Repleting calcium in the ICU

Motivation: The association between hypocalcemia and critical illness is well established. On call in the ICU, I am frequently asked to give IV calcium supplementation for low ionized calcium/calcium levels. Calcium should of course be repleted in cases where hypocalcemia is associated with EKG changes or symptoms of hypocalcemia...But what about asymptomatic hypocalcemia without EKG changes - should we be aggressively repleting low calcium levels in critically ill patients? Here, I provide a quick summary of some of the existing data in humans (and animals if there is information available in animal studies that have not been shown in human studies):

SOME POSITIVE EFFECT WITH IV CA
Vincent JL, Bredas P, Jankowski S, Kahn RJ. Correction of hypocalcaemia in the critically ill: what is the haemodynamic benefit? Intensive Care Med. 1995 Oct;21(10):838-41.
Vincent et al. administered 1 g IV CaCl to 17 ICU patients with low ionized calcium levels. There was a statistically significant increase in mean arterial pressure from 77+/-8 to 90+/-12 mmHg (but this effect was only transient) and  in LV stroke work index, but the increase in cardiac index and SVR were not statistically significant.

NO DIFFERENCE WITH IV CA
Forsythe RM, Wessel CB, Billiar TR, Angus DC, Rosengart MR. Parenteral calcium for intensive care unit patients. Cochrane Database Syst Rev. 2008 Oct 8;(4):CD006163.
A literature review was performed of RCT and controlled clinical trials of ICU patients on IV calcium chloride or gluconate versus no treatment or placebo. These studies were heterogeneous in population/indication/threshold for supplementation, so a pooled estimate could not be calculated, but there was no evidence that IV calcium supplementation impacted outcomes.

On a side note, it does not seem unsafe to give IV calcium along with ceftriaxone (Dalton BR, Zuege DJ, Shahpori R, Laupland KB. Concomitant ceftriaxone and high-concentration intravenous calcium therapy in adult critical care patients: a matched cohort study. Ann Pharmacother. 2010 Jul-Aug;44(7-8):1158-63).

WORSE OUTCOMES WITH IV CA
Zaloga GP, Sager A, Black KW, Prielipp R. Low dose calcium administration increases mortality during septic peritonitis in rats. Circ Shock. 1992 Jul;37(3):226-9.
In a rat model for endogenous sepsis, IV Ca increased iCa levels slightly (not statistically significant), but actually DECREASED survival (statistically significant). While survival was 67% with a lower rate of Ca infusion of 4 mg/ml/hr, survival was 44% with a higher rate of Ca infusion of 6 mg/ml/hr.

Malcolm DS, Zaloga GP, Holaday JW. Calcium administration increases the mortality of endotoxic shock in rats. Crit Care Med. 1989 Sep;17(9):900-3.

In a rat model of sepsis, increasing iCa levels were associated with increased endotoxin lethality, despite improvement in MAP.

TAKE HOME POINTS

Animal, though not human studies, suggest that calcium administration is associated with increased mortality in sepsis mediated by endotoxins; this evidence will likely make me think twice about aggressively repleting calcium in patients with sepsis – given this data (even though this has not been shown as far as I have found in human studies), I would consider avoiding giving IV Ca in asymptomatic hypocalcemia without EKG changes in the setting of sepsis. However, in critically ill patients in general, the data remains equivocal about whether or not to replete calcium. The study by Vincent et al. in 1995 does provide some evidence (in a small population) of some transient, limited benefit of calcium administration in terms of improving hemodynamics, so in ICU patients with no sepsis, IV calcium administration is certainly an intervention that can be considered, with the understanding that no study has clearly shown that repletion of asymptomatic hypocalcemia without EKG changes has impacted patient outcomes.

Albuterol for congenital myasthenia syndrome

Motivation: Overnight, a patient developed SVT. Cause? Likely secondary to uptitration of albuterol. I was intrigued to see that the indication for albuterol was congenital myasthenia syndrome. What is the evidence for this medication in congenital myasthenia syndromes?

Study: Beneficial effects of albuterol in congenital endplate acetylcholinesterase deficiency and Dok-7 myasthenia. Liewluck T, Selcen D, Engel AG. Muscle Nerve. 2011 Nov;44(5):789-94. doi: 10.1002/mus.22176.

Study Design: This was a study in which 3 patients with end plate acetylcholinesterase deficiency and 15 patients with Dok-7 myasthenia were treated with albuterol in an open label study, and pre- and post-intervention questionnaires on disease specific symptoms (9 questions long) were completed. Adverse effects were also queried. These two diseases in particular were chosen because they have been reported to respond to ephedrine (several patients with EP AchE deficiency, reference = Neurology. 2005 Jul 12;65(1):144-6; and Class IV evidence in Dok-7 myasthenia, reference = Neurology. 2010 May 11;74(19):1517-23; Neuromuscul Disord. 2009 Dec;19(12):828-32.), another drug that stimulates the sympathetic system.

Study Result: The study reported a beneficial response to albuterol based on the 9-question survey in terms of patient-reported improved walking distance and stair climbing. In one patient, the trial drug was stopped early because of development of atrial flutter. Other adverse effects included muscle cramps, insomnia, HTN, mild tremor/jittery feeling.

Discussion: This is a small study that offered promising pilot results that - as its authors note - should trigger further testing in larger RCTs, given that the limitations of this study included its small sample size (not surprising given the rarity of diseases studied), and potential bias in patient responses (especially given that it was an open label study). Authors note that the mechanism of symptomatic improvement is unclear. Nevertheless, given the lack of alternative therapies, and in the absence of contraindications to beta-agonists (such as certain tachyarrythmias), albuterol does seem like a reasonable therapy to further pursue in clinical trials for EP AchE deficiency and Dok-7 myasthenia. Currently, however, patients who are prescribed this medication for these diseases need to weigh the risks of a therapy that has not undergone full RCT testing with its potential (and anecdotal) benefits.