Blood Pressure Management in Spontaneous Intracerebral Hemorrhage

Journal Club Podcast #31: October 2016

A short discussion of optimal blood pressure management in ICH, looking at intensive BP control vs. guideline-based control...

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Articles:

Article 1: Tsivgoulis G, Katsanos AH, Butcher KS, Boviatsis E, Triantafyllou N, Rizos I, Alexandrov AV. Intensive blood pressure reduction in acute intracerebral hemorrhage: a meta-analysis. Neurology. 2014 Oct 21;83(17):1523-9. Answer Key.

Article 2: Qureshi AI, Palesch YY, Barsan WG, et al; ATACH-2 Trial Investigators and the Neurological Emergency Treatment Trials Network. Intensive Blood-Pressure Lowering in Patients with Acute Cerebral Hemorrhage. N Engl J Med. 2016 Sep 15;375(11):1033-43. Answer Key.

Article 3: Butcher KS, Jeerakathil T, Hill M, et al; ICH ADAPT Investigators. The Intracerebral Hemorrhage Acutely Decreasing Arterial Pressure Trial. Stroke. 2013 Mar;44(3):620-6. Answer Key.

Article 4: Anderson CS, Heeley E, Huang Y, et al; INTERACT2 Investigators. Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage. N Engl J Med. 2013 Jun 20;368(25):2355-65. Answer Key.

Vignette:

It's a slow Sunday morning in TCC when you get a page that a fifty-year-old patient with a sudden onset of confusion is en route. Per the page, the patient's BP is 210/110, with a heart rate of 85. The patient arrives to the ED awake, alert, but clearly confused. He answers all questions inappropriately and only follows commands with repeated questioning. His BP is still elevated (208/113).

After getting a finger-stick blood sugar, which is 105, a normal ECG, and sending off labs, you rush the patient for a head CT. The CT shows an intraparenchymal hemorrhage in the left basal ganglia without intraventricular extension. The volume of blood is about 30 mL.

You immediately place a consult to neurology while the patient is transported back to the room. The nurse rechecks the patient's BP, which is now 218/115, and asks what you would like to do to treat this hypertension. You remember learning that when managing BP in intracerebral hemorrhage (ICH) there is a balance between reducing further bleeding and perfusing the rest of the brain, but you aren't sure what the optimal goal BP is or how quickly you should try and achieve this goal. After discussing this with the neurologist, you decide to do a quick literature search and see what the evidence shows...

PICO Question:

Population: Adult patients with spontaneous ICH and elevated BP

Intervention: Aggressive lowering of blood pressure

Comparison: Standard lowering of blood pressure (i.e. SBP below ~180 mmHg)

Outcome: Death, functional status, quality of life, cost, length of stay

Search Strategy:

A PubMed “Clinical Queries” search was performed using the terms “intracerebral hemorrhage” AND “blood pressure” with category set to Therapy and scope to Broad. The search was then limited to studies published in the last 5 years using human subjects (http://tinyurl.com/zhj7zgs). This strategy resulted in 143 articles, of which 3 randomized controlled trials and 1 meta-analysis were chosen. The Cochrane database of systematic reviews was also searched, but did not identify an additional meta-analysis.

Bottom Line:

Optimal blood pressure management in patients with spontaneous intracerebral hemorrhage (ICH) is complicated by the balance between hematoma size and cerebral perfusion. An association between maximum systolic blood pressure and hematoma enlargement has been shown (Ohwaki 2004), but must be tempered by the opposing risk of reduced cerebral blood flow with overly aggressive reductions in blood pressure (Butcher 2003). A small study published in 2013, however, found no difference in relative perihematoma blood flow in patients treated with more aggressive BP goals (SBP < 150 mmHg) compared to traditional goals (SBP < 180 mmHg). This finding opened the door to further clinical research on the effects of aggressive BP lowering in ICH.

In 2010, the AHA guidelines for management of ICH suggested that in patients with significantly elevated blood pressure (SBP > 180 or MAP > 130), a “modest reduction” in BP should be considered (SBP < 160, MAP < 110). This arbitrary BP goal was challenged in 2013 by the publication of the INTERACT2 trial. This seminal trial compared traditional BP management to more intensive BP lowering (goal SBP < 140 mm Hg within one hour), and found no statistically significant improvement in the primary outcome of functional status. The authors performed a post hoc analysis of the data, however, and did find an improvement in functional status using the newly popularized “ordinal analysis” of the data. This finding spurred further debate, resulting in additional studies on this subject.

A meta-analysis published in 2014 sought to shed further light on this subject, pooling the results of the INTERACT2 trial with its pilot study (INTERACT1), the ICH ADAPT study, and one additional study that lacked the funding to devise a kickass acronym. This meta-analysis confirmed the results of the INTERACT2 trial, which is far from surprising when you consider that the vast majority of patients (~85) came from that particular study.

Earlier this year, the ATACH-2 trial was published. Using similar methodology to the INTERACT2 trial investigators, the authors of this international, multi-center trial also found no statistically significant improvement in functional outcomes with more aggressive BP reduction, thereby confirming the prior results of INTERACT2 and the pursuant meta-analysis.

Medical Expulsive Therapy (Tamsulosin) for Ureteral Colic

Journal Club Podcast #31: September 2016

A brief discussion of the growing literature on the use of tamsulosin (and sometimes nifedipine) in ureteral colic...

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Articles:

Article 1: Singh A, Alter HJ, Littlepage A. A systematic review of medical therapy to facilitate passage of ureteral calculi. Ann Emerg Med. 2007 Nov;50(5):552-63. Answer Key.

Article 2: Vincendeau S, Bellissant E, Houlgatte A, Doré B, Bruyère F, Renault A, Mouchel C, Bensalah K, Guillé F; Tamsulosin Study Group. Tamsulosin hydrochloride vs placebo for management of distal ureteral stones: a multicentric, randomized, double-blind trial. Arch Intern Med. 2010 Dec 13;170(22):2021-7. Answer Key.

Article 3: Pickard R, Starr K, MacLennan G, et al. Medical expulsive therapy in adults with ureteric colic: a multicentre, randomised, placebo-controlled trial. Lancet. 2015 Jul 25;386(9991):341-9. Answer Key.

Article 4: Furyk JS, Chu K, Banks C, Greenslade J, Keijzers G, Thom O, Torpie T, Dux C, Narula R. Distal Ureteric Stones and Tamsulosin: A Double-Blind, Placebo-Controlled, Randomized, Multicenter Trial. Ann Emerg Med. 2016 Jan;67(1):86-95.e2. Answer Key.

Vignette:

You are working in TCC one busy evening, kicking ass and saving lives. In the middle of the primary survey of a critically ill level one trauma, you are suddenly hit by a sharp, 10 out of 10 pain in your right side. Thinking that Doug Schueurer might have punched you, you turn around swiftly and see that he is on the other side of the room. After the patient is stabilized, you run to bathroom and begin vomiting. Dr. Wagner knocks on the door and tells you to quit being dramatic and get back to work, which you faithfully do.

The pain continues though to the end of your shift, at which time you check yourself in as a patient. You vitals are stable, with a heart rate of 105. You have some improvement in your pain with IV morphine and toradol. Your creatinine is normal and your UA shows a moderate amount of blood, with no signs of infection. An ultrasound (which you remember from a previous journal club is useful for diagnosing ureteral stones) reveals a 4 mm stone in the right distal ureter with mild hydronephrosis.

After tolerating a PO challenge (and yes, eating one of our turkey sandwiches is a challenge), you are ready to home. You leave with prescriptions for zofran, vicodin, and Flomax. Having heard horror stories about people developing orthostatic hypotension while taking Flomax, you wonder if there is any real efficacy. When you get home, you decide to do a literature search and see what the evidence shows.

PICO Question:

Population:Adult patients with ureteral stones not requiring urgent surgical intervention

Intervention: Tamsulosin

Comparison: Usual treatment (oral hydration, pain control, etc.)

Outcome: Time to stone passage, pain level, need for surgical intervention, quality of life, patient satisfaction

Search Strategy:

The articles chosen for the 2008 journal club were reviewed, and the meta-analysis used at that time was chosen as one of the articles. PubMed was then searched using the terms “tamsulosin AND (stones or colic)” limited to the last 10 years (http://tinyurl.com/jj8qysm). This results in 167 studies, of which 3 relevant randomized controlled trials were selected.

Bottom Line:

In 2008, the Washington University emergency medicine journal club looked at the efficacy of medical expulsive therapy in the management of ureteral stones. The conclusion at that time, based largely on a systematic review and meta-analysis from the Annals of EM the year before, was that tamsulosin and nifedipine may “improve moderate sized (more than 5mm) distal kidney stone expulsion rates compared with standard medical therapy.” This review did suggest the need for further large randomized controlled trials to further evaluate this topic, given that the results were based largely on “Low-quality RCT’s.”

Since then, several larger RCT’s have been performed. One study with mostly small stones (70% being 2-3 mm in diameter) found that tamsulosin did not improve time to stone expulsion or need for urgent intervention (Vincendeau 2010). This finding was supported by a subsequent trial in which ~75% of stones were < 5 mm in diameter (Pickard 2015). Despite a trend toward improved spontaneous stone passage at 4 weeks (the primary outcome) in patients with stones > 5 mm in size receiving tamsulosin, the authors of this paper haughtily conclude that “further trials involving these agents for increasing spontaneous stone passage rates will be futile.” Ignoring this advice, an additional study was recently published in Annals of EM (Furyk 2016). While this study also did not demonstrate improved stone passage when considering all patients (absolute risk reduction 5.1%; 95% CI -3.0% to 13.0%), a prespecified subset analysis of patients with stones 5-10 mm in diameter resulted in a significant improvement in this outcome (ARR 22.4%; 95% CI 3.1% to 41.6%; NNT = 4.5.)

This body of data, overall, suggests that tamsulosin likely provides no benefit to patients with small kidney stones (i.e. those smaller than 5 to 6 mm in diameter), but does seem to provide benefit in larger stones. A recent meta-analysis that includes all of these studies came to a similar conclusion (Wang 2016). For patients with stones 5-10 mm in diameter, this meta-analysis found an ARR of 22% (95% confidence interval 12% to 33%) with a NNT of 5.

Anticoagulation of Isolated Calf DVTs

Journal Club Podcast #30: August 2016

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A quick review of the literature on anticoagulation in isolated below the knee DVTs, and why we still don't have an answer...

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Articles:

Article 1: Schwarz T, Buschmann L, Beyer J, Halbritter K, Rastan A, Schellong S. Therapy of isolated calf muscle vein thrombosis: a randomized, controlled study. J Vasc Surg. 2010 Nov;52(5):1246-50. Answer Key.

Article 2: Lagerstedt CI, Olsson CG, Fagher BO, Oqvist BW, Albrechtsson U. Need for long-term anticoagulant treatment in symptomatic calf-vein thrombosis. Lancet. 1985 Sep 7;2(8454):515-8. Answer Key.

Article 3: Utter GH, Dhillon TS, Salcedo ES, Shouldice DJ, Reynolds CL, Humphries MD, White RH. Therapeutic Anticoagulation for Isolated Calf Deep Vein Thrombosis. JAMA Surg. 2016 Jul 20:e161770. Answer Key.

Article 4: Horner D, Hogg K, Body R, Nash MJ, Baglin T, Mackway-Jones K. The anticoagulation of calf thrombosis (ACT) project: results from the randomized controlled external pilot trial. Chest. 2014 Dec;146(6):1468-77. Answer Key.

Vignette:

Mr. M is a 53-year-old patient with a history of high blood pressure and high cholesterol who flew back to St. Louis from Shanghai five days ago. Two days after getting back he noted pain and swelling in his left calf, which he thought was due to a muscle strain while getting off of the airplane. Since then, the swelling has remained constant while the pain has worsened slightly. He reports a dull ache that is worse with ambulation and improves with rest. He denies shortness of breath or chest pain.

On physical exam his vitals are normal, his lungs are clear, and he has a normal S1 and S2 without a cardiac murmur or gallop. He has mild swelling noted to the left calf with focal calf tenderness. There is no erythema, warmth, or induration, and his pulses are symmetric bilaterally.

Concerned for a possible DVT given his recent long flight, you obtain lower extremity dopplers which reveal echogenic material in the peroneal and soleal veins consistent with acute DVT, but no signs of DVT proximal to the calf.

You call the patients PMD to discuss management, and she recommends sending the patient home with no therapy because, "It's just a calf DVT. You don't treat those." While you understand that has been the classic teaching, you also remember listening to an ERCAST Podcast in the last couple of years that spoke about the controversy surrounding this dogma. You send Mr. P home and recommend repeat dopplers in 5-7 days, but later decide to search the literature in order to make your own evidence-based decision...

PICO Question:

Population: Adult patients with isolated calf DVT distal to the popliteal veins

Intervention: Therapeutic anticoagulation (heparin, low molecular weight heparin, factor Xa inhibitor, direct thrombin inhibitor, or vitamin K antagonist)

Comparison: No anticoagulation.

Outcome: Propagation of clot to the popliteal veins or beyond, PE, bleeding, death, cost, patient satisfaction, quality of life.

Search Strategy:

An advanced PubMed search was conducted using the strategy “calf AND (thrombosis OR DVT) AND anticoagulation” (http://tinyurl.com/hx4onng) with 180 articles resulting. From these, the four most relevant articles were chosen.

Bottom Line:

The management of DVTs isolated to the calf veins has remained a controversial topic for many years. The 2008 guidelines produced by the American College of Chest Physicians (ACCP) recommended long-term (3 month) anticoagulation for all patients with DVT, regardless of proximal extension. Updated ACCP guidelines produced this year, on the other hand, make no specific recommendation, offering options of either treating or not treating isolated calf DVTs, as long as surveillance ultrasounds are performed. This lack of a firm recommendation seems based less on actual evidence, as it is on the low quality of evidence, which we will review.

This clinical conundrum has persisted for decades, with research extending at least into the 1980s. In 1985, Lancet published a randomized, controlled trial from Sweden (Lagerstedt 1985), in which patients with DVT isolated to the calf vein (as detected by phlebography) received either warfarin or no further anticoagulation (following a 5-day course of IV heparin in both groups). With 52 patients randomized, the authors found that the risk of recurrent clot was significantly lower in the warfarin group, with a NNT of 3.5 (95% CI 2.2 to 8.5). Unfortunately, this does not seem to be a very patient-centered outcome, and no patient in either group developed a PE.

In 2010, an article published in the Journal of Vascular Surgery (Schwarz 2010) randomized patients with isolated calf muscle vein (soleal or gastrocnemius) DVT to naroparin or compression therapy alone. They found no difference in progression of clot into either deep calf veins (peroneal or posterior tibial) or proximal veins, with a RR of 0.98 (95% CI 0.14 to 6.7). Unfortunately, this small study was poorly reported and failed to adhere to CONSORT guidelines, making assessment of internal validity nearly impossible. Additionally, the inclusion of calf muscle veins only, which may be less likely to propagate or result in PE, would not detect benefit in patients with deep calf vein clot.

A recent pilot randomized, controlled trial conducted in the UK (Horner 2014) randomized patients with any isolated calf DVT to either warfarin or anti-inflammatory medication. Seventy patients were analyzed, and for the composite outcome of proximal propagation, symptomatic PE, VTE-related sudden death, or major bleeding, they found a statistically nonsignificant trend towards benefit with anticoagulation (absolute risk reduction 11.4%, 95% CI -1.5% to 26.7%). Although the study was small, it was designed to demonstrate the feasibility of a much larger study, which is currently underway. Such a study will provide the best evidence to date regarding this treatment.

The most recent evidence on this subject was a retrospective observational study conducted at UC Davis. Outcomes of patients with isolated calf DVT were assessed based on whether or not there was an intention for them to receive any form of anticoagulation. The composite outcome of proximal DVT or PE was less likely in those treated with anticoagulation (RR 0.36, 95% CI 0.15 to 0.84). This benefit persisted after adjustment was made for several confounders. Unfortunately, observational studies are never able to control for the unknown confounders, and such evidence does little to inform us of whether anticoagulation provides any actual benefit. Also, less than half the patients in the study underwent repeat testing to assess for propagation of DVT, and such testing was more likely to occur in the control group, biasing the results in favor of the treatment group. The study also included primarily inpatients, and less than 4% were from the ED.

The evidence reviewed here is notably lacking in large, randomized controlled trials of good methodology, making it difficult to make firm recommendations. The current Chest guidelines make sense given this lack of evidence, and the decision to treat or not treat isolated calf DVTs should be based on several factors, including location (muscle vs. deep veins), need for ongoing immobilization, and bleeding risk. Emergency physicians will have to work closely with primary care physicians and admitting teams when making such decisions, given the controversy surrounding this topic.