Cooling in status asthmaticus

Motivation: A case of status asthmaticus refractory to continuous nebs, steroids, theophylline, heliox, etc. Ventilation was a major issue, with severe respiratory acidosis and unacceptably high plateau pressures, despite optimization of vent settings and paralysis. This patient was cooled in an attempt to decrease the body's CO2 production, in the hope of decreasing PaCO2 and the patient's overall ventilatory requirement. Physiologically, this makes sense, but what has the literature reported about similar cases?

Literature search and results: Looking into the literature, there is a case published about treatment of severe asthma with hypothermia: Browning D, Goodrum DT. Treatment of acute severe asthma assisted by hypothermia. Anaesthesia. 1992 Mar;47(3):223-5. In this case report, a patient in refractory status asthmaticus was cooled to 30 degrees Celsius for 5 days due to rising PaCO2. While hypothermia helped with ventilatory settings, her ventilation was compromised by development of steroid-induced myopathy.

Discussion: My search for similar cases came up quite short. Hypothermia was used in our case and in this reported case in the literature was in the setting of status asthmaticus with poor/very guarded prognosis despite maximal therapy and optimal support. As predicted by physiology, cooling helped with allowing more reasonable vent parameters, but could not change the underlying process and complications related to status asthmaticus and its necessary therapies (e.g. steroid side effects, infections secondary to vent/lines/etc.). Furthermore, cooling/rewarming  is associated with its own complications. Thus, hypothermia can be seen as a temporizing agent to be considered within a plethora of medical issues in these severe cases of status asthmaticus.

Chronic Kidney Disease and Bleeding

Motivation: A man with kidney failure from polycystic kidney disease abruptly bled inside his head.  We blamed it on dysfunctional platelets and used desmopressin (DDAVP) to try to reverse his dysfunctional platelets.  Did not work, and he herniated.  Does desmopressin or other interventions really improve bleeding from dysfunctional platelets?

As way of background, chronic kidney disease increases bleeding time through dysfunction of platelet adhesion and aggregation via a variety of mechanisms including dysfunctional von Willebrand Factor (vWF), anemia, and uremic toxin accumulation.

Paper: Hedges, S.J., Dehoney, S.B., Hooper, J.S. et. al. Evidence-based treatment recommendations for uremic bleeding. Nature Clin. Prac. Neph. (2007); 3: 138-156

Methods: Systematic review of published trials.

Results: 

Cryoprecipitate: Two small controlled trials evaluated cryoprecipitate infusion to replete dysfunctional vWF.  In a prospective trial, seven patients with bleeding time > 15 minutes were infused 10 bags of cryoprecipitate resulting in decreased bleeding time in all patients after 4 hours.  In a retrospective single center analysis, 5 patients were infused with cryoprecipitate resulting in decreased bleeding time in 2 patients and no effect in three others.

Desmopressin (DDAVP): In the one randomized trial with patients on hemodialysis with bleeding time > 15 minutes, one dose of 0.4 ug/kg of DDAVP resulted in normalization of bleeding time in two of eight patients and reduction in seven of eight patients randomized to DDAVP arm.  In another prospective single center trial, one dose of 0.4 ug/kg of DDAVP resulted in normalization of bleeding time in six of twelve patients in one hour.  In two hours, 3 out of 12 had normal bleeding times.  After 24 hours, all patients reverted back to prolonged bleeding time.  Finally, in a retrospective study, one dose of 0.3 ug/kg of DDAVP resulted in normalized bleeding time in 5/12 one hour post-infusion, 2/12 four hours post-infusion, and 1/12 eight hours post-infusion.

Estrogens: Has been tested in three randomized, placebo controlled trials.  In first trial, patients received 0.6 mg/kg of IV conjugated estrogens for five days.  All patients in the estrogen treated group had normalized bleeding time within six hours.  In subsequent randomized trial, the dose used was again 0.6 mg/kg of IV conjugated estrogen for five days.  Patients receiving estrogen had significantly decreased bleeding time at days  seven and fourteen with no significant effects on day 21 and day 28.  In the final trial, patients on HD were randomized to oral conjugated estrogen (50 mg) or placebo for nine days or till normalization of bleeding time.  In the five patients randomized to estrogen, bleeding time normalized in 3 of 5 patients and decreased to less than 50% in remaining 2 patients.  The most common adverse effect was flushing.

Discussion: For the actively bleeding patient with renal failure, dysfunctional uremic platelets can be treated successfully!  In the actively bleeding patient, besides desmopressin, cryoprecipitate can also be helpful.  But, perhaps more intriguingly, conjugated estrogens may be beneficial in the short term even after six hours.  While desmopressin is presumed to induce secretion of Factor VIII from endothelial cells, the mechanism of estrogen is less clear - may work by decreasing NO production or decreasing Factor S concentrations.  I had not really considered estrogen as part of the acute therapy.  In the future, when desmopressin does not appear to stop bleeding, I will turn to cryoprecipitate and conjugated estrogens.

This was a post after a while.  Next posts will appear more frequently.

CD4 Count in the Immunocompetent

Motivation: A sick, critically ill - possibly infected - patient remains somnolent despite many bags of antibiotics.  A question that often occurs in this setting: is the patient immunocompromised?  The answer determines whether to broaden antibiotic coverage. Occasionally, one of the clinical tests used to assess immune function is to measure the CD4 T cell subset count.  But, is this is a valid tool in the setting of critical illness?  Does the CD4 count stay normal in immunocompetent patients even when critically ill?

Paper: Aldrich, J., Gross, R., Adler, M., et. al. "The Effect of Acute Severe Illness on CD4+ Lymphocyte Counts in Nonimmunocompromised Patients." Arch. Intern. Med. (2000); 160: 715-716.

Methods: Prospective observational study in which patients admitted to the medical intensive care unit of Hospital of the University of Pennsylvania from 2/1996 to 4/1997 had CD4 cell count measured.  Exclusion criteria were known HIV diagnosis, primary immunosuppressing disease, treatment with glucocorticosteroids, radiation therapy, or chemotherapy.  Mortality outcomes were recorded for all patients.

Results: 
Cohort: Of 353 admissions, 144 met inclusion criteria (exclusion criteria most frequently met were recent steroid use, immunosuppressive therapy, or refusal to be tested for HIV).  Of the 144 meeting inclusion criteria, only 53 consented to participate in the study.  In the final cohort, median age was 56 with 47% male.   The four top admitting diagnoses were infection, gastrointestinal bleeding, end stage liver failure, and respiratory failure.

CD4+ Cell Count: The median CD4 cell count was 510 (normal range of 560 to 1840).  Nine patients (17%) had counts lower than 200 while 29 (55%) had counts lower than 500.  The median CD4/CD8 ratio was 2.2 (normal range: 0.9-3.4)

Mortality: Of the nine patients with CD4 counts less than 200, five (56%) died while only ten (23%) died with higher CD4 counts. The relative risk of death was 2.4 (95% CI: 1.1-5.3).  The median CD4 count of those who died was 401 compared to the CD4 count of  510 for survivors (p = 0.05).

Discussion:

This observational study shows that critical illness alone is associated with depleted blood CD4 counts.  In HIV, the blood CD4 count is a reflection of systemic T cell depletion in the tissue and lymph nodes.  In critical illness, the CD4 count is likely changed by redistribution from the circulation to activated tissue sites.  In this setting, the blood CD4 count may not be an accurate assessment of immune function and perhaps reflects severity of illness (increased mortality in lower CD4 group).  Consequently, CD4 count in critical illness should be interpreted with caution. 

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.