Blood Pressure Goals

Motivation: 150?? Since medical school, we have been firmly taught that the upper limit of normal for systolic blood pressure is 140 mmHg.  Recently, the panel JNC8 ruled that for adults over 60, a reasonable systolic goal is less than 150 mmHg.  After having counseled countless times about the importance of blood pressure control, this increase sounded traitorous.  What is the data?  There have been two randomized trials addressing this issue over the past decade.  I will review here the one of the larger and latest one here.

Paper: Ogihara, T, Saruta, T, Raguki, H, et. al.  "Target Blood Pressure for Treatment of Isolated Systolic Hypertension in the Elderly" Hypertension (2010) 56: 196-202.

Methods: The study (VALISH) was a multicenter, prospective, randomized, open-label, blinded end point trial in Japanese adults between 70-85 years of age with isolated systolic hypertension (SBP > 160 mmHg with diastolic less than 90 mmHg).  Patients were randomly treated with valsartan (titrated first with addition of second agent if necessary) into two groups: (1) Systolic blood pressure < 140 mmHg (strict control) or (2) systolic blood pressure < 150 mm Hg (moderate control).  Patients were followed for minimum of two years.  Primary outcome was a composite of cardiovascular events (sudden death, stroke, MI,  death from cardiovascular cause, renal dysfunction).

Results:
Cohort: A total of 3260 patients were randomized.  There were 181 patients lost to follow-up (95% follow-up).  In total, 3079 patients were followed for average of 2.85 years.  Average age was 76.1 years with 62% women.  Baseline characteristics were mostly balanced between groups except there were more smokers in the strict control group vs. moderate control (21% vs. 17.4%; p = 0.01).  There was history of stroke in 6.5%, ischemic heart disease in 5%, heart failure in 1.7%, and diabetes mellitus in 13%.

Blood Pressure Control: At 36 months of follow-up, the blood pressure was 13.6./74.8 in strict control group and 142/76.5 in moderate control groups.  Heart rate did not differ significantly between the two groups.

Outcome: In the primary combined cardiovascular outcome, the overall rate did not differ between the groups in intention-to-treat analysis (10.6 events per 1000 patient years in strict control; 12 per 1000 patient years in moderate control group, p = 0.38).  There was no difference in any of the individual components of the composite outcome.  In subgroup analysis, there was not a statistical difference in patients with diabetes, dyslipidemia, and chronic kidney disease.

Adverse Effect: There was no difference in adverse effect between the two groups.

Discussion: After an average of 2.8 years of follow-up, there did not appear to be a difference in cardiovascular outcome by controlling blood pressure tighter in patients with isolated systolic hypertension.  While rather remarkable and against popular medical conception, I think that the lack of longitudinal data beyond 2.8 years is cautionary is depending on these blood pressure parameters too much.  This trial shows that systolic blood pressure control less than 150 mmHg versus 140 mm Hg may not make much of a difference in the short term, but what about in five to ten years?  We still do not know the answer.  Another problem with extending this dataset is that patients included in the cohort had low burden of disease (ischemic heart disease in only 5%).  For the patient with angina, the trial may not be powered enough to detect difference in this subgroup.    But then again, these arguments are probably my ingrained cognitive biases against change.  The bottom line, I think, is that we need more longitudinal data before having a blood pressure parameter in mid.

Stroke Recovery for How Long

Motivation: So, how long does it take to recover? Even after more than a year of treating patients with acute stroke, I am not sure how to answer this question.  I sometimes put it vaguely as "months."  But, really, after how many months do most post-stroke patients complete their recovery?

Paper: Jorgensen HS, Nakayama H, Raaschou HO, Vive-Larsen J, Stoier M, Olsen TS. "Outcome and time course of recovery in stroke: Part II: Time course of recovery. The copenhagen stroke study." Arch Phys Med Rehabil (1995); 76: 406-412.

Methods: All patients with acute stroke in Copenhagen, Denmark between September, 1991 to 1993 were followed from time of acute admission to end of rehabilitation to six months post-stroke.  Time course of recovery was plotted.

Results:
Cohort: The cohort of stroke survivors consisted of 947 patients (53% female) of mean age 73.3.  The strokes were 93% ischemic and 7% hemorrhagic.  The median time between symptom onset and admission was 16 hours.  After rehabilitation, 19% were placed in nursing homes while 81% were discharged home.

Recovery: When assessed by the Scandinavian Stroke Scale (0-58 points, higher indicating milder deficits), best neurological recovery was reached in 80% by 4.5 weeks (95% CI: 4 to 5 weeks) and in 95% by 11 weeks (95% CI: 10.1 to 11.9 weeks) from stroke onset.  Best ADL function (measured by Barthel Index) was reached in 80% by 6 weeks (95% CI: 5.3 to 6.7 weeks) and in 95% by 12.5 weeks (95% CI: 11.6 to 13.4).

Initial Severe Functional Deficits: Severity of functional deficits were judged by the Barthel Index (scale of 0 to 100 with very severe disability in 0-20 and no disability with score of 100).  In those with very severe initial disability (index of 0-20), best ADL function was reached in 80% of patients within 11 weeks (95% CI: 10-12) and in 95% within 17 weeks (95% CI: 15-19).

Initially Mild Disability: In those with mild disability (Barthel Index 75-95), best ADL function was reached in 80% of patients within 2.5 weeks (95% CI: 2-3) in 95% of patients within 5 weeks (95% CI: 4-6).  

Discussion: In this remarkable study with 100% follow-up of all stroke patients in Copenhagen over two years, the overall message is that 95% will regain their best ADL function in about three months.  The rate of recovery is slower in those with more severe disability and more rapid in those with mild disability.  However, even in those with very severe initial functional deficits, best ADL function was reached in 17 months.  For general counseling purposes, an appropriate summary statement might be that mild strokes take about a month to regain best function while severe strokes take about four to five months to regain best function.  While this study is well done, some cautionary aspects are that (1) acute stroke therapy has changed since  the study, and (2) physical therapy has changed since the early 1990s.  How these aspects change the natural history of stroke disorders is unclear.  Also note that this study also talks about the rate of recovery and not the extent of recovery.

Time to Defibrillation and Survival - How soon?

Motivation: Last year, a man walked into my clinic, shook my hand, and said that he had survived a v-fib cardiac arrest.  My heart skipped a beat.  He told me that he had been unconscious for more than ten minutes.  I did not know whether to believe him.  What is the relation between survival and time to defibrillation in out of hospital cardiac arrest?

Paper: De Maio, V.J., Stiell, I.G., Wells, G.A. et al. "Optimal Defibrillation Response Intervals for Maximum Out-of-Hospital Cardiac Arrest Survival Rates"  Ann Emerg Med. (2003) 42: 242-250.

Methods: Prospective cohort study of the Ontario Prehospital Advanced Life Supports (OPALS) study, in which 21 Ontario study communities received a basic life support level of care with defibrillation by EMS.  The study assessed the relation of survival to defibrillation response time by EMS between 1991-1997.

Results:

Cohort: There were a total of 9,273 out of hospital cardiac arrests.  The mean age of 68.3 with 67.7% male sex.  The initial rhythm was ventricular fibrillation in 38.5%, asystole in 42.3%, and pulseless electrical activity in 19.1%.  There was return of spontaneous circulation in 10.4%.  Of the total 9,273 patients with cardiac arrest, 392 were discharged alive from hospital (4.2%).

Defibrillation: Of the 9,273 cardiac arrests, 4,059 received defibrillation (43.8%).  The median time to defibrillation was 6 minutes.  The 90th percentile for defibrillation response was 9.3%.

Survival:  When survival to hospital discharge is related to response time to defibrillation:

• Response time less than 4 minute: 7.6% survival.
• Response time between 4-6 minutes: 4.0% survival
• Response time between 6-8 minutes: 2.8% survival
• Response time greater than 8 minutes: 1.6% survival

When survival is modeled continuously to time to defibrillation, the predicted survival is (90th percentile prediction):

• Defibrillation time 1 min: 28.1% survival
• Defibrillation time 2 mins: 23.1% survival
• Defibrillation time 3 mins: 18.8% survival
• Defibrillation time 4 mins: 15.1% survival
• Defibrillation time 5 mins: 12.0% survival
• Defibrillation time 6 mins: 9.5% survival
• Defibrillation time 7 mins: 7.5% survival
• Defibrillation time 8 mins: 5.9% survival

Discussion: I think that the overall lesson is that surviving an out of hospital cardiac arrest is hard!  Even with good response time between 4-6 minutes, there is only a 4% survival.  While defibrillation definitely appears to increase survival (by almost four fold when comparing response time less than 4 minutes to greater than 8 minutes), the really steep drop in survival comes at the very beginning of the cardiac arrest (for example, almost 20% drop in predicted survival from two minutes to three minutes).  This study, however, has some flaws in accounting for the benefit of defibrillation.  Most notably, there were more defibrillations performed than there were ventricular fibrillations.  Consequently, some PEA and asystole arrests were also defibrillated without a clear indication.  Including these in the accounting probably dilutes the effect of defibrillation. 

Heart Failure Hospitalization - How Bad?

Motivation: Last year I saw an 85 year old man with a stroke.  After never having walked into a hospital or doctor's office, he was in the hospital for diastolic heart failure and was then found to have difficulty moving his left hand.  When talking to him about preventing future strokes and the necessary tests, I wondered whether his heart or his brain was his bigger problem.  What is the prognosis after hospitalization for heart failure?

Paper: Jong, P, Vowinckel, E, Liu, P et. al. "Prognosis and Determinants of Survival in Patients Newly Hospitalized for Heart Failure" Arch Intern Med (2002); 162 (15): 1689-1694.

Methods: Retrospective population-based cohort of 38,702 consecutive patients with first admission for heart failure in Ontario, Canada between 1994 and 1997.  Outcome was mortality at thirty days and at one year.

Results:
Cohort: The cohort of 38702 patients consisted of 51.1% women with 84.6% older than age 65 and 57.9% older than age 75.

Mortality: The net mortality rate was 11.6% at thirty days and 33.1% at one year.  Men had a slightly higher mortality rate at thirty days (OR: 1.09, p = 0.001) and at one year (OR: 1.16, p < 0.001).

Age Relation: Age very significantly affected the prognosis.  The one year mortality rate was 13.5% in those younger than age 50 and 40.1% in those 75 or older.

Comorbidities: Using the Charlson composite index (a composite scale with higher score meaning more number and severity of comorbidities), a patient with score of 0 had one year mortality of 26.8% while a patient with score of 3 or greater had mortality of 50.6%.  Among specific conditions, malignancy, renal disease, dementia, cerebrovascular disease, and previous myocardial infarction all independently and significantly increased one year mortality.

Conclusion: Excepting in those younger than fifty without significant comorbidities, the prognosis of hospitalization for heart failure is quite grim.  I think that a general figure to keep in mind is that roughly a third will be dead after one year.  For someone, with history of stroke, diabetes, and chronic kidney disease (a quite common combination with Charlson score of 3), roughly half will be dead in a year.  I do not think that families or patients are quite aware or counseled adequately of the implications of heart failure.  Of course, this study has some serious limitations as well - most particularly, therapeutics for heart failure have become more standardized with incorporation of beta-blockers, ACE inhibitors, and ischemic heart disease treatment than in the 1990s.  We really need a similar study on a more modern population though I am not sure that the conclusions will be that significantly different.

The anti-nuclear antibody

Motivation: Midway last year, the anti-nuclear antibody (ANA) test started appearing rather useless to me.  The ANA was positive at some titer in just about everyone we tested, and even when it was positive, we discarded it under the mantra of "non-specific."  What is the range of ANA in the "healthy" population?

Paper: Tan, E.M., Feltkamp, T.E.W., Smolen, J.S. et. al. "Range of antinuclear antibodies in "healthy" individuals." Arthritis & Rheumatism (1997); 40: 1601-1611.

Methods:   Fifteen international laboratories experienced in performing the ANA assay were asked to give samples from healthy individuals of different age groups and from patients with systemic lupus erythematosus (SLE), scleroderma, Sjogren's syndrome, rheumatoid arthritis (RA), and soft tissue rheumatism.  Healthy was defined as working individuals between 20-60 years of age without physical or mental disabilities.  Soft tissue rheumatism consisted of patients with non-articular pain.

Results:
Measurement Variability: Among the fifteen laboratories, inter-laboratory coefficient of variation for ANA was: 50.7% for 1:40 dilution, 44.3% for 1:80, 37.9% for 1:160, and 36% for 1:320.  Intra-laboratory variation was about three times lower than the inter-laboratory coefficient of variation.

Normal Individuals: Overall, 46.7% tested negative on ANA.  31.7% tested positive at 1:40 dilution, 13.3% at 1:80 , 5% at 1:160, and 3.3% at 1:320 dilution.

1:160 dilution: At the the 1:160 dilution, the ANA was 95% sensitive for SLE, 86.5% sensitive for scleroderma, 74% sensitive for Sjogren's, 13.5% sensitive for RA, and 7.7% sensitive for soft tissue rheumatism.  Compared to healthy controls, cutoff of 1:160 is 95% specific.

1:320 dilution: At the the 1:320 dilution, the ANA was 86.8% sensitive for SLE, 83.8% sensitive for scleroderma, 71.1% sensitive for Sjogren's, 2.7% sensitive for RA, and 3.8% sensitive for soft tissue rheumatism.  Compared to healthy controls, cutoff of 1:320 is 96.7% specific.

Discussion: A cutoff of 1:160 appears to me a more reasonable value to use to separate possible pathology from variation in healthy individuals with only 5% of healthy population having titers of ANA higher than 1:160.  To me, other surprising findings were how variable ANA is between laboratories and how poorly the ANA performs in detecting rheumatoid arthritis (only 13.5% sensitive for RA) even though it is a immunologic disorder with positive serologic markers.  These figures must, of course, be interpreted with caution because the healthy population was derived from random samples submitted to laboratories.  Aside from individuals having no physical disability, we do not know more specifics which could affect the performance of ANA.  For instance, would a population of young women or older individuals with cancer have different characteristics in the ANA?

Fever and Pulmonary Embolism

Motivation: Clinical lore has it that pulmonary embolism (PE) causes low grade fevers and should not cause a fever as high as 103F.  While deciding on the often pondered question of whether or not a person has PE, I have seen the degree of fever sway the decision one way or the other.  But, is this true?

Paper: Stein, PD, Afzal, A, Henry, J, et. al. "Fever in Acute Pulmonary Embolism" Chest (2000); 117:39-42.

Methods: In the PIOPED (Prospective Investigation of Pulmonary Embolism Diagnosis) study, retrospective analysis was made of presence of fever in patients with angiographically proven pulmonary embolism (PE).

Results:
Cohort: There were 363 patients from PIOPED study analyzed for this study.  Fever was present in 95 patients (26%; 95% CI: 22-31%).  Of the 95 patients with fever, 43 (45.3%) did not have other causes of fever - solely attributed to PE.  There were 46 (48.4%) patients who had an alternative possible etiology of fever - 15 with malignancy, 10 with infection, 6 with recent operation (top three causes).   Six did not have further investigation (so indeterminate cause).  Fever was not more frequent in patients with pulmonary hemorrhage or infarction than in those without.

Maximum Temperature: Of the 43 patients with available information on temperature, the maximum temperature was 100 to 100.9F in 24, 101 to 101.9F in 14, 102-102.9 in 3.  One patient each had maximum temperature between 103-103.9 and greater than 104F.

Discussion: The clinical lore turns out to be mostly true - majority of patients with PE associated fever have maximum temperature less than 102F.  What I thought was most cautionary, however, is that fever is an infrequent finding in PE (present in only about a fourth).  Even among those with fever, they were just as likely to have an alternate explanation as pulmonary embolism.  What I took away from this paper is that if patients with PE have fever, they still need a thoughtful workup.

Taking a Chance on Chantix

Motivation: Last month, I met a man in clinic who said that his life had changed after his stroke.  Now, after years of fruitless contemplation, he was going to quit smoking.  He asked me about Chantix (generic varenicline).  Is it safe?

My instinct was to say yes.  But, the partial nicotinic agonist effects also make varenicline a sympathomimetic agent.  In patients with cardiovascular disease, are there excess side effects?  Turns out that the issue has been tested in a randomized fashion in 2010.

Paper: Rigotti, N.A., Pipe, A.L., Benowitz, N.L., et. al. "Efficacy and Safety of Varenicline for Smoking Cessation in Patients with Cardiovascular Disease." Circulation (2010); 121: 221-229.

Methods: Multi-center randomized placebo-controlled blinded trial testing varenicline (1 mg daily; quit day eight days after start of therapy) versus placebo in adult (35 to 75 years) smokers with cardiovascular disease (coronary artery disease, peripheral vascular disease, or cerebrovascular disease) existing for more than two months.  Patients with depression, severe neurological deficits from stroke, or severe renal and hepatic diseases were excluded.  Treatment group received 12 weeks of therapy.  Primary outcome was carbon monoxide confirmed abstinence between weeks 9 to 12 after start of therapy.  Patients were followed for 52 weeks.

Results:
Subjects: In total, 714 subjects were randomized to varenicline (355) or to placebo (359).  Study completion rate was 82.8% in varenicline group and 85.1% in placebo group.  Baseline characteristics were comparable between groups.  In the varenicline group, average age was 57 with 75% male and 80% white.  Average smoking history was for forty years.  For CVD, majority had CAD.  Only 4.5% had suffered a stroke.

Efficacy: The abstinence rate at weeks 9 through 12 was 47% in the varenicline group versus 13.9% in placebo (p<0.0001).  The rate of abstinence from week 9 to end of follow-up at week 52 was 19.2% for varenicline versus 7.2% for placebo (p<0.0001).

Adverse Effect: Patients on varenicline suffered more adverse effects than placebo (81.6 vs. 64.9%, CI for difference: 10.3-23.2%) resulting in more participants who stopped drug in varenicline group (9.6%) versus placebo (4.3%).  There were no differences in mortality.  The most common side effect was nausea (29.5% in varenicline vs. 8.6%).  Sleep disorder consisting of abnormal dreams, insomnia, and nightmare was significantly more frequent in treatment group (22.1%) vs placebo (9.7%).  There was a trend towards higher frequency of cardiovascular events in varenicline group (7.1% vs 5.7%) which did not reach significance.

Discussion: In summary, varenicline does not appear to increase risk of cardiovascular events significantly within the power of the study.  It was sobering to see though that after a year, only 19% will be abstinent even after being motivated enough to enroll in a trial and take a drug for twelve weeks.  Varenicline is certainly not free of adverse effects with nausea (30%) and sleep disorder (22%).  Prior to prescribing, patients need to be warned of these potentially bothersome side effects.  Also, of note, the trial was conducted in patients with stable CVD (defined as no events within the past two months).  So, I would likely wait for two to three months before prescribing varenicline to the patient seeking to stop smoking.

Causes of Flapping

Motivation: Look - the hands are flapping.  One of the useful tests in a confused patients is to ask them to stop traffic with outstretched hands.  If the hands start flapping in a non-rhythmic way ('asterixis'), that is interpreted as proof of generalized toxic-metabolic encephalopathy.  But, then again, there is probably a neural pathway underlying this mechanism.  We often dismiss asterixis in a blase way, but can there be focal brain lesions underlying asterixis?

Paper: Degos, J-D., Verroust, J., Bouchareine, A., et. al. "Asterixis in Focal Brain Lesions"  Arch Neurol. (1979); 36: 705-707

Methods: At Henri Mondor Hospital (Creteil, France), one of the authors documented twenty cases of asterixis with focal brain lesions.  EMG was available for nine patients.

Results:
Midbrain Lesions: Four patients ranging from 38 to 62 years presenting with unilateral asterixis after abrupt onset weakness in the affected side.

Parietal Lesions: Seven cases of asterixis with pathologic proof in four occurred from parietal lesions.  These lesions could occurred on contralateral side from the asterixis and could be from mass lesions (glioblastoma, abscess, metastatic lesion) or from stroke (hemorrhagic or ischemic).

Suspected Midbrain and Parietal Lesions: Six cases with suspected lesions.  One of these cases was a right temporal glioblastoma invading the lenticular nuclei with left sided asterixis and another had an expanding right thalamic tumor with left sided asterixis.

Unclear lesions: Three cases of unilateral asterixis with accompanying unilateral weakness or numbness of unclear etiology.

EMG Recordings: During episodes of asterixis, there were 50-100 ms periods of electrical silence in both agonist and antagonist.

Discussion: This old paper shows that true asterixis is not purely a toxic-metabolic phenomenon.  Apparently, parietal, midbrain, and thalamic lesions can result in contralateral asterixis.  While this paper certainly does not suggest a pathophysiological explanation of asterixis, some important points are that: (1) asterixis appeared contralateral to the lesion meaning that usually the side with asterixis is the one that is weak or numb, (2) both cortical and deep lesions can result in asterixis,.  I think that this account provides a cautionary note of dismissing asterixis as purely toxic phenomenon.

Interfering with RNA

Motivation: In medical school, while watching cartoons depicting disease pathophysiology pathways, I have thought many times that if we could just somehow block that damaged protein, we will cure that disease.  In mice, of course, multiple techniques exist including creating mutant breeds, transfecting with viruses, or injecting short RNA interfering sequences.  I was thrilled to read last month that such magic has for the first time been tried successfully in human beings.  Given the momentous significance of the recent trial testing RNA interference in transthyretin amyloidosis, we will cover the technique and consequences.

Paper: Coelho, T., Adams, D., Silva, A., et. al. "Safety and Efficacy of RNAi Therapy for Transthyretin Amyloidosis" NEJM (2013); 369: 819-29.

Methods: This Phase I study consisted of two parts.  In the first portion, eligible patients were older than 18 years with biopsy proven transthyretin amyloidosis with mild-to-moderate neuropathy.  Patients were excluded if they had liver, renal, or thyroid dysfunction.  These patients were injected in a blinded way with lipid nanoparticles containing RNA interfering (RNAi) sequences or with placebo.  In the second part, seventeen healthy patients were injected with a second generation lipid nanoparticle containing RNAi sequences testing for safety.

The lipid nanoparticles consisted of ionizable lipid components with RNA sequence that targets a conserved sequence at the 3' untranslated region of mRNA of Transthyretin protein (TTR).

Results:
Cohort: In the cohort with disease, there were 32 patients with 56% male and median age of 37.  Majority of participants were recruited from Portugal (23/32 patients).  The healthy volunteer cohort were all 17 male subjects with mean age of 27 (all were from England).

Amyloidosis Cohort: Patients with TTR amyloidosis treated with placebo did not have change in serum transthyretin levels.  In the group receiving 1mg/kg lipid nanoparticle dose, there was a mean reduction of 38% in serum transthyretin levels with recovery to close to baseline levels by day 28.

Healthy Volunteers: Using the second generation lipid nanoparticles, peak reduction of serum transthyretin level was reached at approximately day 10.  At 0.3 mg/kg and 0.5 mg/kg doses, the mean levels of suppression were 82.3% and 86.8%.  The serum transthyretin levels remained suppressed even at day 28.

Safety: There were no drug related serious adverse events or study drug discontinuation.  No significant changes in hematologic, liver, or renal measurements were seen.  Mild to moderate infusion reactions occurred in 7 to 20% of reactions responding to temporary interruption of infusion or administration of glucocorticosteroids.  Antibodies to pegylated lipid components were not seen.

Discussion: This trial demonstrated successful use of lipid nanoparticle RNAi to suppress transthyretin levels.   In the four week follow-up, there were remarkably no drug related side effects.  This Phase I trial, while promising, does not show efficacy of treatment on important clinical variables.  Transthyretin is primarily synthesized by the liver but is also synthesized to a smaller extent in the retina and choroid plexus.  The hepatic suppression may still leave the patient vulnerable to retinal and CNS side-effects.  In normal physiology, transthyretin is associated with retinol binding protein levels and Vitamin A levels.  Long term suppression of transthyretin may also interfere with Vitamin A metabolism.  Also, it is unclear whether repeated administration of lipid nanoparticles will generate an immunologic response.  Nonetheless, the trial is an encouraging start on selective suppression of hepatic protein synthesis.

Propofol and sepsis

Motivation: Sepsis is one of the most common issues in the ICU, and for any number of reasons, patients with sepsis also could require intubation and sedation. Practically speaking, propofol and midazolam are both commonly used in the ICU for septic patients who require sedation, weighing their risks and benefits in the individual patient. There are some benefits of propofol over midazolam in critical care patients in general (1), so I wondered whether there were risks associated with using propofol in the setting of sepsis. This discussion excludes the issue of contaminated propofol preparations. I found one paper that raised clinical concerns about the association between propofol and infection/sepsis.

Study:  Haddad S, Tamim H, Memish ZA, Arabi Y. Association of preservative-free propofol use and outcome in critically ill patients. Am J Infect Control. 2011 Mar;39(2):141-7. 

Design: Nested cohort study of patients who were enrolled in a randomized control trial on another topic (comparing different regimens of insulin therapy). Patients who were on propofol were compared to those who were not on propofol, in terms of baseline characteristics and outcomes. ICU-acquired infections were defined as those found at least 48 hours after ICU admission and up to 48 hours after discharge, while ICU-acquired sepsis was defined as per standard criteria (2).

Results: There were differences in baseline characteristics between the two groups of patients; compared to no propofol, propofol group were more likely to be mechanically ventilated but less likely to have severe illness, chronic renal disease, immunosuppression or cardiovascular disease. In adjusted statistical analysis, propofol use was associated with increased risk of ICU-acquired infection (95 CI 1.17-3.05, p=0.009), and ICU-acquired severe sepsis and septic shock (95 CI 1.12-3.28,p=0.02). There were no statistically significant differences in ICU or hospital length of stay or ICU or hospital mortality (2). 

Discussion: This study had convincing evidence as above for a relationship between propofol use and infections, and discusses potential reasons why propofol may be associated with increased risk of infectious including impairment of host immune cell function, increased lipid levels affecting mitochondrial oxygen use, growth of bacteria in propofol emulsion, increased lipid caloric intake (2); however, it is important to emphasize that these are potential reasons based on studies or observations in other contexts that are not necessarily generalizable to the septic ICU patient. In terms of study limitations, it is important to note that the study showed a statistical association (not causation) between use of propofol and increased risk of ICU-acquired infection or sepsis in a post-hoc study on a trial designed for another indication (2). Noted that this study did not compare propofol versus midazolam, nor did I find a similarly designed study for midazolam.

I was surprised to see that there were several animal studies that showed benefit of propofol (versus no propofol) in animal models of sepsis. A few examples of these studies are here; most of the sample sizes are modest. In an animal study specifically designed to study the effect of propofol on a rat model of sepsis (cecal ligation and puncture), rats treated with early or late propofol had statistically significant higher survival rates than rats without propofol treatment (3). Propofol-treated rats also had statistically significant lower levels of ALT, AST, BUN, Cr and CK (3). In the same rat model of sepsis, rats treated with propofol had improved hypotension, lower plasma levels of TNF-alpha, IL-6, and more suppression of NF-kappaB activation (4). Another study reported that midazolam had an overall anti-inflammatory effect in a macrophage cell line through various mechanisms (5).

Looking for more studies of animal models of sepsis and sedation, I found a paper on the same rat model of sepsis comparing the effects of propofol and midazolam on neutrophil function (6). In both early and late time points of sepsis, propofol and midazolam decreased hydrogen peroxide production by neutrophils with propofol associated with statistically signficantly more decreased production than midazolam (6). These results suggest at least in the in vitro context that propofol might attenuate neutrophil function in this rat model of sepsis, favoring midazolam over propofol if results could be extrapolated to clinical context (6). Also, it was very interesting to note in this study that there was negligible effect of the lipid propofol carrier on neutrophil hydrogen peroxide production (6).

Conclusion: Overall, there lacks definitive evidence comparing propofol and midazolam in ICU patients with sepsis; however, one clinical study brought up concerning associations between propofol and ICU-related infection (2), while one animal model study showed that midazolam would be better than propofol in rat models of sepsis as it interfered less with neutrophil function (6). These concerns should be taken into account when weighing the risks and benefits of midazolam versus propofol for the septic ICU patient.

References:

1.     Carrasco G, Molina R, Costa J, Soler JM, Cabré L. Propofol vs midazolam in short-, medium-, and long-term sedation of critically ill patients. A cost-benefit analysis. Chest. 1993 Feb;103(2):557-64.

2.     Haddad S, Tamim H, Memish ZA, Arabi Y. Association of preservative-free propofol use and outcome in critically ill patients. Am J Infect Control. 2011 Mar;39(2):141-7.

3.     Bao HG, Li S. Effects of propofol on the outcomes of rats with sepsis. J Surg Res. 2011 Jun 1;168(1):e111-5. doi: 10.1016/j.jss.2010.12.034. Epub 2011 Jan 22.

4.     Song XM, Wang YL, Li JG, Wang CY, Zhou Q, Zhang ZZ, Liang H. Effects of propofol on pro-inflammatory cytokines and nuclear factor kappaB during polymicrobial sepsis in rats. Mol Biol Rep. 2009 Nov;36(8):2345-51. doi: 10.1007/s11033-009-9456-z. Epub 2009 Feb 4.

5.     Kim SN, Son SC, Lee SM, Kim CS, Yoo DG, Lee SK, Hur GM, Park JB, Jeon BH. Midazolam inhibits proinflammatory mediators in the lipopolysaccharide-activated macrophage. Anesthesiology. 2006 Jul;105(1):105-10.

6.     Inada T, Taniuchi S, Shingu K, Kobayashi Y, Fujisawa J, Nakao S. Propofol depressed neutrophil hydrogen peroxide production more than midazolam, whereas adhesion molecule expression was minimally affected by both anesthetics in rats with abdominal sepsis. Anesth Analg. 2001 Feb;92(2):437-41.

Abdominal pain and seizures

Motivation: A man walks in to the hospital with seizures also complains of periodic stomach pain.  I wonder could it also be a seizure?  After all, migraines in children are clearly linked to episodes of abdominal pain.  Could epileptic discharges create a similar phenomenon?

Turns out that this issue has been thought of by many - in fact, Trousseau had also thought about the issue in 1868.  Reviewed here is a compilation of the common clinical presentation.

Paper: Zinkin, NT, Peppercorn, MA. "Abdominal epilepsy" Best Practice & Research Clinical Gastroenterology (2005); 19(2): 263-274.

Methods: Review of 36 reported cases in english literature.  Patients were required to have paroxysmal EEG abnormalities with correlated clinical spells.

Results:
Clinical Characteristics: In meta-analysis of 36 published cases, most frequent feature was a sharp pain (86%) commonly in peri-umbilical and upper abdominal pain.  Nausea and vomiting was an infrequent feature in 28% followed by diarrhea (5%) and bloating (3%).  Besides abdominal pain, some disturbance in consciousness was observed in 64% ranging from generalized seizures to dizziness.  Duration of seizures was at most a few minutes.  EEG did not have a consistent localization for inter-ictal epileptiform activity.

Discussion: I think that abdominal epilepsy is worth considering as a diagnosis in someone with bouts of brief abdominal pain with some change in consciousness/"funny" feeling.  There are many people - often hard to treat people - with unexplained abdominal pain.  Some get unsatisfactory diagnosis of irritable bowel syndrome or somatoform disorders.  If there is no other explanation, an EEG may be in order.

After statin-induced myopathy: What next?

Motivation: A frequent finding in both the hospital and outpatient setting is the patient with hyperlipidemia and/or coronary artery disease who was on a statin, but had to stop due to side effects, mainly muscle cramps. Some of these patients have been switched to a different statin, are on a lower dose of the same statin, or not on any statin at all. There appears to be no consensus on what comes next. This observation had me running toward the literature wondering what the data shows for best treatment option in patients who have had adverse effects (e.g. myopathies) from statin use.

Papers:
Reinhart KM and Woods AJ. Strategies to preserve the use of statins in patients with previous muscular adverse effects. Am J Health Sys Pharm 2012; 69:291-300.
Robenson, RS. Current overview of statin-induced myopathy. Am J Med 2004;116:408-416.

Background: Statins have a number of adverse effects, the most common being myopathies (usually bilateral leg cramping) that may cause serum elevations of the muscle enzyme creatine kinase (CK). About 10% patients discontinue statins after 1 year and 28% after 4 years and nearly half of these due so because of the adverse effects. An estimated 1 out of 5 people on statins will have some adverse myopathic reaction in their lifetime. The mechanism is not entirely understood, but the most convincing hypothesis is that statins as HMG-CoA reductase inhibitors inhibit the production of mevolonate, a precursor to not only artery-clogging cholesterol but also the "good" cholesterol that supply our cellular membranes. Furthermore, mevalonate is a precursor of ubiquinone (coenzyme Q10) which is a powerful antioxidant, membrane stabilizer, and essential player in the ATP chain that leads to the production of energy that myocytes rely on to do their job.

Methods:
Unfortunately, no large-scale randomized trials have been done to address this issue. Reinhard and Woods conducted the largest literature review on an understudied field that included 16 restrospective studies, and some intereventional (not all randomized or controlled) trials that examined the outcomes of a strategy for the preventon of recurrent statin-associated myalgia.

Results:
Five options were found in the literature: 1) reduced dosing of statin 2) addition of vitamin D or E to statin therapy 3) addition of supplemental coenzyme Q10 to statin therapy 4) red yeast rice as substitution for statin (RYR contains a naturally occuring lovastatin) 5) trial of a different statin. For patients reduced from once daily to once or twice a week regimen of atorvastatin, about 20% were able to significantly lower their statins to reach goal and there was no difference compared to placebo in the incidence of myalgias suggesting that this is a more tolerable, if less effective option. Vitamin E did not show any benefit in reducing myalgias, while vitamin D added to statins showed a mild effect. CoQ added to a statin had conflicting data with some showing significant decrease in myalgias in RCT, and others showing none. RYR had difficult to interpret data mainly because it is a supplement that is not approved by FDA to contain any lovastatin in US (whereas it contained varying degrees of lovastatin in the reviewed studies). Trial of alternative statins showed fairly good results (>90% tolerability in 3 RCTs) when patients were switched from a different statin to an equivalent dose of fluvastatin (80mg), atorvastatin (10-20mg), or rosuvastatin (5-10mg).

Discussion:
Overall, using an alternative statin may be the most tolerable and efficacious option after discontinuance of a previous statin due to adverse effects. It is thought that hydrophilic (water-loving) statins are less likely to cause symptoms as they cannot cross the cell membrane easily through passive diffusion (unlike lipophilic statins). For example, simvastatin is a commonly used lipophilic statin that is known to cause adverse effects whereas rosuvastatin, a hydrophilic drug, is much less likely to do so. Vitamin D or CoQ supplementation may be helpful in patients with mild symptoms and no elevation of creatine kinase. RYR should not be used because it does not include the active ingredient (e.g. lovastatin) when purchased in the US and has previously been shown to contain nephrotoxic additives. These interpretations are very limited given that there has been no head to head studies and the few trials that exist are in relatively small samples with poor controls and ample potential for bias. As a future preventative cardiologist, I must advocate against the discontinuation of statins altogether. The data showing the ability of statins to prevent MI and death from cardiovascular causes even in patients with normal lipid levels is powerful, indeed. The biggest conclusion I can draw is that pragmatic, randomized clinical trials comparing these options are desperately needed.

Intravascular Lymphoma

Motivation: Zebras are growing more frequent these days.  Though thought to be quite rare, I have seen two of my favorite patients diagnosed with intravascular lymphoma within the past year.  In both, the diagnosis could not be made for months because of the non-traditional lymphoma findings - for instance, no enlarged lymph nodes.  Intravascular lymphoma is characterized by growth of lymphoid neoplastic cells with the lumen of blood vessels.  Given lack of systemic masses, are there clinical clues to its diagnosis?  We will review here one of the largest review of cases for this rare disorder.

Paper: Ferreri, A.J.M., Campo, E., Seymour, J.F. et. al. "Intravascular lymphoma: clinical presentation, natural history, management and prognostic factors in a series of 38 cases, with special emphasis on the 'cutaneous variant'" Brit. J. of Haematol. (2004); 127: 173-183

Methods: Data gathered from 22 centers forming the International Extranodal Lymphoma Study Group (IELSG) on patients who were  HIV negative and were diagnosed with intravascular lymphoma between 1985 and 2003.

Results: 
Cohort: Intravascular lymphoma was diagnosed in 38 patients - postmortem in eight (21%) and while living in 30 (79%).  The median age was 70 years with male/female ratio of 0.9.

Clinical Presentation: The most common presenting symptom was fever in 45%.  Systemic symptoms including fever, weight loss, or night sweats were present in 55%.  Cutaneous lesions were present in 39% made up of a wide variety of lesions including erythematous eruption, plaques, swelling, nodular discolorations, or small red palpable spots situated in upper arms, thighs, legs, lower abdomen, or breast.  The next most common finding was neurological symptoms present in 34% with a wide range of symptoms from focal deficits to meningoradiculitis.

Laboratory Variables: The most common lab abnormality was elevated serum LDH (86%) followed by elevated beta-2 microglobulin (82%).  ESR was elevated in 43%.  Anemia was present in 63% while leukopenia and thrombocytopenia were present in 24 and 29% respectively. 

Discussion: Intravascular lmphoma remains a difficult disorder to diagnose.  I think that patients with unclear lesions in the brain and skin with systemic symptoms should raise suspicion of intravascular lymphoma.  The present large series also contrasts with previous reports from Japan where intravascular lymphoma presented more commonly with hemophagocytic syndrome and less commonly with cutaneous or neurological symptoms suggesting that there may be ethnic variance versus diagnostic bias in the previous report.  Laboratories are helpful for elevated beta-2 microglobulin present in more than 80%.  In summary, I learnt that if I suspect patient of having intravascular lymphoma in the brain, I will conduct a skin exam.  

Cefepime Encephalopathy

Motivation: My favorite fourth generation cephalosporin is cefepime.  Only a definite history of anaphylaxis to penicillins holds me back from prescribing cefepime.  More recently, I have met a few patients with confusion allegedly caused by cefepime.  Amazingly, stopping the cefepime improved the encephalopathy.

So, what is wrong with my favorite cephalosporin?  The literature on cefepime neurotoxicity is evolving and is still at the case report level.  Reviewed here is a case report and literature summary.

Paper: McNally, A., Pithie, A., and Jardine, D. "Cefepime: a rare cause of encephalopathy." Internal Medicine Journal (2012); 42 (6): 732-3.

Method: Case report and review of published literature.

Result: 
Case report:  A 70 year old woman after eleven days of cefepime for Pseudomonas osteomyelitis developed myoclonus and stupor.  Concurrently, patient also suffered from hepatic cirrhosis and acute on chronic renal failure.  For presumed drug toxicity, cefepime and all psychotropic drugs in patient's regimen (including morphine, gabapentin, oxazepam) were stopped.  Over three days, encephalopathy and myoclonus resolved.  Patient was re-challenged with cefepime at renal-adjusted dose.  Encephalopathy and myoclonus recurred in the next two days despite now resolved renal failure and normal ammonia.  Cefepime was stopped, and patient's encephalopathy cleared.

Literature Review: Eetrospective review of 42 cases showed that encephalopathy consisted of temporospatial disorientation (96%), myoclonus (33%), and seizures (13%).  The clearest association of cefepime toxicity exists with renal impairment though cefepime toxicity has also been described in patients with normal renal function.  The reported latency of symptoms from cefepime initiation is 1-10 days.  After stopping cefepime, symptoms regress over 2-7 days.

Discussion:
While the case for cefepime toxicity in this case report is weakened by concurrent hepatic and renal failure, the history of encephalopathy linked temporally with cefepime initiation along with improved mental clarity with cefepime cessation makes a good causal argument for cefepime causing encephalopathy.  There do not appear to be symptoms characteristic of cefepime neurotoxicity though seizures and myoclonus are frequent occurrences.    Without a larger case series, it is hard to attribute causality to cefepime.  On the other hand, if a patient with renal failure on cefepime develops confusion, I would recommend cefepime cessation (despite my personal attachment to the drug).

Tennis Elbow - Work or Rest or Steroids

Motivation: Summer is the time for tennis and tennis elbow.  Anyone who has suffered a tennis elbow - known in medial lingo as lateral epicondylalgia -  can attest to the frustration and pain that keeps people away from the beautiful sport after waiting all winter.  I have often wondered what works.  Using an injured elbow hardly seems wise but then again, exercise sounds like a good idea.  If all else fails, do steroid injections work?  Recently, this idea was tested in a randomized way.

Paper: Coombes, B.K., Bisset, L., Brooks, P. et. al. "Effect of Corticosteroid Injection, Physiotherapy, or Both on Clinical Outcomes in Patients with Unilateral Lateral Epicondylalgia." JAMA (2013); 309(5): 461-469.

Methods: 2x2 factorial multi-center randomized blinded placebo controlled trial.  Inclusion critera were essentially untreated unilateral lateral elbow pain of greater than six weeks duration provoked by palpation or stretching the region.  The two intervention arms were a single corticosteroid (triamcinolone) vs. placebo injection and physiotherapy for eight weeks vs. no physiotherapy.  The primary outcomes were one year rating of change score (using Likert scale from "complete recovery" to "much worse") and one year recurrence.  Secondary outcomes were rate of complete recovery to much improvement at four and 26 weeks.

Results:
 Cohort: A total of 165 patients were randomized with mean age of 49 years and male predominance of 62%.  Average duration of symptoms was 16 weeks. On visual analog scale (VAS), resting median pain level was 7.5 out of 100 with worst pain of 61.7 out of 100.  In total , 41 patients only got placebo, 41 got placebo plus physiotherapy, 43 got corticosteroids, and 40 got corticosteroids plus physiotherapy.

Primary Outcome (one year): Corticosteroids resulted in lower recovery or improvement at one year compared to placebo (83% with steroids vs. 96% without, p = 0.01).  There was increased recurrence of elbow pain at one year with corticosteroids (54% with steroids vs. 12%, p < 0.001).  There was no difference between physiotherapy or no physiotherapy in terms of recovery or rate of recurrence.  There was no interaction between corticosteroids and physiotherapy.

Four week Outcome: In absence of physiotherapy, complete recovery or much improvement was greater following steroid injection than placebo (RR: 7.32, NNT 1.6, p < 0.001).  With physiotherapy, steroids did not significantly improve recovery compared to placebo (RR: 1.73 (95% CI, 0.97 to 3.08)) though combination had some additional benefit on pain scores.  Physiotherapy alone in absence of steroids also significantly improved recovery (RR: 4,.0, NNT: 3.4, p = 0.004).  There was no major difference between steroids plus physiotherapy versus steroids alone.

Discussion: This paper points out an instance where trials with short term follow-up miss deleterious effects in the long term.  Steroids are quite efficacious in four weeks but result in greater recurrence of pain and with lower recovery in one year.  In comparison, while physiotherapy does not make a difference in the long term, it is comparable to steroids for recovery at four weeks.  Consequently, for someone with a tennis elbow, a reasonable strategy would be to use physiotherapy in the short term and expect spontaneous recovery in the long term (96% recovery naturally) - avoid the steroids.

Albuterol, levalbuterol and tachycardia

Motivation:  In the ICU and inpatient setting, tachycardia is a common vital sign abnormality that has many different root causes. One of the measures taken in attempt to decrease heart rate is to limit beta-agonists such as inhaled or nebulized albuterol, a common medication used for the shortness of breath or wheezing experienced by many patients. One solution that has been suggested to me was to use levalbuterol instead of albuterol...Physiologically it makes sense that albuterol or levalbuterol would increase heart rate, but I was not sure about any physiological/molecular reason why levalbuterol would be associated with less tachycardic side effects, and was also concerned about levalbuterol's higher cost. So does albuterol really contribute to increased tachycardia, and would levalbuterol be a better option?

Study:  Khorfan FM, Smith P, Watt S, Barber KR. Effects of nebulized bronchodilator therapy on heart rate and arrhythmias in critically ill adult patients. Chest. 2011 Dec;140(6):1466-72.

Methods: This was a 2:1 randomized, prospective, single-blind crossover study in 70 adult ICU patients who were randomized to alternating 4-6 hour courses of nebulized albuterol (2.5 mg) or levalbuterol, along with ipratropium. Group A received 0.63 mg, while Group B received 1.25 mg of levalbeterol. Cardiac monitoring was performed to measure heart rate and rhythm before, during and after treatment.

Results: The 70 patients consisted of almost equal numbers of men and women, with age ranges from 35-92, and slightly more than half on mechanical ventilation. Multisystem organ problems were common in this population. The median number of treatments per patient was 23, ranging from 1 to 45. There was no significant difference in change in heart rate after albuterol (0.89 ± 4.5 bpm) or levalbuterol (0.85 ± 5.3 bpm) treatment in Group A. In Group B, levalbuterol actually was associated with faster heart rate (increase of 1.4 ± 5.4 bpm) compared to albuterol (decrease of 0.16 ± 5.1 bpm) (p=0.03); but when analyzing for measures that were taken >= 5 hours apart, this difference was no long statistically significant. There was only one patient who had to be discontinued on treatment, after experience a 5 beat run of NSVT after 6x albuterol treatment.

Discussion: As for levalbuterol, its substitution for albuterol was not justified in this study - in fact, in Group B, in which a higher levalbuterol dose was used, post-therapy heart rate was actually faster than post-albuterol heart rate. Unexpectedly, from this study, it seemed that albuterol or levalbuterol did not significantly worsen tachycardia, even in this very sick population of patients. This is useful - and comforting - to know for patients who are tachycardic, but also have wheezes or increased airway resistance who would benefit from temporary courses of nebulized beta-agonists. One limitation of the applicability of this study is the fact that heart rate comparisons were made only after a limited number of treatments per patient, so it could be possible that over longer term and more treatments +/- higher frequency +/- higher dosing, there would be significantly increased heart rate. So in a patient receiving longer term albuterol therapy, I would still consider tapering down or decreasing albuterol therapy if tachycardia were a problem, since this would make sense physiologically.

VZV Vasculitis

Motivation: This year, I have seen quite a number of middle aged otherwise healthy patients present with shingles.  Usually, initial questioning leads to some complaints of headaches, which results in a lumbar puncture showing a few cells.  Now the possibilities open.  Could the patient have VZV vasculitis?  I was once asked this question, and I had no clue what VZV vasculitis looked like.

Paper: Nagel, M.A., Cohrs, R.J., Mahalingam, R., et. al. "The varicella zoster virus vasculopathies." Neurology (2008); 70: 853-860.

Methods: Review of thirty patients (previous published cases and unpublished cases) with serologic or PCR proof of positive VZV and neurologic signs or symptoms attributed to VZV infection by the reviewing authors.

Results:

Cohort: Of the thirty patients, the age ranged from one year to 88 years with fifty percent of patients male and the rest female.  Of the thirty patients, eleven patients had important comorbid disorders - 2 with AIDS, 3 with HIV, 2 with leukemia, 1 with CREST syndrome, 1 with lymphoma, 1 with decreased CD4 count, and 1 on immunosuppression for lupus and rheumatoid arthritis.

Clinical Features: In total, of 30 patients, nineteen (63%) had rash, twenty (67%) had CSF pleocytosis of >5 wbc.  Average interval between onset of rash and neurological symptoms was 4.1 months.  Of the eleven immunocompromised patients, six (54%) had rash, nine (82%) had CSF pleocytosis, six (54%) had positive VZV PCR, and eleven (100%) had anti-VZV IgG antibody.  In the 19 immunocompentent, thirteen (68%) had rash, eleven (58%) had CSF pleocytosis, three (16%) had positive PCR, and seventeen (89%) had positive anti-VZV IgG in CSF.  PCR was positive more frequently in the immunocompromised.  Of note, all patients with CSF anti-VZV IgG had reduced serum to CSF ratio.

Imaging:  Of the entire cohort, 29 (97%) had abnormal brain imaging on MRI or CT scans.  Descriptively, these lesions often were centered in white matter and gray-white junction.  Of 23 who had vascular imaging, sixteen (70%) showed abnormalities.  Larger artery disease occurred exclusively in four (13%) while mixed small and large vessel and small vessel involvement occurred in fifteen (50%) and eleven (37%).

Discussion: This case-series of VZV vasculopathy suggests that it defies some of our conventional thoughts about vasculitis.  About 30% had no pleocytosis, and 37% had no preceding rash to suggest shingles.  Also, despite our initial impression that severe disease is more common in the immunocompromised, nineteen patients had no known immune suppressing conditions.  Finally, VZV PCR has little diagnostic sensitivity, and serology remains the better diagnostic test.  I think that overall, what this series suggests is that for multi-focal strokes of uncertain etiology, VZV should always be on the differential.   

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.