Week 9 – Albumin in SBP

“Effect of Intravenous Albumin on Renal Impairment and Mortality in Patients with Cirrhosis and Spontaneous Bacterial Peritonitis”

N Engl J Med. 1999 Aug 5;341(6):403-9. [free full text]

Renal failure commonly develops in the setting of spontaneous bacterial peritonitis (SBP), and its development is a sensitive predictor of in-hospital mortality. The renal impairment is thought to stem from decreased effective arterial blood volume secondary to the systemic inflammatory response to the infection. In our current practice, there are certain circumstances in which we administer albumin early in the SBP disease course in order to reduce the risk of renal failure and mortality. Ultimately, our current protocol originated from the 1999 study of albumin in SBP by Sort et al.

The trial enrolled adults with SBP and randomized them to treatment with either cefotaxime and albumin infusion 1.5 gm/kg within 6hrs of enrollment, followed by 1 gm/kg on day 3 or cefotaxime alone. The primary outcome was the development of “renal impairment” (a “nonreversible” increase in BUN or Cr by more than 50% to a value greater than 30 mg/dL or 1.5 mg/dL, respectively) during hospitalization. The secondary outcome was in-hospital mortality.

126 patients were randomized. Both groups had similar baseline characteristics, and both had similar rates of resolution of infection. Renal impairment occurred in 10% of the albumin group and 33% of the cefotaxime-alone group (p = 0.02). In-hospital mortality was 10% in the albumin group and 29% in the cefotaxime-alone group (p = 0.01). 78% of patients that developed renal impairment died in-hospital, while only 3% of patients who did not develop renal impairment died. Plasma renin activity was significantly higher on days 3, 6, and 9 in the cefotaxime-alone group than in the albumin group, while there were no significant differences in MAP among the two groups at those time intervals. Multivariate analysis of all trial participants revealed that baseline serum bilirubin and creatinine were independent predictors of the development of renal impairment.

In conclusion, albumin administration reduces renal impairment and improves mortality in patients with SBP. The findings of this landmark trial were refined by a brief 2007 report by Sigal et al. entitled “Restricted use of albumin for spontaneous bacterial peritonitis.” “High-risk” patients, identified by baseline serum bilirubin of ≥ 4.0 mg/dL or Cr ≥ 1.0 mg/dL were given the intervention of albumin 1.5gm/kg on day 1 and 1gm/kg on day 3, and low-risk patients were not given albumin. None of the 15 low-risk patients developed renal impairment or died, whereas 12 of 21 (57%) of the high-risk group developed renal impairment, and 5 of the 21 (24%) died. The authors conclude that patients with bilirubin < 4.0 and Cr < 1.0 did not need scheduled albumin in the treatment of SBP. The current (2012) American Association for the Study of Liver Diseases guidelines for the management of adult patients with ascites due to cirrhosis do not definitively recommend criteria for albumin administration in SBP. Instead they summarize the aforementioned two studies. A 2013 meta-analysis of four reports/trials (including the two above) concluded that albumin infusion reduced renal impairment and improved mortality with pooled odds ratios approximately commensurate with those of the 1999 study by Sort et al. Ultimately, the current recommended practice per expert opinion is to perform albumin administration per the protocol outlined by Sigal et al. (2007).

References / Further Reading:
1. AASLD Guidelines for Management of Adult Patients with Ascites Due to Cirrhosis (skip to page 77)
2. Sigal et al. “Restricted use of albumin for spontaneous bacterial peritonitis”
3. Meta-analysis: “Albumin infusion improves outcomes of patients with spontaneous bacterial peritonitis: a meta-analysis of randomized trials”
4. Wiki Journal Club
5. 2 Minute Medicine

Summary by Duncan F. Moore, MD

Week 5 – Dexamethasone in Bacterial Meningitis

Streptococcus pneumoniae

“Dexamethasone in Adults With Bacterial Meningitis”

N Engl J Med 2002; 347:1549-1556 [free full text]

The current standard of care in the treatment of suspected bacterial meningitis in the developed world includes the administration of dexamethasone prior to or at the time of antibiotic initiation. The initial evaluation of this practice in part stemmed from animal studies, which demonstrated that dexamethasone reduced CSF concentrations of inflammatory markers as well as neurologic sequelae after meningitis. RCTs in the pediatric literature also demonstrated clinical benefit. The best prospective trial in adults was this 2002 study by de Gans et al.

The trial enrolled adults with suspected meningitis and randomized them to either dexamethasone 10mg IV q6hrs x4 days started 15-20 minutes before the first IV antibiotics or a placebo IV with the same administration schedule. The primary outcome was the Glasgow Outcome Scale at 8 weeks (1 = death, 2 = vegetative state, 3 = unable to live independently, 4 = unable to return to school/work, 5 = able to return to school/work). Secondary outcomes included death and focal neurologic abnormalities. Subgroup analyses were performed by organism.

301 patients were randomized. At 8 weeks, 15% of dexamethasone patients compared with 25% of placebo patients had an unfavorable outcome of Glasgow Outcome Scale score 1-4 (RR 0.59, 95% CI 0.37 – 0.94, p= 0.03). Among patients with pneumococcal meningitis, 26% of dexamethasone patients compared with 52% of placebo patients had an unfavorable outcome. There was no significant difference among treatment arms within the subgroup of patients infected with meningococcal meningitis. Overall, death occurred in 7% of dexamethasone patients and 15% of placebo patients (RR 0.48, 95% CI 0.24 – 0.96, p = 0.04). In pneumococcal meningitis, 14% of dexamethasone patients died, and 34% of placebo patients died.  There was no difference in rates of focal neurologic abnormalities or hearing loss in either treatment arm (including within any subgroup).

In conclusion, early adjunctive dexamethasone improves mortality in bacterial meningitis. As noted in the above subgroup analysis, this benefit appears to be driven by the efficacy within the pneumococcal meningitis subgroup. Of note, the standard initial treatment regimen in this study was amoxicillin 2gm q4hrs for 7-10 days rather than our standard ceftriaxone + vancomycin +/- ampicillin. Largely on the basis of this study alone, the IDSA guidelines for the treatment of bacterial meningitis (2004) recommend dexamethasone 0.15 mg/kg q6hrs for 2-4 days with first dose administered 10-20 min before or concomitant with initiation of antibiotics. Dexamethasone should be continued only if CSF Gram stain, CSF culture, or blood cultures are consistent with pneumococcus.

References / Further Reading:
1. IDSA guidelines for management of bacterial meningitis (2004)
2. Wiki Journal Club
3. 2 Minute Medicine

Summary by Duncan F. Moore, MD

Image Credit: CDC / Dr. Richard Facklam, US Public Domain, via Public Health Image Library

Week 4 – ARDSNet

“Ventilation with Lower Tidal Volumes as Compared with Traditional Tidal Volumes for Acute Lung Injury and the Acute Respiratory Distress Syndrome”

by the Acute Respiratory Distress Syndrome Network (ARDSNet)

N Engl J Med. 2000 May 4;342(18):1301-8. [free full text]

Acute respiratory distress syndrome (ARDS) is an inflammatory and highly morbid lung injury found in many critically ill patients. In the 1990s, it was hypothesized that overdistention of aerated lung volumes and elevated airway pressures might contribute to the severity of ARDS, and indeed some work in animal models supported this theory. Prior to the ARDSNet study, four randomized trials had been conducted to investigate the possible protective effect of ventilation with lower tidal volumes, but their results were conflicting.

The ARDSNet study enrolled patients with ARDS (diagnosed within 36 hours) to either a lower initial tidal volume of 6ml/kg, downtitrated as necessary to maintain plateau pressure ≤ 30 cm H2O, or to the “traditional” therapy of an initial tidal volume of 12 ml/kg, downtitrated as necessary to maintain plateau pressure ≤ 50 cm of water. The primary outcomes were in-hospital mortality and ventilator-free days within the first 28 days. Secondary outcomes included number of days without organ failure, occurrence of barotrauma, and reduction in IL-6 concentration from day 0 to day 3.

861 patients were randomized before the trial was stopped early due to the increased mortality in the control arm noted during interim analysis. In-hospital mortality was 31.0% in the lower tidal volume group and 39.8% in the traditional tidal volume group (p = 0.007, NNT = 11.4). Ventilator free days were 12±11 in the lower tidal volume group vs. 10±11 in the traditional group (n = 0.007). The lower tidal volume group had more days without organ failure (15±11 vs. 12±11, p = 0.006). There was no difference in rates of barotrauma among the two groups. Decrease in IL-6 concentration between days 0 and 3 was greater in the low tidal volume group (p < 0.001), and IL-6 concentration at day 3 was lower in the low tidal volume group (p = 0.002).

In summary, low tidal volume ventilation decreases mortality in ARDS relative to “traditional” tidal volumes. The authors felt that this study confirmed the results of prior animal models and conclusively answered the question of whether or not low tidal volume ventilation provided a mortality benefit. In fact, in the years following, low tidal volume ventilation became the standard of care, and a robust body of literature followed this study to further delineate a “lung-protective strategy.” Critics of the study noted that, at the time of the study, the “traditional” (standard of care) tidal volume in ARDS was less than the 12 ml/kg used in the comparison arm. (Non-enrolled patients at the participating centers were receiving a mean tidal volume of 10.3 ml/kg.) Thus not only was the trial making a comparison to a faulty control, but it was also potentially harming patients in the control arm. An excellent summary of the ethical issues and debate regarding this specific issue and regarding control arms of RCTs in general can be found here.

Corresponding practice point from Dr. Sonti and Dr. Vinayak and their Georgetown Critical Care Top 40: “Low tidal volume ventilation is the standard of care in patients with ARDS (P/F < 300). Use ≤ 6 ml/kg predicted body weight, follow plateau pressures, and be cautious of mixed modes in which you set a tidal volume but the ventilator can adjust and choose a larger one.”

PulmCCM is an excellent blog, and they have a nice page reviewing this topic and summarizing some of the research and guidelines that have followed.

Further Reading/References:
1. ARDSNet @ Wiki Journal Club
2. ARDSNet @ 2 Minute Medicine
3. PulmCCM “Mechanical Ventilation in ARDS: Research Update”
4. Georgetown Critical Care Top 40, page 6
5. PulmCCM “In ARDS, substandard ventilator care is the norm, not the exception.” 2017.

Summary by Duncan F. Moore, MD

Week 3 – NICE-SUGAR

“Intensive versus Conventional Glucose Control in Critically Ill Patients”

by the Normoglycemia in Intensive Care Evaluation–Survival Using Glucose Algorithm Regulation (NICE-SUGAR) investigators

N Engl J Med 2009;360:1283-97. [free full text]

On the wards we often hear 180 mg/dL used as the upper limit of acceptable for blood glucose with the understanding that tighter glucose control in inpatients can lead to more harm than benefit. The relevant evidence base comes from ICU populations, with scant direct data in non-ICU patients. The 2009 NICE-SUGAR study is the largest and best among this evidence base.

The study randomized ICU patients (expected to require 3 or more days of ICU-level care) to either “intensive” glucose control (target glucose 81 to 108 mg/dL) or conventional glucose control (target of less than 180 mg/dL). The primary outcome was 90-day all-cause mortality.

6104 patients were randomized to the two arms, and both groups had similar baseline characteristics. 27.5% of patients in the intensive-control group died versus 24.9% in the conventional-control group (OR 1.14, 95% CI 1.02-1.28, p= 0.02). Severe hypoglycemia (< 40 mg/dL) was found in 6.8% of intensive patients but only 0.5% of conventional patients.

In conclusion, intensive glucose control increases mortality in ICU patients. The fact that only 20% of these patients had diabetes mellitus suggests that much of the hyperglycemia treated in this study (97% of intensive group received insulin, 69% of conventional) was from stress, critical illness, and corticosteroid use. For ICU patients, intensive insulin therapy is clearly harmful, but the ideal target glucose range remains controversial and by expert opinion appears to be 140-180. For non-ICU inpatients with or without diabetes mellitus, the ideal glucose target is also unclear – the ADA recommends 140-180, and the Endocrine Society recommends a pre-meal target of < 140 and random levels < 180.

References / Further Reading:
1. ADA Standards of Medical Care in Diabetes 2016 (skip to page S99)
2. NICE-SUGAR @ Wiki Journal Club

Summary by Duncan F. Moore, MD

Week 43 – FREEDOM

“Strategies for Multivessel Revascularization in Patients with Diabetes”

by the FREEDOM (Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease) Trial investigators

N Engl J Med. 2012 Dec 20;367(25):2375-84. [free full text]

Previous studies, such as the 1996 BARI trial), have demonstrated that patients who have multivessel coronary artery disease (CAD) and diabetes mellitus (DM) and who received coronary artery bypass grafting (CABG) surgery lived longer than patients undergoing balloon angioplasty. However, since that publication, percutaneous coronary intervention (PCI) technology advanced significantly. Prior to the publication of FREEDOM in 2012, there had only been small, underpowered studies comparing PCI with drug-eluting stent (DES) to CABG. FREEDOM was powered appropriately to discover superiority of revascularization strategy (PCI with DES vs. CABG) in patients with DM and multivessel CAD.

Population:

Inclusion criteria:

      • 18 years or older
      • Diabetes mellitus – defined by American Diabetes Association
      • Multivessel Coronary Artery Disease
        • > 70% stenosis (angiographically confirmed)
        • 2 or more epicardial vessels
        • 2 or more coronary-artery territories

Selected exclusion criteria:

      • NYHA Class III-IV heart failure
      • Prior CABG, valve surgery, or PCI (< 6 months)
      • Prior significant bleed (< 6 months)
      • Left main stenosis ≥ 50%

 

Design:
Patients meeting criteria were assigned 1:1 into PCI with first-generation paclitaxel-eluting stent (51%) or sirolimus-eluting stent (43%) versus CABG. The PCI group was placed on aspirin and clopidogrel for dual antiplatelet therapy (DAPT) for at least 12 months. For the CABG group, arterial revascularization was encouraged. The mean SYNTAX score (tool used to score complexity of CAD) was 26.2 and did not significantly differ between groups. Guideline-driven targets for lowering medical risk factors were used: LDL <70, BP <130/80, HgbA1c <7. Minimum follow-up was 2 years.


Outcomes:

Primary: Composite of death from any cause, non-fatal myocardial infarction (MI), and non-fatal stroke

Secondary

      1. Rate of major adverse cardiovascular and cerebrovascular events at 30 days and 12 months
      2. Repeat revascularization
      3. Annual all-cause mortality
      4. Annual cardiovascular mortality


Results:
953 patients and 947 patients were randomized into the PCI and CABG groups, respectively. At 5 years, the primary outcome (combined death, MI, or stroke) occurred in 200 of the PCI group and 146 of the CABG group (26.6% vs 18.7%, p = 0.005). The curves started diverging at 2 years. All-cause mortality was higher in the PCI group versus the CABG group (16.3% vs 10.9%, p = 0.049). Regarding secondary outcomes, 13.9% of patients in the PCI group had a repeat MI versus 6.0% in the CABG group (p < 0.001). There were fewer strokes in the PCI group than in the CABG group (2.4% vs 5.2%, p = 0.03). There was no statistically significant difference between study groups regarding cardiovascular death (10.9% vs 6.8%, p = 0.12).

At 5 years, the analysis of outcomes according to category of SYNTAX score (≤ 22, 23 to 32, ≥ 33) showed no significant subgroup interaction (p = 0.58).

Regarding safety, major bleeding between the two groups at 30 days was 0.02% for PCI vs 0.04% for CABG (p = 0.13). The incidence of acute renal failure requiring hemodialysis was observed in one patient in the PCI group and eight patients in the CABG group (p = 0.02)

Implication/Discussion:
The BARI Trial (1996) was the first trial to show that patients with DM and multivessel CAD derive mortality benefit from bypass grafting over PCI with balloon angioplasty. Furthermore, the BARI 2D (2009) trial demonstrated this benefit of bypass grafting over PCI with bare metal stents (BMS). At the time of the FREEDOM Trial, there had not been a randomized comparison of CABG versus PCI with newer technology and first-generation paclitaxel/sirolimus DES. In this study, CABG showed a 5.3% absolute reduction in all-cause mortality over PCI as well decreased rates of MI and repeat revascularization. CABG was associated with a mild absolute increase in stroke (2.8%). However, this mild increased stroke risk is consistent with most other comparative trials of the two treatment strategies. There was no statistical difference in major bleeding between the two groups.

CABG is likely better than PCI for various reasons. For one, diabetic arteries are affected diffusely and tend to have more extensive atherosclerotic disease compared to those without diabetes, so the likelihood of successful PCI alone is low. Many suspected that with advancement in PCI (i.e. DES) that the BARI data would become irrelevant. However, CABG continued to show benefit despite the technological advancements of drug-eluting stents and PCI. Improvement in surgical technique as well as the use of arterial revascularization (i.e. internal mammary artery) helped maintain superior outcomes with CABG compared to PCI.

The study was limited by the fact that due to low numbers, the subgroup analysis (i.e. SYNTAX scores) was not appropriately powered for statistical significance. Further, the study was not blinded, and patients may have been treated differently on the basis of their surgical procedure. Also, there was variability of STYNAX scores between the study groups, but this circumstance was thought to reflect real world heterogeneity.

Bottom Line:
CABG was superior to PCI with DES in patients with DM and multivessel CAD in that it significantly reduced rates of death and MI despite a small increased risk of stroke.

Further Reading/References:
1. BARI Trial @ NEJM
2. BARI 2D Trial @ NEJM
3. ACCF/AHA 2011 Guideline for Coronary Artery Bypass Graft Surgery
4. FREEDOM @ Wiki Journal Club
5. FREEDOM @ 2 Minute Medicine
5. FREEDOM @ Visualmed

Summary by Patrick Miller, MD.

Image Credit: Jerry Hecht, US Public Domain, via Wikimedia Commons

Week 41 – Transfusion Strategies for Upper GI Bleeding

“Transfusion Strategies for Acute Upper Gastrointestinal Bleeding”

N Engl J Med. 2013 Jan 3;368(1):11-21. [free full text]

A restrictive transfusion strategy of 7 gm/dL was established following the previously discussed 1999 TRICC trial. Notably, both TRICC and its derivative study TRISS excluded patients who had an active bleed. In 2013, Villanueva et al. performed a study to establish whether there was benefit to a restrictive transfusion strategy in patients with acute upper GI bleeding.

The study enrolled consecutive adults presenting to a single center in Spain with hematemesis (or bloody nasogastric aspirate), melena, or both. Notable exclusion criteria included: a clinical Rockall score* of 0 with a hemoglobin level higher than 12g/dL, massive exsanguinating bleeding, lower GIB, patient refusal of blood transfusion, ACS, stroke/TIA, transfusion within 90 days, recent trauma or surgery

*The Rockall score is a system to assess risk for further bleeding or death on a scale from 0-11. Higher scores (3-11) indicate higher risk. Of the 648 patients excluded, the most common reason for exclusion (n = 329) was low risk of bleeding.

Intervention: restrictive transfusion strategy (transfusion threshold Hgb = 7.0 gm/dL) [n = 444]

Comparison: liberal transfusion strategy (transfusion threshold Hgb = 9.0 gm/dL) [n = 445]

During randomization, patients were stratified by presence or absence of cirrhosis.

As part of the study design, all patients underwent emergent EGD within 6 hours and received relevant hemostatic intervention depending on the cause of bleeding.

 

Outcome:
Primary outcome: 45-day mortality

Secondary outcomes, selected:

      • Incidence of further bleeding associated with hemodynamic instability or hemoglobin drop > 2 gm/dL in 6 hours
      • Incidence and number of RBC transfusions
      • Other products and fluids transfused
      • Hgb level at nadir, discharge, and 45 days

Subgroup analyses: Patients were stratified by presence of cirrhosis and corresponding Child-Pugh class, variceal bleeding, and peptic ulcer bleeding. An additional subgroup analysis was performed to evaluate changes in hepatic venous pressure gradient between the two strategies.

Results:
The primary outcome of 45-day mortality was lower in the restrictive strategy (5% vs. 9%; HR 0.55, 95% CI 0.33-0.92; p = 0.02; NNT = 24.8). In subgroup analysis, this finding remained consistent for patients who had Child-Pugh class A or B but was not statistically significant among patients who had Class C. Further stratification for variceal bleeding and peptic ulcer disease did not make a difference in mortality.

Secondary outcomes:
Rates of further bleeding events and RBC transfusion, as well as number of products transfused, were lower in the restrictive strategy. Subgroup analysis demonstrated that rates of re-bleeding were lower in Child-Pugh class A and B but not in C. As expected, the restrictive strategy also resulted in the lowest hemoglobin levels at 24 hours. Hemoglobin levels among patients in the restrictive strategy were lower at discharge but were not significantly different from the liberal strategy at 45 days. There was no group difference in amount of non-RBC blood products or colloid/crystalloid transfused. Patients in the restrictive strategy experienced fewer adverse events, particularly transfusion reactions such as transfusion-associated circulatory overload and cardiac complications. Patients in the liberal-transfusion group had significant post-transfusion increases in mean hepatic venous pressure gradient following transfusion. Such increases were not seen in the restrictive-strategy patients.

Implication/Discussion:
In patients with acute upper GI bleeds, a restrictive strategy with a transfusion threshold 7 gm/dL reduces 45-day mortality, the rate and frequency of transfusions, and the rate of adverse reactions, relative to a liberal strategy with a transfusion threshold of 9 gm/dL.

In their discussion, the authors hypothesize that the “harmful effects of transfusion may be related to an impairment of hemostasis. Transfusion may counteract the splanchnic vasoconstrictive response caused by hypovolemia, inducing an increase in splanchnic blood flow and pressure that may impair the formation of clots. Transfusion may also induce abnormalities in coagulation properties.”

Subgroup analysis suggests that the benefit of the restrictive strategy is less pronounced in patients with more severe hepatic dysfunction. These findings align with prior studies in transfusion thresholds for critically ill patients. However, the authors note that the results conflict with studies in other clinical circumstances, specifically in the pediatric ICU and in hip surgery for high-risk patients.

There are several limitations to this study. First, its exclusion criteria limit its generalizability. Excluding patients with massive exsanguination is understandable given lack of clinical equipoise; however, this choice allows too much discretion with respect to the definition of a massive bleed. (Note that those excluded due to exsanguination comprised only 39 of 648.) Lack of blinding was a second limitation. Potential bias was mitigated by well-defined transfusion protocols. Additionally, there a higher incidence of transfusion-protocol violations in the restrictive group, which probably biased results toward the null. Overall, deviations from the protocol occurred in fewer than 10% of cases.

Further Reading/References:
1. Transfusion Strategies for Acute Upper GI Bleeding @ Wiki Journal Club
2. Transfusion Strategies for Acute Upper GI Bleeding @ 2 Minute Medicine
3. TRISS @ Wiki Journal Club

Summary by Gordon Pelegrin, MD

Image Credit: Jeremias, CC BY-SA 3.0, via Wikimedia Commons

Week 39 – POISE

“Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery: a randomised controlled trial”

Lancet. 2008 May 31;371(9627):1839-47. [free full text]

Non-cardiac surgery is commonly associated with major cardiovascular complications. It has been hypothesized that perioperative beta blockade would reduce such events by attenuating the effects of the intraoperative increases in catecholamine levels. Prior to the 2008 POISE trial, small- and moderate-sized trials had revealed inconsistent results, alternately demonstrating benefit and non-benefit with perioperative beta blockade. The POISE trial was a large RCT designed to assess the benefit of extended-release metoprolol succinate (vs. placebo) in reducing major cardiovascular events in patients of elevated cardiovascular risk.

The trial enrolled patients age 45+ undergoing non-cardiac surgery with estimated LOS 24+ hrs and elevated risk of cardiac disease, meaning: either 1) hx of CAD, 2) peripheral vascular disease, 3) hospitalization for CHF within past 3 years, 4) undergoing major vascular surgery, 5) or any three of the following seven risk criteria: undergoing intrathoracic or intraperitoneal surgery, hx CHF, hx TIA, hx DM, Cr > 2.0, age 70+, or undergoing urgent/emergent surgery.

Notable exclusion criteria: HR < 50, 2nd or 3rd degree heart block, asthma, already on beta blocker, prior intolerance of beta blocker, hx CABG within 5 years and no cardiac ischemia since

Intervention: metoprolol succinate (extended-release) 100mg PO starting 2-4 hrs before surgery, additional 100mg at 6-12 hrs postoperatively, followed by 200mg daily for 30 days. (Patients unable to take PO meds postoperatively were given metoprolol infusion.)

Comparison: placebo PO / IV at same frequency as metoprolol arm

Outcome:
Primary – composite of cardiovascular death, non-fatal MI, and non-fatal cardiac arrest at 30 days

Secondary (at 30 days)

        • cardiovascular death
        • non-fatal MI
        • non-fatal cardiac arrest
        • all-cause mortality
        • non-cardiovascular death
        • MI
        • cardiac revascularization
        • stroke
        • non-fatal stroke
        • CHF
        • new, clinically significant atrial fibrillation
        • clinically significant hypotension
        • clinically significant bradycardia

Pre-specified subgroup analyses of primary outcome:

Results:
9298 patients were randomized. However, fraudulent activity was detected at participating sites in Iran and Colombia, and thus 947 patients from these sites were excluded from the final analyses. Ultimately, 4174 were randomized to the metoprolol group, and 4177 were randomized to the placebo group. There were no significant differences in baseline characteristics, pre-operative cardiac medications, surgery type, or anesthesia type between the two groups (see Table 1).

Regarding the primary outcome, metoprolol patients were less likely than placebo patients to experience the primary composite endpoint of cardiovascular death, non-fatal MI, and non-fatal cardiac arrest (HR 0.84, 95% CI 0.70-0.99, p = 0.0399). See Figure 2A for the relevant Kaplan-Meier curve. Note that the curves separate distinctly within the first several days.

Regarding selected secondary outcomes (see Table 3 for full list), metoprolol patients were more likely to die from any cause (HR 1.33, 95% CI 1.03-1.74, p = 0.0317). See Figure 2D for the Kaplan-Meier curve for all-cause mortality. Note that the curves start to separate around day 10. Cause of death was analyzed, and the only group difference in attributable cause was an increased number of deaths due to sepsis or infection in the metoprolol group (data not shown). Metoprolol patients were more likely to sustain a stroke (HR 2.17, 95% CI 1.26-3.74, p = 0.0053) or a non-fatal stroke (HR 1.94, 95% CI 1.01-3.69, p = 0.0450). Of all patients who sustained a non-fatal stroke, only 15-20% made a full recovery. Metoprolol patients were less likely to sustain new-onset atrial fibrillation (HR 0.76, 95% CI 0.58-0.99, p = 0.0435) and less likely to sustain a non-fatal MI (HR 0.70, 95% CI 0.57-0.86, p = 0.0008). There were no group differences in risk of cardiovascular death or non-fatal cardiac arrest. Metoprolol patients were more likely to sustain clinically significant hypotension (HR 1.55, 95% CI 1.38-1.74, P < 0.0001) and clinically significant bradycardia (HR 2.74, 95% CI 2.19-3.43, p < 0.0001).

Subgroup analysis did not reveal any significant interaction with the primary outcome by RCRI, sex, type of surgery, or anesthesia type.

Implication/Discussion:
In patients with cardiovascular risk factors undergoing non-cardiac surgery, the perioperative initiation of beta blockade decreased the composite risk of cardiovascular death, non-fatal MI, and non-fatal cardiac arrest and increased the overall mortality risk and risk of stroke.

This study affirms its central hypothesis – that blunting the catecholamine surge of surgery is beneficial from a cardiac standpoint. (Most patients in this study had an RCRI of 1 or 2.) However, the attendant increase in all-cause mortality is dramatic. The increased mortality is thought to result from delayed recognition of sepsis due to masking of tachycardia. Beta blockade may also limit the physiologic hemodynamic response necessary to successfully fight a serious infection. In retrospective analyses mentioned in the discussion, the investigators state that they cannot fully explain the increased risk of stroke in the metoprolol group. However, hypotension attributable to beta blockade explains about half of the increased number of strokes.

Overall, the authors conclude that “patients are unlikely to accept the risks associated with perioperative extended-release metoprolol.”

A major limitation of this study is the fact that 10% of enrolled patients were discarded in analysis due to fraudulent activity at selected investigation sites. In terms of generalizability, it is important to remember that POISE excluded patients who were already on beta blockers.

Currently, per expert opinion at UpToDate, it is not recommended to initiate beta blockers preoperatively in order improve perioperative outcomes. POISE is an important piece of evidence underpinning the 2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery, which includes the following recommendations regarding beta blockers:

      • Beta blocker therapy should not be started on the day of surgery (Class III – Harm, Level B)
      • Continue beta blockers in patients who are on beta blockers chronically (Class I, Level B)
      • In patients with intermediate- or high-risk preoperative tests, it may be reasonable to begin beta blockers
      • In patients with ≥ 3 RCRI risk factors, it may be reasonable to begin beta blockers before surgery
      • Initiating beta blockers in the perioperative setting as an approach to reduce perioperative risk is of uncertain benefit in those with a long-term indication but no other RCRI risk factors
      • It may be reasonable to begin perioperative beta blockers long enough in advance to assess safety and tolerability, preferably > 1 day before surgery

Further Reading/References:
1. Wiki Journal Club
2. 2 Minute Medicine
3. UpToDate, “Management of cardiac risk for noncardiac surgery”
4. 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines.

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

Summary by Duncan F. Moore, MD

Week 35 – CORTICUS

“Hydrocortisone Therapy for Patients with Septic Shock”

N Engl J Med. 2008 Jan 10;358(2):111-24. [free full text]

Steroid therapy in septic shock has been a hotly debated topic since the 1980s. The Annane trial in 2002 suggested that there was a mortality benefit to early steroid therapy and so for almost a decade this became standard of care. In 2008, the CORTICUS trial was performed suggesting otherwise.

The trial enrolled ICU patients with septic shock onset with past 72 hrs (defined as SBP < 90 despite fluids or need for vasopressors and hypoperfusion or organ dysfunction from sepsis). Excluded patients included those with an “underlying disease with a poor prognosis,” life expectancy < 24hrs, immunosuppression, and recent corticosteroid use. Patients were randomized to hydrocortisone 50mg IV q6h x5 days plus taper or to placebo injections q6h x5 days plus taper. The primary outcome was 28-day mortality among patients who did not have a response to ACTH stim test (cortisol rise < 9mcg/dL). Secondary outcomes included 28-day mortality in patients who had a positive response to ACTH stim test, 28-day mortality in all patients, reversal of shock (defined as SBP ≥ 90 for at least 24hrs without vasopressors) in all patients and time to reversal of shock in all patients.

In ACTH non-responders (n = 233), intervention vs. control 28-day mortality was 39.2% vs. 36.1%, respectively (p = 0.69). In ACTH responders (n = 254), intervention vs. control 28-day mortality was 28.8% vs. 28.7% respectively (p = 1.00). Reversal of was shock 84.7%% vs. 76.5% (p = 0.13). Among all patients, intervention vs. control 28-day mortality was 34.3% vs. 31.5% (p = 0.51) and reversal of shock 79.7% vs. 74.2% (p = 0.18). The duration of time to reversal of shock was significantly shorter among patients receiving hydrocortisone (per Kaplan-Meier analysis, p<0.001; see Figure 2) with median time to of reversal 3.3 days vs. 5.8 days (95% CI 5.2 – 6.9).

In conclusion, the CORTICUS trial demonstrated no mortality benefit of steroid therapy in septic shock regardless of a patient’s response to ACTH. Despite the lack of mortality benefit, it demonstrated an earlier resolution of shock with steroids. This lack of mortality benefit sharply contrasted with the previous Annane 2002 study. Several reasons have been posited for this difference including poor powering of the CORTICUS study (which did not reach the desired n = 800), inclusion starting within 72 hrs of septic shock vs. Annane starting within 8 hrs, and the overall sicker nature of Annane patients (who were all mechanically ventilated). Subsequent meta-analyses disagree about the mortality benefit of steroids, but meta-regression analyses suggest benefit among the sickest patients. All studies agree about the improvement in shock reversal. The 2016 Surviving Sepsis Campaign guidelines recommend IV hydrocortisone in septic shock in patients who continue to be hemodynamically unstable despite adequate fluid resuscitation and vasopressor therapy.

Per Drs. Sonti and Vinayak of the GUH MICU (excepted from their excellent Georgetown Critical Care Top 40): “Practically, we use steroids when reaching for a second pressor or if there is multiorgan system dysfunction. Our liver patients may have deficient cortisol production due to inadequate precursor lipid production; use of corticosteroids in these patients represents physiologic replacement rather than adjunct supplement.”

The ANZICS collaborative group published the ADRENAL trial in NEJM in 2018 – which demonstrated that “among patients with septic shock undergoing mechanical ventilation, a continuous infusion of hydrocortisone did not result in lower 90-day mortality than placebo.” The authors did note “a more rapid resolution of shock and a lower incidence of blood transfusion” among patients receiving hydrocortisone. The folks at EmCrit argued [https://emcrit.org/emnerd/cc-nerd-case-relative-insufficiency/] that this was essentially a negative study, and thus in the existing context of CORTICUS, the results of the ADRENAL trial do not change our management of refractory septic shock.

Finally, the 2018 APPROCCHSS trial (also by Annane) evaluated the survival benefit hydrocortisone plus fludocortisone vs. placebo in patients with septic shock and found that this intervention reduced 90-day all-cause mortality. At this time, it is difficult truly discern the added information of this trial given its timeframe, sample size, and severity of underlying illness. See the excellent discussion in the following links: WikiJournal Club, PulmCrit, PulmCCM, and UpToDate.

References / Additional Reading:
1. CORTICUS @ Wiki Journal Club
2. CORTICUS @ Minute Medicine
3. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock (2016), section “Corticosteroids”
4. Annane trial (2002) full text
5. PulmCCM, “Corticosteroids do help in sepsis: ADRENAL trial”
6. UpToDate, “Glucocorticoid therapy in septic shock”

Post by Gordon Pelegrin, MD

Image Credit: LHcheM, CC BY-SA 3.0, via Wikimedia Commons

Week 31 – Early TIPS in Cirrhosis with Variceal Bleeding

“Early Use of TIPS in Patients with Cirrhosis and Variceal Bleeding”

N Engl J Med. 2010 Jun 24;362(25):2370-9. [free full text]

Variceal bleeding is a major cause of morbidity and mortality in decompensated cirrhosis. The standard of care for an acute variceal bleed includes a combination of vasoactive drugs, prophylactic antibiotics, and endoscopic techniques (e.g. banding). Transjugular intrahepatic portosystemic shunt (TIPS) can be used to treat refractory bleeding. This 2010 trial sought to determine the utility of early TIPS during the initial bleed in high-risk patients when compared to standard therapy.

The trial enrolled cirrhotic patients (Child-Pugh class B or C with score ≤ 13) with acute esophageal variceal bleeding. All patients received endoscopic band ligation (EBL) or endoscopic injection sclerotherapy (EIS) at the time of diagnostic endoscopy. All patients also received vasoactive drugs (terlipressin, somatostatin, or octreotide). Patients were randomized to either TIPS performed within 72 hours after diagnostic endoscopy or to “standard therapy” by 1) treatment with vasoactive drugs with transition to nonselective beta blocker when patients were free of bleeding followed by 2) addition of isosorbide mononitrate to maximum tolerated dose, and 3) a second session of EBL at 7-14 days after the initial session (repeated q10-14 days until variceal eradication was achieved). The primary outcome was a composite of failure to control acute bleeding or failure to prevent “clinically significant” variceal bleeding (requiring hospital admission or transfusion) at 1 year after enrollment. Selected secondary outcomes included 1-year mortality, development of hepatic encephalopathy (HE), ICU days, and hospital LOS.

359 patients were screened for inclusion, but ultimately only 63 were randomized. Baseline characteristics were similar among the two groups except that the early TIPS group had a higher rate of patients with previous hepatic encephalopathy. The primary composite endpoint of failure to control acute bleeding or rebleeding within 1 year occurred in 14 of 31 (45%) patients in the pharmacotherapy-EBL group and in only 1 of 32 (3%) of the early TIPS group (p = 0.001). The 1-year actuarial probability of remaining free of the primary outcome was 97% in the early TIPS group vs. 50% in the pharmacotherapy-EBL group (ARR 47 percentage points, 95% CI 25-69 percentage points, NNT 2.1). Regarding mortality, at one year, 12 of 31 (39%) patients in the pharmacotherapy-EBL group had died, while only 4 of 32 (13%) in the early TIPS group had died (p = 0.001, NNT = 4.0). There were no group differences in prevalence of HE at one year (28% in the early TIPS group vs. 40% in the pharmacotherapy-EBL group, p = 0.13). Additionally, there were no group differences in 1-year actuarial probability of new or worsening ascites. There were also no differences in length of ICU stay or hospitalization duration.

Early TIPS in acute esophageal variceal bleeding, when compared to standard pharmacotherapy and endoscopic band ligation, improved control of index bleeding, reduced recurrent variceal bleeding at 1 year, and reduced all-cause mortality. Prior studies had demonstrated that TIPS reduced the rebleeding rate but increased the rate of hepatic encephalopathy without improving survival. As such, TIPS had only been recommended as a rescue therapy. Obviously, this study presents compelling data that challenge these paradigms. The authors note that in “patients with Child-Pugh class C or in class B with active variceal bleeding, failure to initially control the bleeding or early rebleeding contributes to further deterioration in liver function, which in turn worsens the prognosis and may preclude the use of rescue TIPS.” Authors at UpToDate note that, given the totality of evidence to date, the benefit of early TIPS in preventing rebleeding “is offset by its failure to consistently improve survival and increasing morbidity due to the development of liver failure and encephalopathy.” Today, TIPS remains primarily a salvage therapy for use in cases of recurrent bleeding despite standard pharmacotherapy and EBL. There may be a subset of patients in whom early TIPS is the ideal strategy, but further trials will be required to identify this subset.

Further Reading/References:
1. Wiki Journal Club []
2. 2 Minute Medicine []
3. UpToDate, “Prevention of recurrent variceal hemorrhage in patients with cirrhosis

Summary by Duncan F. Moore, MD

Week 29 – 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. 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

Image Credit: Joseaperez, CC BY-SA 3.0, via Wikimedia Commons