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.

Choices for Testing Latent TB

Motivation: You suspect latent TB in a high-risk patient.  Which test do you order: an expensive blood test or a cheaper skin test that needs to be read after two days?  Ever since the interferon-gamma release assay for latent TB testing has been available, I have noticed that we often use the blood test rather than PPD to screen for TB.  Is there a rational basis for this?  Are we driven by convenience or by sound science?

As way of background, there are two commercial interferon-gamma release assays (QuantiFERON and T-SPOT) available.  The assay depends on in-vitro production of interferon-gamma by patient's immune cells in response to M. tuberculosis specific antigens.  In contrast to the PPD testing which also cross-reacts with bacille Calmette-Guerin (BCG) vaccine and many nontuberculous mycobacteria (NTM), the interferon release assay is more specific for  tuberculosis though M. marinum and M. kansasei also cross-react in the interferon release assay.

Paper: Menzies, D., Pai, M., and Comstock, G. "Meta-analysis: New Tests for the Diagnosis of Latent Tuberculosis Infection: Areas of Uncertainty and Recommendations for Research" Ann Intern Med. (2007); 146: 340-354.

Methods: Meta-analysis of studies measuring sensitivity and specificity of interferon-gamma release assays and tuberculin skin testing.  For sensitivity, the study sample was counted positive if the person had active TB (therefore should also test positive for latent infection) or exposure to person with active TB.  For specificity, healthy life-long residents of low-incidence populations without high-risk exposure were counted as negative for TB.

Results: 
Tuberculin Skin Test: There were fourteen studies assessing sensitivity and eight studies measuring specificity.    For the skin test, the sensitivity depends on diameter of induration set as the threshold for positive testing.
Sensitivity:
- 5 mm cutoff, sensitivity of 74% (95% CI of 0.66-0.82)
- 10 mm cutoff, sensitivity of 72% (CI: 0.50-0.95)
- 15 mm cutoff, sensitivity of 40% (CI: 0.25-0.56)
- Pooled pediatric data, sensitivity of 55% (0.43-0.67)
Specificity: 
- All studies: 66% (CI: 0.46-0.86)
- Non-BCG vaccinated: 98% (0.96-1.0)
- BCG vaccinated: 0.56 (0.34-0.78)
- 10 mm cutoff: 58% (0.37-0.79)
- 15 mm cutoff: 87% (0.7-1.0)

QuantiFERON: Thirteen studies assessed sensitivity and nine studies measured specificity
Sensitivity: 
- All studies: 76% (CI: 0.7-0.83)
- Pediatric: 66% (CI: 0.5-0.83)
Specificity: 
- All studies: 97% (CI: 0.95-0.99)
- BCG vaccinated: 96% (CI: 0.93-0.99)
- Non-vaccinated: 100% (CI: 0.94-1.0)

T-SPOT: Twelve studies assessed sensitivity and four studies measured specificity.
Sensitivity:
- All studies: 88% (CI: 0.81-0.95)
- Pediatric: 62% (CI: 0.43-0.81)
Specificity:
- All studies: 92% (CI: 0.88-0.95)
No data available for assessing specificity based on BCG status.

Discussion: For patients at risk of latent tuberculosis, screening by tuberculin skin test or interferon release assay is acceptable.  Although the confidence intervals overlap, there is a trend for higher sensitivity for the T-spot assay compared to the tuberculin skin testing and QantiFERON assay.  This will need to be verified further in future studies.  The specificity of the tubeculin skin testing is affected primarily by BCG status.  For patients without BCG vaccine, specificity is quite high for skin testing as well.  Skin testing is additionally affected by multiple non-tuberculous mycobacteria (NTM) strains.  There was no data presented on results of interferon-release assay or skin testing on patients with confirmed NTM infections.  Another point of caution in the results is that testing data in adults do not necessarily translate to pediatrics, where the sensitivity of the assays could be lower.

One of the major problems with this field at large is that there is no gold standard for latent tuberculosis.  By definition, latent TB does not cause symptoms and is held in check.  So far, the only way to verify prior exposure is when patients develop active TB or have high exposure to active TB infection.  Of the estimated 2 billion people with TB, only a minority will ever develop active TB.  It is quite unclear what the sensitivity of these assays are in patients with well-controlled TB for years.  

Rasburicase in gout

Question: Rasburicase is an IV medication that is a recombinant urate oxidase found in many organisms but NOT humans. There is a clear role for rasburicase in tumor lysis syndrome especially in the setting of hematological malignancy/chemotherapy and urate nephropathy, but what is the role of rasburicase in an acute gout flare, which is also characterized by high serum uric acid levels? I found one study that dealt with this, as well as a few case reports that shared their experiences using rasburicase for severe gout flares.

Study:

Rasburicase for tophaceous gout not treatable with allopurinol: an exploratory study.

Richette P, Brière C, Hoenen-Clavert V, Loeuille D, Bardin T.

J Rheumatol. 2007 Oct;34(10):2093-8. 

Summary of results:  10 patients with gout that did not improve with allopurinol therapy were selected for this study. These patients received rasburicase 0.2 mg/kg 1) in 6 monthly infusions (Group 1, N=5) and 2) in 5 daily infusions (Group 2, N=5). It was reported that Group 1 had statistically significant lowered serum uric acid levels after 6 months. In Group 2, serum uric acid levels decreased in the acute setting of treatment, but were not significantly lowered from baseline at 1 or 2 months. Reportedly, 2/5 patients in Group 1 (versus 0/5 in Group two) also had decreased tophus sizes. However, 2/5 patients in Group 1 and 4/5 patients in Group 2 had gout flares, despite colchicine treatment. (Richette et al., 2007)

Other papers to note: On a case report level, rasburicase has been shown to be useful in cases of severe gout. This is NOT an exhaustive list, just a few examples from the literature:

1) Rasburicase treatment in severe tophaceous gout: a novel therapeutic option.

Moolenburgh JD, Reinders MK, Jansen TL.

Clin Rheumatol. 2006 Sep;25(5):749-52. 

• This case reports the use of rasburicase in a severe case of gout that persisted despite standard therapy. Rasburicase helped improve the burden of tophaceous gout in this patient.

2) Successful treatment with rasburicase of a tophaceous gout in a patient allergic to allopurinol.

Richette P, Bardin T.

Nat Clin Pract Rheumatol. 2006 Jun;2(6):338-42; quiz 343.

• This case reports the use of rasburicase in a severe of gout in a patient who could not tolerate allopurinol. This patient also had some renal insufficiency likely secondary to urate nephropathy. The rasburicase helped to lower uric acid levels in this patient. 

3) Urate oxidase (rasburicase) for treatment of severe tophaceous gout.

Vogt B.

Nephrol Dial Transplant. 2005 Feb;20(2):431-3

• This case reports the use of rasburicase in a patient with severe gout and allopurinol allergy. Use of rasburicase was reported to lower serum uric acid levels, improve gouty arthritis symptoms and decrease tophaceous burden.

Thoughts: The current data supporting use of rasburicase in gout remains on the case series or report level. Undoubtedly, rasburicase lowers uric acid levels and may thereby possibly help with gout symptoms in some patients as reported by multiple authors, but I have not been convinced by current data that rasburicase effectively and consistently treats gout flares. It makes sense to use rasburicase in a gout flare when there is concurrent urate nephropathy or TLS - but the main indication would be for urate nephropathy  or TLS, and not the gout per se.

Dissection and Looking for Zebras

Motivation: A cervical artery dissection is a frightening event.  I met a middle age woman last year, who described sitting in a bench listening to a street musician playing guitar then feeling a twinge in her neck and then not being able to move her left side.  She had a carotid dissection leading to a large stroke - chances are that she will never be able to move her left side.  For other patients with stroke, we often feel that perhaps if the patient had not smoked and snacked on hamburgers, we could have prevented the stroke.  With dissections, we do not know the cause most of the time.  One of the more common maneuvers in rounds though is to see if the patient is flexible and can bend her fingers backwards without breaking - attempts to infer underlying connective tissue disorders.  But, how commonly are connective tissue diseases associated with cervical artery dissection?

Paper: Brandt, T., Orberk, E., Weber, R. et. al. "Pathogenesis of cervical artery dissections: Association with connective tissue abnormlities." Neurology (2001); 57: 24

Methods: Prospective study of patients with non-traumatic spontaneous symptomatic cervical artery dissection.  Dissections were confirmed by MRI of neck, CTA, and angiography.  Patients also received thorough clinical evaluation and had skin biopsy.  Ten controls with strokes from other mechanisms were also evaluated and biopsied.

Results:
Cohort: Total of 65 patients with dissection were recruited into the study - 36 with single vessel dissection  (29 with internal carotid artery and 7 with vertebral arter), 22 with multi-vessel dissection, and 7 with recurrent dissection.  Of the 65 patients, 52 presented with cerebral ischemia while the remaining had neck and cranial nerve palsies.

Family Inheritance: Six patients (9%) had first degree relative with cervical artery dissection.

Connective Tissue Disease: Three patients (5%) had systemic signs of connective tissue disorder such as hyperextensible skin, marfanoid appearance, and hypertrophic pseudo-molluscoid scars.

Vascular Disease: In total, six patients (9%) had other vascular anomalies: 2 with intracranial aneurysm, 3 with aortic dissection, and 1 with renal artery dissection.

Biopsy: On electron microscopy, ultrastructural aberrations of the connective tissue disease was found in 36 patients (55%).    None of the controls had similar abnormalities.  These abnormalities were typically in the collagen fibrils and elastic fibers.

Discussion: This exploratory study demonstrates, I think, that there probably exists new classes of connective tissue disorders affecting vascular structures that we do not at present know.  Interestingly, only 5% had other clinical signs of connective tissue disease yet more than half had microscopic evidence.  One of the other cautionary points from this paper is that a significant percentage (9%) had concurrent vascular anomalies such as dissection or aneurysms.  When treating a patient with newly diagnosed dissection, we should probably be extra vigilant for other anomalies as well.  This study, of course, suffers from the small number of controls, and it is unclear how many apparently normal people in a larger study would have microscopic abnormalities without every having any clinical symptoms.
 

Your urine tox screen was positive for cocaine...

Motivation: Awkwardness arises when a patient with bacterial endocarditis denies use of IV drugs, but his or her urine tox screen comes back positive for cocaine. Urine tox screens come with the disclaimer from the lab that these tests are not definitive, and further confirmatory testing is required. When a urine tox screen comes back positive for cocaine, how accurate is this result? Surprisingly, few studies have investigated this common issue, and it is difficult to compare study results to the exact test used in the hospital, as there are many different urine tox screen assays...but I did manage to find one article that dealt with this question:

Study: Linder MW, Bosse GM, Henderson MT, Midkiff G, Valdes R. Detection of cocaine metabolite in serum and urine: frequency and correlation with medical diagnosis. Clin Chim Acta. 2000 May;295(1-2):179-85.

Study design and results: A retrospective chart review was performed at a level 1 trauma center. 500 sequential subjects with urine tox screens in the ED were included. Urine specimens positive for the cocaine metabolite (benzoylecgonine-BE) were confirmed with GC/MS technique. 54 patients were positive for BE in the urine; of these patients, 10 had a medical diagnosis of acute cocaine intoxication. 25% of these 54 patients reported using cocaine in the past, and 1 reported use of cocaine on day of testing. Based on their chart review, the authors estimated sensitivity of 100%, specificity of 90.6%, NPV of 100%, but a PPV of only 18.5% for identifying acute cocaine intoxication in the urine test. (Linder et al., 2000)

Thoughts: This study addresses the relationship between cocaine positivity in the urine test and acute cocaine intoxication. I would have been interested in the relationship between cocaine positivity in the urine test and recent cocaine intake in general-but this is difficult because it would rely on actually knowing whether or not a patient took cocaine (which could be practically impossible to know with 100% certainty) or comparing to a gold standard (which is possible, but once again, no test is perfect). From this study, I take home the point that a negative result is useful, but a positive result may not be accurate and requires further testing. This is a key point to remember in keeping the trust in a therapeutic patient-physician relationship, when a patient lets a physician know in good faith that he or she has not taken cocaine, but a positive cocaine test results. One should then verify with further tests if a true positive result would change medical management.

Lyme cardiomyopathy

Question: Can Lyme disease be associated with cardiomyopathy?
Motivation: A patient presents with new onset cardiomyopathy and heart failure. She lives in a Lyme endemic area. EKG does not show any conduction abnormalities - which is the more common manifestation of Lyme disease in cardiac disease - but ECHO shows dramatically decreased LVEF. This study examines the evidence for Lyme cardiomyopathy from a pathological perspective.

Study: Kubánek M, Šramko M, Berenová D, Hulínská D, Hrbáčková H, Malušková J, Lodererová A, Málek I, Kautzner J. Detection of Borrelia burgdorferi sensu lato in endomyocardial biopsy specimens in individuals with recent-onset dilated cardiomyopathy. Eur J Heart Fail. 2012 Jun;14(6):588-96. doi: 10.1093/eurjhf/hfs027.

Design and results: This study was a pathological/molecular analysis of endomyocardial biopsy (EMB) specimens for the Borrelia (Borrelia burgdorferi sensu lato) genome in cases of dilated cardiomyopathy (DCM). The authors compared EMB of patients with new-onset DCM and of patients with CAD (as controls). Specimens were analyzed by PCR and EM. There was a higher frequency of Borrelia burgdorferi sensu lato in the DCM (24%) versus the control group (0%) (p=0.035), while CMV and parvovirus B19 were similar in both groups. (Kubanek et al., 2012)

Thought: The presence of the Borrelia genome in EMB specimens of DCM does not PROVE causation - it does not necessarily prove that Lyme disease causes DCM. Lyme disease may be incidentally found in DCM, and/or related to another etiological factor for DCM. It is also important to ensure in these cases of DCM that there does not exist a more obvious etiology for cardiomyopathy. Nevertheless, I find these data supportive of the hypothesis that Lyme disease can be an underlying pathological etiology for cardiomyopathy. I will be sending off Lyme serologies for patients from endemic areas who present with new cardiomyopathy, especially if it is DCM.