New Way for Hypertension

Motivation: Last weekend, I was flipping through an old issue of TIME magazine when I noticed an article with large picture of pink kidneys.  Wondering why TIME magazine would be concerned with urine production, I read a little more and learnt about a "revolutionary" new treatment for hypertension discovered in England in 2010.  The article refers to amazing results published in a trial in Lancet in 2010 from renal sympathetic ablation.  Throughout intern year, we had never seriously considered this therapy.  Why? How good is the data?

Paper: Symplicity HTN-2 Investigators. "Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial" Lancet (2010); 376: 1903-09.

Methods: Multicenter randomized unblinded trial of renal denervation with treatment resistant hypertension, defined as SBP > 160 mmHg (SBP > 150 with DM2) despite compliance on 3 or more anti-hypertensives.  Important exclusion criteria were GFR < 45 and history of MI, unstable angina, or stroke.  Study conducted at Europe, Australia, and New Zealand.  Patients randomized to renal denervation had endovascular catheter directed radioablation through renal artery access.  Primary endpoint was change in average office-based SBP from baseline to 6 months.

Results:
Cohort: In total, 52 patients were randomized to renal denervation while 54 were in the control group.  The two groups were overall similar except for differences in gender (35% female in intervention vs. 50% in control group) and difference in baseline GFR (77 ml/min in intervention vs. 86 in control group). Three patients were lost to follow-up in each group.

Efficacy: In per-protocol analysis, at six-months, renal denervation resulted in mean decrease in BP of 33/11 mmHg compared to no changed in the control group.  The baseline was 178/96 in the intervention group and the same in the control group.  The result is statistically significant, p < 0.0001.  Similar changes were noted in BP measurements at home-based and 24 hour ambulatory measurements.  At least 84% of patients in intervention group had >10 mmHg decrease in SBP at 6 months.

Secondary End Points: There were no differences in serum creatinine, eGFR, and cystatin C between baseline and 6 months in both groups.  There were no differences in composite cardiovascular between the two groups.

Safety: No serious procedure-related or device related complications noted in the six month follow-up.

Discussion: In this preliminary phase trial of renal denervation, the procedure appears remarkably efficacious.  The degree of BP measurement is clearly better than any other current medicinal or lifestyle approach.  Yet, before adopting this intervention, the paper has multiple limitations that need to be clarified.  First, the control and intervention groups were different some important baseline parameters such as gender distribution and GFR.  Second, there were no hard endpoints used in the paper such as MI or long-term cardiovascular outcomes.  It is unclear whether renal denervation has any long-term risks that may outweigh short-term benefits in BP reduction.  Finally, this entire study was funded, designed, and analyzed by Ardian, the maker of the denervation catheter.  The data would gain more integrity if the trial was designed and analyzed independently.  Thus, this therapy is promising but needs a larger follow-up trial before widespread use. 

Color of the Eyes

Motivation: Part of the checklist on the physical exam is looking at patients' eyes and deciding on paleness. I would love to be able to gauge degree of anemia without Q6 blood draws, but are the eyes a good way to decide on degree of anemia?

For background, while looking at the conjunctiva, pallor is determined by comparing the posterior edge of the palpebra (just where it intersects with the conjunctiva) with the anterior edge of the palpebra bordering the eyelashes.  Normally, the anterior edge is redder than the posterior edge.  In anemia, the anterior and posterior edge are the same color.  Pasted below are pictures of a normal and anemia conjunctival exam:

Normal Conjunctiva

Conjunctival Pallor

 Paper: Sheth, T.N., Choudhry, N.K., Bowes, M. et. al. "The Relation of Conjunctival Pallor to the Presence of Anemia." J. Gen. Intern. Med. (1997); 12: 102-106.





















Methods: 302 medical and surgical inpatients at The Toronto Hospital were prospectively assessed for conjunctival pallor (present/borderline/absent) and compared to the patient's hemoglobin.  The observers (medical students and general internists) were initially trained on 25 patients but were blinded to the hemoglobin levels.  While no primary endpoint was stated, the overall goal was the utility of conjunctival pallor in ruling in or ruling out moderate anemia (hemoglogin < 9 g/dL).

Results:
Cohort: Of the 302 patients examined, 171 were male and 131 were female.  55 had hemoglobin less than 9 g/dL while 247 had higher values.

Conjunctival Pallor:  With hemoglobin cutoff of 9 g/dL, the performance of pallor is as below:
- Sensitivity (pallor present):  14.5%
- Sensitivity (pallor present/borderline): 54.5%
- Specificity (pallor absent): 74.4%.


Discussion: In the final analysis, conjunctival pallor is just not a reliable test for anemia even for trained observers.  A definitely positive test only has sensitivity of about 15%.  Even stretching the boundary to positive or borderline positive only yields a sensitivity of about 54%.  So, anemia cannot be ruled out by conjunctival  pallor.  On the other hand, specificity is somewhat higher though 25% of patients with hemoglobin > 9 g/dL remarkably also had conjunctival pallor.  Thus, if pallor is observed, the patient likely has anemia though even that is not a sure thing (in the study, positive likelihood ratio of 4.49)!  I guess CBC are here to stay.

Mood Enhancement

Motivation: Recently, one of my friends in psychiatry commented that the blog almost never touches upon psychiatry.  And, that is unfortunately true despite the amount of psychiatric diseases in the medical wards.  So, today, I wanted to examine the question of what happens when the SSRI just does not work after a good six weeks.  Often, I have seen psychiatrists "augment" the treatment with a variety of anti-psychotics.  Is there data behind the practice, and which anti-psychotic is the best one?

Paper: Nelson, J.C. and Papakostas, G.I.  "Atypical Antipsychotic Augmentation in Major Depressive Disorder: A Meta-Analysis of Placebo-Controlled Randomized Trials" Am. J. Psychiatry (2009) 166: 980-991.

Methods: Meta-analysis of double blind randomized trials comparing addition of atypical anti-psychotic versus placebo in patients with non-responsive major depression.  Response was defined as >50% improvement in baseline scores of a depression rating scale (Montgomery-Asberg Depression Scale or Hamilton Depression Scale).

Results:
Trials: In total, 16 trials were analyzed with trial duration ranging from 4-12 weeks (9 trials lasted 8 weeks, 5 lasted 6 weeks, 1 lasted 12 weeks, and 1 lasted 4 weeks).  The agents tested were olanzapine, risperidone, quetiapine, and aripiprazole.  These anti-psychotics were added to anti-depressants which were typically a SSRI or SNRI.

Olanzapine: Overall, meta-analysis of 586 in treatment arm and 414 in control group.  Odds ratio as listed below (higher OR with favorable treatment):
- Response: 1.39 (95% CI: 1.05-1.84), Remission: 1.83 (1.30-2.56)
- Adverse Effect: 3.85 (2.03-7.29)

Risperidone: Analyzed 211 in treatment arm and 175 in control group.  Odds ratios as below:
- Response: 1.83 (1.18-2.82), Remission: 2.63 (1.51-4.57)
- Adverse Effect: 2.84 (0.91-8.91)

Quetiapine:Analyzed 677 in treatment arm and 352 in control group. Odds ratios as below:
- Response: 1.60 (1.24-2.08), Remission: 1.89 (1.41-2.54)
- Adverse Effect: 5.52 (2.71-11.24)

Aripiprazole: Analyzed 540 in treatment arm and 525 in control group. Odds ratios as below:
- Response: 2.07 (1.58-2.72), Remission: 2.09 (1.55-2.81)
- Adverse Effect: 2.68 (1.23-5.81)

Duration of Trial: No effect seen in response to drug based on duration ranging from 4 to 12 weeks.

Discussion:  This meta-analysis both demonstrates the utility of anti-psychotics in treatment resistant depression and the equivalence for the four examined anti-psychotics (despite aripiprazole being the only FDA approved augmentation anti-psychotic).  Interestingly, addition of anti-psychotics also resulted in increased adverse effects pretty uniformly.  The meta-analysis did not describe the most common adverse effects (such as mild or severe or suicidal).  Another limitation of this analysis is that only the acute phase of treatment (4-12 weeks) was examined.  No data about maintenance phase was available although treatment is often extended to the maintenance phase as well.  In summary, when faced with a depressed patient unresponsive to usual first line SSRI/SNRI agents, addition of an accessible anti-psychotic (whether risperidone or aripiprazole) is reasonable though patients should be monitored closely for severity of adverse effects.

Is this MDS?

Motivation: In the past few months, I have come across multiple patients with chronic unexplained macrocytosis.  I am often tempted to diagnose MDS and request a bone marrow biopsy.  But, is there a better non-invasive scoring system to triage the likelihood of MDS?  Recently, while searching this topic, I came across this paper that estimates a pre-test likelihood of MDS.

Paper: Rauw, J., Wells, R.A., Chesney, A., et. al.  Validation of a scoring system to establish the probability of myelodysplastic syndrome in patients with unexplained cytopenias or macrocytosis.  Leukemia Research (2011) 35: 1335-38.

Methods: Retrospective review of bone marrow biopsies (2006-2008) at an academic hospital in Toronto, Canada.  Inclusion criteria were anemia (hemoglobin <12 g/dL), thrombocytopenia (platelet < 150), leukopenia (WBC < 4), neutropenia, or macrocytosis (MCV > 96).  Patients with known or suspected hemato-lymphoid diseases (such as lymphoma or widespread lymphadenopathy) were excluded.  BM biopsies were classified as MDS, suspected MDS (met most but not all pathological criteria), or not MDS.

Results:
Scoring System: The authors designed a scoring system with four parameters: (1) age >= 65, (2) RDW > 14.5%, (3) MCV > 96, and (4) LDH  > 250.

Bone Marrow Diagnoses: Of the 313 biopsies reviewed, 100 had MDS, 27 had suspected MDS, and 186 did not have MDS.  Among those not having MDS, 34% were normal, 10% had AML, and the rest had other diagnoses.

Sensitivity and Specificity of Confirmed/Suspected MDS Based on Risk Factors:
Risk Factors              Sensitivity              Specificity
>=1 factor                  95%                       18%
>=2 factors                74%                        46%
>=3 factors                39%                        79%
    4 factors                6%                          96%

Discussion: I liked this paper because it provided a risk assessment of MDS based on parameters that are easily and routinely measured.  Having multiple risk factors should lower the threshold for referral to hematology and having a bone marrow biopsy.  As in other retrospective reviews from tertiary medical centers, the numbers in this paper are affected significantly by referral bias.  In the patients with anemia and macrocytosis getting BM biopsy, probably all had B12 and folate checked and had MCV measured when abstaining alcohol.  In the regular inpatient setting, alcoholism as well as B12 deficiency probably accounts for a significant portion of macrocytosis.  For patients without these other more straightforward explanations, stratifying patients for MDS by these risk factors is a quick clinical tool.

G-CSF for Acute Liver Injury

Motivation: When patients do not respond to steroids for acute alcoholic hepatitis, there is little else you can do - besides watching them wither away.  While observing another such tragedy, I wondered if there is anything else to do.  Most patients with acute alcohol use do not qualify for a liver transplant.  I came across this paper published recently evaluating the remarkable potency of G-CSF for acute on chronic liver injury.

For background, the theory is that G-CSF mobilizes bone marrow derived stem cells (CD 34+), and one hopes that with more stem cells floating around, some will engraft in the liver and lead to regeneration.

Paper: Garg, V., Garg, H., Khan, A. et. al. "Granulocyte Colony-Stimulating Factor Mobilizes CD34+ Cells and Improves Survival of Patients with Acute-on-Chronic Liver Failure" Gastroenterology (2012); 142: 505-512.

Methods: Blinded randomized trial in a hospital in New Delhi, India.   Between December 2008 and August 2010, consecutive patients with acute on chronic liver failure (defined as acute rise in bilirubin, INR, ascites, or encephalopathy in patients with known liver disease) were randomized to placebo or 5 ug/kg G-CSF (12 doses over month).  Exclusion criteria included hepatocellular carcinoma, portal vein thrombosis, multi-organ failure, sepsis, or grade 3 or 4 encephalopathy.  Primary end point was survival at day 60.

Results:
Cohort: In total, 47 patients were randomized with 23 patients to G-CSF and 24 patients to placebo.  Majority of patients were male in each group (3 females in each group).  Mean age was 40 in either arm.  Both groups were balanced in terms of MELD score, grade of varices, CTP score, liver enzyme levels, and encephalopathy.  Most patients had acute alcoholic hepatitis.  The placebo group had more HBV reactivation liver injury.

CD 34 Cells: To verify whether G-CSF actually led to stem cell engrafment, authors compared CD34 cells in liver at baseline and at day 30.  Compared to baseline value of 27.5% CD34 cells in sinusoids (based on cell counting in immunohistochemistry), G-CSF treatment resulted in 45% CD34 cells in sinusoids.  No increase was seen in the placebo group (CD34 cells decreased from 30% to 20%).

Survival: The actuarial probability of survival was 66% with G-CSF versus 26% with placebo (p=0.001).  In total, 7 patients died in G-CSF group versus 17 deaths in placebo arm (majority from progressive multi-organ failure, mostly HRS)

MELD Scores: .Median change in MELD score at days 7, 30, and 60 was -7.4%, -18.23%, and -15.34% in G-CSF group versus +3.33%, +6.25%, and +11.76% in placebo group.

Adverse Effects: G-CSF treatment resulted in three adverse events - one had transient rash, one had herpes zoster, and one had high fevers.  Other patients completed therapy without reported adverse effects.

Discussion: This small randomized trial suggests that G-CSF has significant mortality benefit in acute on chronic liver failure!  In the two month trial period, there were 10 fewer deaths in the G-CSF group suggesting an amazingly large benefit.  There are, of course, a few caveats to this trial.  With the number of recruited patients numbering in the 20s in each group, there is no guarantee that the groups were actually well-balanced.  Also, with two month follow-up, it is unclear whether the effects of G-CSF are persistent or transient.  Clearly, this smaller trial calls for a larger, better designed randomized trial.  In the meantime, if someone with acute on chronic liver failure is perishing on standard therapy, I would strongly consider G-CSF therapy.

CSF Cortisol in Meningitis

Motivation: This year, I have seen two patients with community acquired meningitis - both had viral meningitis.   When we stopped antibiotics on both, I had slight trepidation about what if we were wrong.  After all, microbiologic data on CSF can be misleading.  For example, in about 10% of patients, bacterial meningitis can present with lymphocytic predominance.  Low plasma glucose is present in only 50-60% of patients with bacterial meningitis.  Recently, I came across this article evaluating CSF cortisol as a specific marker of acute bacterial meningitis.

Paper:  Holub, M., Beran, O., Dzupova, O., et. al. "Cortisol levels in cerebrospinal fluid correlate with severity and bacterial origin of meningitis." Critical Care (2007) 11:R41

Methods: Study conducted in an academic hospital in Prague.  Inclusion criteria were symptoms of menigitis (fever, headache, meningismus) for less than 72 hours and lumbar puncture performed on admission prior to administration of steroids as part of meningitis treatment.  Bacterial meningitis was diagnosed by positive bacterial CSF culture or detection of bacterial DNA in CSF using PCR.  These patients were compared retrospectively to data from 37 patients with asceptic meningitis as well as data from CSF of 13 control patients who had received LP as part of headache workup.

Results:
Cohort: In total, 47 patients were diagnosed with bacterial meningitis (mean age of 42) with mean APACHE II score of 12.3.  At day 28, there was 15% mortality.  For the asceptic meningitis group, 37 patients were included with mean age of 38 and average APACHE II score of 3.  There were no deaths at 28 days. 

CSF Cortisol: Mean CSF cortisol level was 8.45 ug/dL (interquartile range: 2.14-10.08 ug/dL) in patients with bacterial meningitis compared to mean CSF cortisol level of 0.62 ug/dL (interquartile range: 0.47-1.02 ug/dL), p = 0.001.  Control patients had mean CSF cortisol level of 0.36 ug/dL (interquartile range: 0.29 - 0.44 ug/dL). 

Correlation: CSF cortisol level correlated with APACHE II score - a measure of severity of sickness ( r = 0.763, p < 0.001).  CSF cortisol also correlated with serum cortisol (r = 0.587, p < 0.001). 

Sensitivity/Specificity: After analyzing receptor operating curves, the best sensitivity/specificity for discriminating bacterial and asceptic meningitis are obtained by setting a threshold of 1.67 ug/dL, which resulted in sensitivity of 82% and specificity of 100%.  When comparing bacterial meningitis and control patients, a threshold value of 0.47 ug/dL results in sensitivity and specificity of 100%. 

Discussion: This paper adds cortisol to one of the panel of factors in CSF chemistry that can aid in discriminating bacterial and asceptic meningitis.  While neutrophilia has higher sensitivity than cortisol, the cortisol level is more sensitive than CSF glucose in detecting bacterial meningitis.  Perhaps, more importantly, the very high specificity makes elevated cortisol a very strong indicator of bacterial meningitis.  The etiology of elevated CSF cortisol appears to be directly related to the overall systemic inflammatory insult in bacterial infection (elevated APACHE II score and serum cortisol).  While this study is a good start, some of the weakness of the design itself are the retrospective nature and generally different clinical condition of bacterial and asceptic meningitis patients (vastly different APACHE scores and 28 day mortality).  If patients are very sick with viral meningitis, do they also have non-specific cortisol elevation?  This paper does not address and was not powered to evaluate this comparable subgroup of patients.  Nonetheless, next time, I do a lumbar puncture to evaluate for meningitis, I will add on a CSF cortisol.

Garlic for Hepatopulmonary Syndrome

Motivation: At some unfortunate moments, you see a person struggling to breathe, and there is not much you can do - even with a tank of oxygen.  Hepatopulmonary syndrome (HPS) falls into this category.  Short of a liver transplant, no effective medical therapies exist.  Multiple vasoconstrictive agents such as somatostatin analogues have been tried without success.  After meeting yet another patient with hepatopulmonary syndrome, I was searching for something out of the ordinary when I came across this paper testing the efficacy of garlic (Allium sativum).  Seems like it might work.

Paper: De, B.K., Dutta, D., Pal, S.K. et. al.  "The role of garlic in hepatopulmonary syndrome: A randomized controlled trial."  Can. J. Gastroenterol.  (2010), 24: 183-88.

Methods: Randomized controlled trial in a single center (Calcutta Medical College in Kolkata, India).  Patients were screened for enrollment if they had portal hypertension.  From this cohort, patients were screened for presence of intrapulmonary vascular dilation with elevated A-a gradient.  Exclusion criteria included intrinsic cardiopulmonary disease, massive ascites, sepsis, or other severe comorbid condions.  The selected patients  were randomized to placebo or garlic (at a dose between 1 to 2 g/m2/day based on multiples of 250 mg pills, mean dose 1.55 g/day).  Follow-up was 9-18 months.  Treatment of primary disease was continued during the trial (antivirals for HBV and HCV and abstinence from alcohol).

Results:
Cohort: Overall, 42 patients were randomized, and 21 patients received either garlic or placebo.  In followup, one patient in the placebo group was lost and not analyzed.  The mean age of the cohort was about 40 years of age, and majority had alcoholic liver disease followed by chronic Hepatitis B.  Majority (at least 85% in both groups) had clubbing on physical exam.  Mean PaO2 was 66 in the garlic group and 64 in the placebo group.  Mean MELD score was about 15 in both groups.

Efficacy:  After nine-months of follow-up, the mean arterial oxygen was higher in the garlic group compared to placebo (83.05 versus 68.75 mmHg, p<0.001).  The mean A-a gradient was lower in the garlic group compared to placebo (21.35 vs. 29.11 mmHg, p<0.001).  In the garlic group, there was a 24.7% increase in arterial oxygen levels compared to baseline (83.05 versus 66.62 mmHg, p<0.001).  Interestingly, in the placebo group, there was also a 7.37% increase in the A-a gradient (68.75 vs. 64.05 mmHg, p = 0.02).

Mortality:  In the garlic group, two patients died on follow-up (GI bleed and sepsis).  In the placebo group, there were seven deaths (mostly sepsis followed by GI bleed).  The mortality, while higher in placebo, did not reach significance (p = 0.052).

Adverse Effects: While no data were presented, authors mentioned that no complications occurred except for "occasional bad breath."

Discussion: This small single center randomized trial suggests that garlic may be efficacious in treating hepatopulmonary syndrome.  For a complex mixture like garlic, it is unclear how it acts, but garlic has been speculated to change vascular tone (particularly by NO signaling).  Since the patients continued to be treated for primary disease (such as by abstinence from alcohol or by antivirals for HBV or HCV), garlic may alternatively act by potentiating therapy for the primary conditions rather than by treating HPS.  In fact, even in the placebo group, the mean PaO2 increased over nine month follow-up indicating that patients getting effective treatment for primary liver condition also had mild subsequent improvement.  Given the surprising findings in this small trial (and some smaller previous trials), I was surprised that there has not been a larger trial yet.  Part of the difficulty likely lies in the fact that garlic is natural, cheap, and hence unlikely to generate large revenue for a drug manufacturer.  Still, a larger trial is very much needed since this current trial suffers from being small, single-center, and likely unblinded to the investigators.  For the next patient I meet with HPS, I will think about suggesting garlic!