are familiar with)
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.
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.

Wednesday, October 21, 2015

Inspiring Change Through Social Media: Our Moral Responsibility in 140 Characters or Less

A couple of weeks ago, I had the privilege of attending the North American Congress of Clinical Toxicology (NACCT). This is the annual conference of the American Academy of Clinical Toxicology (AACT), a multidisciplinary organization focused on all things related to treatment and management of toxins, and offers plenty of opportunities for education and research related to clinical toxicology. It is certainly worth attending this conference, and if you have a strong interest in and/or practice in the specialty and ever have the opportunity to attend, I highly recommend it.

The keynote speaker for this year's meeting was Sandra de Castro Buffington, founding director of the Global Media Center for Social Impact, and the theme for the presentation was "Sparking Storylines: Improving Health and Well-Being Through TV, Film and New Media." During her presentation, she provided several examples and mechanisms in which healthcare providers can dispel misconceptions and bring to light health-related story lines through these media to the general public. It was a worthy presentation, and for me at least, it certainly served as a reminder that our responsibility to the service in healthcare extends beyond the patient care at the bedside to the mass general public in raising education and awareness of issues related to healthcare. There were several questions raised regarding application of some of these principles in the field of clinical toxicology, and it generated a good discussion.

Little did any of us attending the presentation know that we would be applying some of the principles shared during the session at the conference itself only a mere 24 hours later.

The next day, I attended the AACT Acute and Intensive Care Symposium, a session held on an annual basis at the meeting. The session features case presentations by toxicologist fellows-in-training, and a series of questions are posed to an expert panel of toxicologists related to management of the patient case. This year, audience members were encouraged to tweet their questions to the moderators in addition to asking questions at the microphones placed at the center aisles of the room to help further the discussion along.

One of the cases presented featured a bizarre and tragic case of hyperacute sodium toxicity in a pediatric patient occurring as a result of the caregiver administering a sea salt slurry as homeopathic therapy for constipation. The caregiver followed instructions posted on the website livestrong.com, and as the case unfolded with the consequential effects occurring in this patient, we were captivated by the recounted events leading to the untimely death of the patient. If you followed the discussion on Twitter using the hashtag NACCT15 (#NACCT15), what you may have witnessed was only a fraction of the heated emotion generated in the room full of us audience members. The presenter shared one important tidbit of information – the administrators of the Livestrong website were contacted regarding the information posted on the site that led to the patient’s death, but no response was provided…at least at the time leading up to the very presentation.

What happened next can aptly be described below:

We were just doing our part; perhaps we figured that all the tweets, comments, re-tweets, favorites, and shares would spark the attention (and Twitter notifications) of the moderator of the Livestrong Twitter account…and potentially the administrators of the website itself. Shortly thereafter, it was discovered that the information provided within the post was purportedly written by none other than an individual with no background, training, or expertise in the medical field.

What happened after that was nothing short of remarkable (take notice of the date and time):

The folk(s) behind the Livestrong Twitter account quickly followed up this tweet with requests for credentialed medical professionals to provide freelance work in reviewing content posted on this and other affiliated websites.

As I recall these events in this reflective piece, I will be honest and admit that I still get goosebumps. Yes, at the surface, it may seem that this was the most logical thing to do at the time. As the saying goes, strength does come in numbers. In this example, it is clear that the mounting pressure on social media to the company led to an immediate action and change, all in the name of not only re-emphasizing the importance of consulting with a medical professional regarding any information claimed to be health-related shared in the vast Interweb, but also our moral and social obligation in preventing future harm to the members of the general public – yes, the very same community of individuals with whom we grow and thrive with in this thing called life.

Let’s do this.

Wednesday, October 7, 2015

Magnesium as a Pre-Treatment Measure for Rapid Sequence Intubation?

Up until relatively recently, the concept of pre-treatment medications for rapid sequence intubation has remained uncontested. The acronym “LOAD” has often been proposed as a simple way to remember and apply this concept in clinical practice – lidocaine, opioids, atropine, and defasciculating doses of neuromuscular blocking agents. While most of these (classes) of agents have sparked controversy in the literature in recent years regarding their (f)utility as pre-treatment measures in rapid sequence intubation, it may be worth exploring other agents that may replace some of the letters of this acronym.

One agent that has had a surprisingly long and interesting history in the world of anesthesia is one that many that may not even consider for use in this setting for airway management. The agent? Magnesium…yes, magnesium.

Some of the effects of magnesium in this clinical setting, largely derived from the anesthesia literature, are described below:

1 – Catecholamine Blunting Effect

Magnesium is thought to attenuate the release of catecholamine associated with the process of intubation through its action on the adrenal medulla and nerve terminals of the adrenergic system. It has been hypothesized that magnesium competes with the actions of calcium at the ion channels within these systems, which ultimately prevents the response of catecholamine release induced by calcium in the first place (1-3).  One of the earliest studies conducted in human subjects that tested this premise occurred in patients undergoing intubation who were randomized to receive an intravenous bolus of magnesium sulfate at a dose 60 mg/kg or placebo solution of 0.9% sodium chloride placebo with the administration of thiopental and succinylcholine. After intubation, the investigators found that heart rate remained unchanged in patients treated with magnesium and the rate of increase in systolic blood pressure was less in those patients treated with magnesium relative to placebo (p < 0.05). In addition, in those patients treated with magnesium sulfate, measured plasma concentrations of epinephrine and norepinephrine were also found to be significantly lower post-intubation relative to placebo (4).  Several other studies have demonstrated similar results in attenuation an increase in heart rate, systolic blood pressure, and mean arterial pressure following administration of magnesium pre-intubation with significant decrease in measured plasma concentrations of catecholamines (5-8).

2 – Minimization of Fasciculation Associated with Administration of Succinylcholine

In terms of preference of paralytic for the purposes of intubation, some clinicians are of the camp that “succ(inylcholine) sucks and roc(uronium) rocks.” Nonetheless, whether some folks like it or not, succinylcholine still continues to utilized to facilitate intubation in daily practice. Investigators of a few studies have suggested that magnesium may minimize the number and degree of muscle fasciculation associated with the administration of succinylcholine (9-13). There is conflicting evidence related to the downstream effects of this effect, such as reduction in the increase in potassium associated with the administration of succinylcholine and myalgia occurring as a result of fasciculation (14).

3 – Shorter Onset and Prolonged Effect of Non-Depolarizing Neuromuscular Blocking Agents

It has been proposed that magnesium may mitigate the release of acetylcholine from presynaptic nerve terminals at the neuromuscular junction as a result of its actions in antagonizing the action of calcium in mediating this reaction (15). In addition, other mechanisms that have been suggested leading to the effect of shorter onset and prolonged effect of non-depolarizing neuromuscular blocking agents includes reduced sensitivity of the neuronal endplate to acetylcholine and modification of the electrical excitability threshold of the muscle membrane (16-17). Again, the evidence related to this concept is somewhat conflicting, as depending on the study evaluated, the specific neuromuscular blocking agent utilized, and associated outcomes, there may or may not be a demonstrated difference on onset and duration of action of the agent with concomitant administration of magnesium. For some, this practice is certainly not without concern or controversy due to the unpredictability at which this may occur in terms of the potential danger associated with prolonged paralysis as well as the very idea of exploiting the use of a drug-drug interaction in such a critical setting as airway management.

With these purported effects, is it worth administering magnesium as a pre-treatment adjunct for the purposes of intubation? Some may argue that this concept has yet to be evaluated in the setting of the emergency department, and as a result, the clinical applicability is minimal at best, especially as the evidence associated with the outcomes of the effects described above are conflicting and the dose of magnesium evaluated in many of these trials varies (but generally, doses have fallen within 10 mg/kg of 50 mg/kg/dose of intravenous magnesium sulfate). For some who may be interested in thinking outside of the box when it comes to airway management and novel measures of application in the emergency department, this path may be worth future pursuit.

Peer reviewed by: Craig Cocchio, PharmD, BCPS (@iEMPharmD)

  1. Douglas WW, Rubin RP. The mechanism of catecholamine release from the adrenal medulla and the role of calcium in stimulus-secretion coupling. J Physiol 1963; 167:288-310.
  2. Lishajko F. Releasing effect of calcium and phosphate on catecholamines, ATP, and protein from chromaffin cell granules. Acta Physiol Scand 1970; 79:575-85.
  3. Sasaki R, Hirota K, Roth SH, Yamazaki M: Extracellular magnesium ion modifies the actions of volatile anesthetics in area CA1 of rat hippocampus in vitro. Anesthesiology 2002; 96:681-7.
  4. James MFM, Beer RE, Esser JD. Intravenous magnesium sulfate inhibits catecholamine release associated with tracheal intubation. Anesth Analg 1989; 68:772-6.
  5. Puri GD, Marudhachalam KS, Chari P, Suri RK. The effect of magnesium sulphate on hemodynamics and its efficacy in attenuating the response to endotracheal intubation in patients with coronary artery disease. Anesth Analg 1998; 87:808-11.
  6. Durmus M, But AK, Erdem TB, Ozpolat Z, Ersoy MO: The effects of magnesium sulphate on sevoflurane minimum alveolar concentrations and haemodynamic responses. Eur J Anaesthesiol 2006; 23:54-9.
  7. Yap LC, Ho RT, Jawan B, Lee JH. Effects of magnesium sulfate pretreatment on succinylcholine-facilitated tracheal intubation. Acta Anaesthesiol Sin 1994; 32:45-50.
  8. Ashton WB, James MFM, Janicki P, Uys PC. Attenuation of the pressor response to tracheal intubation by magnesium sulphate with and without alfentanil in hypertensive proteinuric patients undergoing caesarean section. Br J Anaesth 1991; 67:741-7.
  9. Stacey MR, Barclay K, Asai T, Vaughan RS. Effects of magnesium sulphate on suxamethonium-induced complications during rapid-sequence induction of anaesthesia. Anaesthesia 1995; 50:933-6.
  10. Sakuraba S, Serita R, Kosugi S, Eriksson LI, Lindahl SG, Takeda J. Pretreatment with magnesium sulphate is associated with less succinylcholine-induced fasciculation and subsequent tracheal intubation-induced hemodynamic changes than precurarization with vecuronium during rapid sequence induction. Acta anaesthesiologica Belgica 2006; 57:253-7.
  11. Danladi KY, Sotunmbi PT, Eyelade OR. The effects of magnesium sulphate-pretreatment on suxamethonium-induced complications during induction of general endotracheal anaesthesia. Afr J Med Med Sci 2007; 36:43-7.
  12. Kumar M, Talwar N, Goyal R, Shukla U, Sethi A. Effect of magnesium sulfate with propofol induction of anesthesia on succinylcholine-induced fasciculations and myalgia. J Anesthesiol Clin Pharmacol 2012; 28:81-5.
  13. Ahsan B, Rahimi E, Moradi A, Rashadmanesh N. The effects of magnesium sulphate on succinylcholine-induced fasciculation during induction of general anaesthesia. J Pak Med Assoc 2014; 64:1151-3.
  14. Schreiber JU, Lysakowski C, Fuchs-Buder T, Tramèr MR. Prevention of succinylcholine-induced fasciculation and myalgia: a meta-analysis of randomized trials. Anesthesiology 2005; 103:877-84.
  15. Ghoneim MM, Long JP. The interaction between magnesium and other neuromuscular blocking agents. Anesthesiology 1970; 32:23-7.
  16. Sinatra RS, Philip BK, Naulty JS, Ostheimer GW. Prolonged neuromuscular blockade with vecuronium in a patient treated with magnesium sulfate. Anesth Analg. 1985;64:1220-2.
  17. Fuchs-Buder T, Wilder-Smith OH, Borgeat A, Tassonyi E. Interaction of magnesium sulphate with vecuronium-induced neuromuscular block. Br J Anaesth. 1995;74:405-9.

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