Week 34 – HACA

“Mild Therapeutic Hypothermia to Improve the Neurologic Outcome After Cardiac Arrest”

by the Hypothermia After Cardiac Arrest Study Group

N Engl J Med. 2002 Feb 21;346(8):549-56. [free full text]

Neurologic injury after cardiac arrest is a significant source of morbidity and mortality. It is hypothesized that brain reperfusion injury (via the generation of free radicals and other inflammatory mediators) following ischemic time is the primary pathophysiologic basis. Animal models and limited human studies have demonstrated that patients treated with mild hypothermia following cardiac arrest have improved neurologic outcome. The 2002 HACA study sought to evaluate prospectively the utility of therapeutic hypothermia in reducing neurologic sequelae and mortality post-arrest.

Population: European patients who achieve return of spontaneous circulation (ROSC) after presenting to the ED in cardiac arrest

inclusion criteria: witnessed arrest, ventricular fibrillation or non-perfusing ventricular tachycardia as initial rhythm, estimated interval 5 to 15 min from collapse to first resuscitation attempt, no more than 60 min from collapse to ROSC, age 18-75

pertinent exclusion criteria: pt already < 30ºC on admission, comatose state prior to arrest due to CNS drugs, response to commands following ROSC

Intervention: Cooling to target temperature 32-34ºC with maintenance for 24 hrs followed by passive rewarming. Patients received pancuronium for neuromuscular blockade to prevent shivering.

Comparison: Standard intensive care

Outcomes:

Primary: a “favorable neurologic outcome” at 6 months defined as Pittsburgh cerebral-performance scale category 1 (good recovery) or 2 (moderate disability). (Of note, the examiner was blinded to treatment group allocation.)

Secondary:

        • all-cause mortality at 6 months
        • specific complications within the first 7 days: bleeding “of any severity,” pneumonia, sepsis, pancreatitis, renal failure, pulmonary edema, seizures, arrhythmias, and pressure sores

Results:
3551 consecutive patients were assessed for enrollment and ultimately 275 met inclusion criteria and were randomized. The normothermia group had more baseline DM and CAD and were more likely to have received BLS from a bystander prior to the ED.

Regarding neurologic outcome at 6 months, 75 of 136 (55%) of the hypothermia group had a favorable neurologic outcome, versus 54/137 (39%) in the normothermia group (RR 1.40, 95% CI 1.08-1.81, p = 0.009; NNT = 6). After adjusting for all baseline characteristics, the RR increased slightly to 1.47 (95% CI 1.09-1.82).

Regarding death at 6 months, 41% of the hypothermia group had died, versus 55% of the normothermia group (RR 0.74, 95% CI 0.58-0.95, p = 0.02; NNT = 7). After adjusting for all baseline characteristics, RR = 0.62 (95% CI 0.36-0.95). There was no difference among the two groups in the rate of any complication or in the total number of complications during the first 7 days.

Implication/Discussion:
In ED patients with Vfib or pulseless VT arrest who did not have meaningful response to commands after ROSC, immediate therapeutic hypothermia reduced the rate of neurologic sequelae and mortality at 6 months.

Corresponding practice point from Dr. Sonti and Dr. Vinayak and their Georgetown Critical Care Top 40: “If after ROSC your patient remains unresponsive and does not have refractory hypoxemia/hypotension/coagulopathy, you should initiate therapeutic hypothermia even if the arrest was PEA. The benefit seen was substantial and any proposed biologic mechanism would seemingly apply to all causes of cardiac arrest. The investigators used pancuronium to prevent shivering; [at MGUH] there is a ‘shivering’ protocol in place and if refractory, paralytics can be used.”

This trial, as well as a concurrent publication by Benard et al. ushered in a new paradigm of therapeutic hypothermia or “targeted temperature management” (TTM) following cardiac arrest. Numerous trials in related populations and with modified interventions (e.g. target temperature 36º C) were performed over the following decade, and ultimately led to the current standard of practice.

Per UpToDate, the collective trial data suggest that “active control of the post-cardiac arrest patient’s core temperature, with a target between 32 and 36ºC, followed by active avoidance of fever, is the optimal strategy to promote patient survival.” TTM should be undertaken in all patients who do not follow commands or have purposeful movements following ROSC. Expert opinion at UpToDate recommends maintaining temperature control for at least 48 hours.

Further Reading/References:
1. HACA @ 2 Minute Medicine
2. HACA @ Wiki Journal Club
3. Georgetown Critical Care Top 40, page 23 (Jan. 2016)
4. PulmCCM.org, “Hypothermia did not help after out-of-hospital cardiac arrest, in largest study yet”
5. Cochrane Review, “Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation”
6. The NNT, “Mild Therapeutic Hypothermia for Neuroprotection Following CPR”
7. UpToDate, “Post-cardiac arrest management in adults”

Summary by Duncan F. Moore, MD

Image Credit: Sergey Pesterev, CC BY-SA 4.0, via Wikimedia Commons

Week 33 – ALLHAT

“Major Outcomes in High-Risk Hypertensive Patients Randomized to Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker vs. Diuretic”

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)

JAMA. 2002 Dec 18;288(23):2981-97. [free full text]

Hypertension is a ubiquitous disease, and the cardiovascular and mortality benefits of BP control have been well described. However, as the number of available antihypertensive classes proliferated in the past several decades, a head-to-head comparison of different antihypertensive regimens was necessary to determine the optimal first-step therapy. The 2002 ALLHAT trial was a landmark trial in this effort.

Population:
33,357 patients aged 55 years or older with hypertension and at least one other coronary heart disease (CHD) risk factor (previous MI or stroke, LVH by ECG or echo, T2DM, current cigarette smoking, HDL < 35 mg/dL, or documentation of other atherosclerotic cardiovascular disease (CVD)). Notable exclusion criteria: history of hospitalization for CHF, history of treated symptomatic CHF, or known LVEF < 35%.

Intervention:
Prior antihypertensives were discontinued upon initiation of the study drug. Patients were randomized to one of three study drugs in a double-blind fashion. Study drugs and additional drugs were added in a step-wise fashion to achieve a goal BP < 140/90 mmHg.

Step 1: titrate assigned study drug

      • chlorthalidone: 12.5 –> 12.5 (sham titration) –> 25 mg/day
      • amlodipine: 2.5 –> 5 –> 10 mg/day
      • lisinopril: 10 –> 20 –> 40 mg/day

Step 2: add open-label agents at treating physician’s discretion (atenolol, clonidine, or reserpine)

      • atenolol: 25 to 100 mg/day
      • reserpine: 0.05 to 0.2 mg/day
      • clonidine: 0.1 to 0.3 mg BID

Step 3: add hydralazine 25 to 100 mg BID

Comparison:
Pairwise comparisons with respect to outcomes of chlorthalidone vs. either amlodipine or lisinopril. A doxazosin arm existed initially, but it was terminated early due to an excess of CV events, primarily driven by CHF.

Outcomes:
Primary –  combined fatal CAD or nonfatal MI

Secondary

      • all-cause mortality
      • fatal and nonfatal stroke
      • combined CHD (primary outcome, PCI, or hospitalized angina)
      • combined CVD (CHD, stroke, non-hospitalized treated angina, CHF [fatal, hospitalized, or treated non-hospitalized], and PAD)

Results:
Over a mean follow-up period of 4.9 years, there was no difference between the groups in either the primary outcome or all-cause mortality.

When compared with chlorthalidone at 5 years, the amlodipine and lisinopril groups had significantly higher systolic blood pressures (by 0.8 mmHg and 2 mmHg, respectively). The amlodipine group had a lower diastolic blood pressure when compared to the chlorthalidone group (0.8 mmHg).

When comparing amlodipine to chlorthalidone for the pre-specified secondary outcomes, amlodipine was associated with an increased risk of heart failure (RR 1.38; 95% CI 1.25-1.52).

When comparing lisinopril to chlorthalidone for the pre-specified secondary outcomes, lisinopril was associated with an increased risk of stroke (RR 1.15; 95% CI 1.02-1.30), combined CVD (RR 1.10; 95% CI 1.05-1.16), and heart failure (RR 1.20; 95% CI 1.09-1.34). The increased risk of stroke was mostly driven by 3 subgroups: women (RR 1.22; 95% CI 1.01-1.46), blacks (RR 1.40; 95% CI 1.17-1.68), and non-diabetics (RR 1.23; 95% CI 1.05-1.44). The increased risk of CVD was statistically significant in all subgroups except in patients aged less than 65. The increased risk of heart failure was statistically significant in all subgroups.

Discussion:
In patients with hypertension and one risk factor for CAD, chlorthalidone, lisinopril, and amlodipine performed similarly in reducing the risks of fatal CAD and nonfatal MI.

The study has several strengths: a large and diverse study population, a randomized, double-blind structure, and the rigorous evaluation of three of the most commonly prescribed “newer” classes of antihypertensives. Unfortunately, neither an ARB nor an aldosterone antagonist was included in the study. Additionally, the step-up therapies were not reflective of contemporary practice. (Instead, patients would likely be prescribed one or more of the primary study drugs.)

The ALLHAT study is one of the hallmark studies of hypertension and has played an important role in hypertension guidelines since it was published. Following the publication of ALLHAT, thiazide diuretics became widely used as first line drugs in the treatment of hypertension. The low cost of thiazides and their limited side-effect profile are particularly attractive class features. While ALLHAT looked specifically at chlorthalidone, in practice the positive findings were attributed to HCTZ, which has been more often prescribed. The authors of ALLHAT argued that the superiority of thiazides was likely a class effect, but according to the analysis at Wiki Journal Club, “there is little direct evidence that HCTZ specifically reduces the incidence of CVD among hypertensive individuals.” Furthermore, a 2006 study noted that that HCTZ has worse 24-hour BP control than chlorthalidone due to a shorter half-life. The ALLHAT authors note that “since a large proportion of participants required more than 1 drug to control their BP, it is reasonable to infer that a diuretic be included in all multi-drug regimens, if possible.” The 2017 ACC/AHA High Blood Pressure Guidelines state that, of the four thiazide diuretics on the market, chlorthalidone is preferred because of a prolonged half-life and trial-proven reduction of CVD (via the ALLHAT study).

Further Reading / References:
1. 2017 ACC Hypertension Guidelines
2. ALLHAT @ Wiki Journal Club
3. 2 Minute Medicine
4. Ernst et al, “Comparative antihypertensive effects of hydrochlorothiazide and chlorthalidone on ambulatory and office blood pressure.” (2006)
5. Gillis Pharmaceuticals
6. Concepts in Hypertension, Volume 2 Issue 6

Summary by Ryan Commins MD

Image Credit: Kimivanil, CC BY-SA 4.0, via Wikimedia Commons

Week 32 – PneumA

“Comparison of 8 vs 15 Days of Antibiotic Therapy for Ventilator-Associated Pneumonia in Adults”

JAMA. 2003 November 19;290(19):2588-2598. [free full text]

Ventilator-associated pneumonia (VAP) is a frequent complication of mechanical ventilation and, prior to this study, few trials had addressed the optimal duration of antibiotic therapy in VAP. Thus, patients frequently received 14- to 21-day antibiotic courses. As antibiotic stewardship efforts increased and awareness grew of the association between prolonged antibiotic courses and the development of multidrug resistant (MDR) infections, more data were needed to clarify the optimal VAP treatment duration.

This 2003 trial by the PneumA Trial Group was the first large randomized trial to compare shorter (8-day) versus longer (15-day) treatment courses for VAP.

The noninferiority study, carried out in 51 French ICUs, enrolled intubated patients with clinical suspicion for VAP and randomized them to either 8 or 15 days of antimicrobials. Antimicrobial regimens were chosen by the treating clinician. 401 patients met eligibility criteria. 197 were randomized to the 8-day regimen. 204 patients were randomized to the 15-day regimen. Study participants were blinded to randomization assignment until day 8. Analysis was performed using an intention-to-treat model. The primary outcomes measured were death from any cause at 28 days, antibiotic-free days, and microbiologically documented pulmonary infection recurrence.

Study findings demonstrated a similar 28-day mortality in both groups (18.8% mortality in 8-day group vs. 17.2% in 15-day group, group difference 90% CI -3.7% to 6.9%). The 8-day group did not develop more recurrent infections (28.9% in 8-day group vs. 26.0% in 15-day group, group difference 90% CI -3.2% to 9.1%). The 8-day group did have more antibiotic-free days when measured at the 28-day point (13.1 in 8-day group vs. 8.7 in 15-day group, p<0.001). A subgroup analysis did show that more 8-day-group patients who had an initial infection with lactose-nonfermenting GNRs developed a recurrent pulmonary infection, so noninferiority was not established in this specific subgroup (40.6% recurrent GNR infection in 8-day group vs. 25.4% in 15-day group, group difference 90% CI 3.9% to 26.6%).

Implications/Discussion:
There is no benefit to prolonging VAP treatment to 15 days (except perhaps when Pseudomonas aeruginosa is suspected based on gram stain/culture data). Shorter courses of antibiotics for VAP treatment allow for less antibiotic exposure without increasing rates of recurrent infection or mortality.

The 2016 IDSA guidelines on VAP treatment recommend a 7-day course of antimicrobials for treatment of VAP (as opposed to a longer treatment course such as 8-15 days). These guidelines are based on the IDSA’s own large meta-analysis (of 10 randomized trials, including PneumA, as well as an observational study) which demonstrated that shorter courses of antibiotics (7 days) reduce antibiotic exposure and recurrent pneumonia due to MDR organisms without affecting clinical outcomes, such as mortality. Of note, this 7-day course recommendation also applies to treatment of lactose-nonfermenting GNRs, such as Pseudomonas.

When considering the PneumA trial within the context of the newest IDSA guidelines, we see that we now have over 15 years of evidence supporting the use of shorter VAP treatment courses.

Further Reading/References:
1. 2016 IDSA Guidelines for the Management of HAP/VAP
2. PneumA @ Wiki Journal Club
3. PulmCCM “IDSA Guidelines 2016: HAP, VAP & It’s the End of HCAP as We Know It (And I Feel Fine)”
4. PulmCrit “The siren’s call: Double-coverage for ventilator associated PNA”

Summary by Liz Novick, MD