Monday, December 16, 2013

Don't Give Mag the Cold Shoulder: The Role of Magnesium in Therapeutic Hypothermia

In light of the JAMA and NEJM articles that have been recently published regarding outcomes associated with therapeutic hypothermia (TH) status post-cardiac arrest, I figured this would be a good time as any to cover complications associated with this phenomenon- namely, shivering.

As we all know, the goal in TH status post-cardiac arrest is to reach a goal core body temperature between 32 and 34 degrees Celsius for a period of 12 to 24 hours in patients who have achieved return of spontaneous circulation (ROSC) secondary to ventricular fibrillation or ventricular tachycardia, or in those patients with a non-shockable rhythm. It is thought that TH delays the progression of cerebral ischemia and serves as a mechanism to prevent and/or reversal neurological dysfunction associated with cardiac arrest. As pharmacists working in the emergency department, we have a critical role when it comes to reaching this body temperature, which generally occurs gradually over a four-hour period, in not only providing sedation and analgesia to these patients, but also in being able to recognize potential complications secondary to TH.

Shivering in TH is mainly an autonomic response that occurs as core body temperature reaches 35 to 37 degrees Celsius. As shivering occurs and heat is generated, not only will this delay achievement to the targeted core body temperature, but it can also increase metabolic rate and oxygen demand, which are both already compromised in patients post-cardiac arrest.

A number of treatment strategies do exist, and in most cases, we do often have to resort to neuromuscular blocking agents (NMBAs) with sedation and analgesia. However, NMBAs are associated with several issues such as the inability to affect vasoconstriction, masking of insufficient sedation and analgesia as well as seizure activity, and the potential for neuropathy with prolonged use.

Interestingly enough, magnesium has been proposed as an agent to be utilized to manage shivering associated with TH. It functions as an N-methyl-D-aspartate (NMDA) receptor antagonist and in doing so, it helps facilitate thermoregulation to non-adrenergic and serotonergic neurons to counter the effects of hyperthermia. In addition, it also may offer neuroprotection through cerebral vasodilation due to its action on smooth muscle cells.

A couple of experimental studies have looked at magnesium as a potential agent for the management of shivering:
  • Wadhwa et al. Br J Anesth 2005; 94:756-762:
    • Healthy human volunteers (n = 9)
    • Invasive cooling via infusion of cooled Lactated Ringer's solution
    • Interventions:
      • Control: Infusion of normal saline solution
      • Magnesium: 80 mg/kg IV bolus followed by infusion of 2 g/hr
    • Results:
      • Reduction in shivering threshold (p = 0.04)
      • Increase in shivering comfort (p = 0.019)
      • No difference in gain of shivering response (p = 0.344) 
  • Zweifler et al. Stroke 2004; 35:2331-2334:
    • Healthy human volunteers (n = 22)
    • Active cooling via surface cooling technique for a maximum of five hours
    • Interventions:
      • Mepiridine 
      • Mepiridine and buspirone
      • Mepiridine and ondansetron
      • Mepiridine, ondansetron, magnesium
        • Magnesium: 4 to 6 g IV bolus followed by infusion of 1 to 3 g/hr
    • Effects of combination therapy with magesium:
      • Greater proportion of patients achieved vasodilation
      • Shorter time to target tympanic temperature
      • Higher comfort scores
      • All hemodynamic parameters with the exception of heart rate maintained
Magnesium in general can be utilized as a treatment option for the management of shivering in patients undergoing TH. These studies have shown that it does reduce the shivering threshold and increase patient comfort. What would be interesting to study is whether magnesium has potential sparing effects when used in conjunction with standard therapies, specifically NMBAs, in terms of the total dose and duration of use of NMBAs.

Some institutional protocols for TH have already incorporated the use of a standard 4 g IV bolus of magnesium for all patients undergoing TH that is to be infused over a two-hour period. For the time being, as long as we continue to institute TH in select patients post-cardiac arrest, magnesium is a reasonable treatment option for patients who experiencing shivering as a complication of this phenomenon.