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


“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 2 – CAST

“Mortality and Morbidity in Patients Receiving Encainide, Flecainide, or Placebo”

The Cardiac Arrhythmia Suppression Trial (CAST)

N Engl J Med. 1991 Mar 21;324(12):781-8. [full text]

Ventricular arrhythmias are common following MI, and studies have demonstrated that PVCs and other arrhythmias such as non-sustained ventricular tachycardia (NSVT) are independent risk factors for cardiac mortality following MI. As such, by the late 1980s, many patients with PVCs post-MI were treated with antiarrhythmic drugs in an attempt to reduce mortality. The 1991 CAST trial sought to prove what predecessor trials had failed to prove – that suppression of such rhythms post-MI would improve survival.

This trial took post-MI patients with PVCs (with no sustained VT) and reduced EF and randomized them to an open-label titration period in which encainide, flecainide, or moricizine was titrated to suppress at least 80% of the PVCs and 90% of the runs of NSVT. Patients were then either randomized to continuation of the antiarrhythmic drug assigned during the titration period or transitioned to a placebo. The primary outcome was death or cardiac arrest with resuscitation, “either of which was due to arrhythmia.”

The trial was terminated early due to increased mortality in the encainide and flecainide treatment groups. 1498 patients were randomized following successful titration during the open-label period, and they were reported in this paper. The results of the moricizine arm were reported later in a different paper (CAST-II). The RR of death or cardiac arrest due to arrhythmia was 2.64 (95% CI 1.60–4.36; number needed to harm = 28.2). See Figure 1 on page 783 for a striking Kaplan-Meier curve. The RR of death or cardiac arrest due to all causes was 2.38 (95% CI 1.59–3.57; NNH = 20.6). Regarding other secondary outcomes, cardiac death/arrest due to any cardiac cause was similarly elevated in the treatment group, and there were no significant differences in non-lethal endpoints among the treatment and placebo arms.

In this large RCT, the treatment of asymptomatic ventricular arrhythmias with encainide and flecainide in patients with LV dysfunction following MI resulted in increased mortality. This study provides a classic example of how a treatment that seems to make intuitive sense based on observational data can be easily and definitively disproven with a placebo-controlled trial with hard endpoints (e.g. death). Although PVCs and NSVT are associated with cardiac death post-MI and reducing these arrhythmias might seem like an intuitive strategy for reducing death, correlation does not equal causation. Modern expert opinion at UpToDate notes no role for suppression of asymptomatic PVCs or NSVT in the peri-infarct period. Indeed such suppression may increase mortality. As noted on Wiki Journal Club, modern ACC/AHA guidelines “do not comment on the use of antiarrhythmic medications in ACS care.”

Further Reading/References:
1. CAST @ Wiki Journal Club
2. CAST @ 2 Minute Medicine
3. CAST-I Trial @ ClinicalTrials.gov
4. CAST-II trial publication, NEJM 1992
5. UpToDate “Clinical features and treatment of ventricular arrhythmias during acute myocardial infarction”

Summary by Duncan F. Moore, MD

Week 1 – CLOT

“Low-Molecular-Weight Heparin versus a Coumarin for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer”

by the Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators

N Engl J Med. 2003 Jul 10;349(2):146-53. [free full text]

Malignancy is a pro-thrombotic state, and patients with cancer are at significant and sustained risk of venous thromboembolism (VTE) even when treated with warfarin. Warfarin is a suboptimal drug that requires careful monitoring, and its effective administration is challenging in the setting of cancer-associated difficulties with oral intake, end-organ dysfunction, and drug interactions. The 2003 CLOT trial was designed to evaluate whether treatment with low-molecular-weight heparin (LMWH) was superior to treatment with a vitamin K antagonist (VKA) in the prevention of recurrent VTE.

The study randomized adults with active cancer and newly diagnosed symptomatic DVT or PE to treatment with either dalteparin subQ daily (200 IU/kg daily x1 month, then 150 IU/kg daily x5 months) or a vitamin K antagonist x6 months (target INR 2.5, with 5-7 day LMWH bridge). The primary outcome was the recurrence of symptomatic DVT or PE within 6 months of follow-up. Secondary outcomes included major bleed, any bleeding, and all-cause mortality.

338 patients were randomized to the LMWH group, and 338 were randomized to the VKA group. Baseline characteristics were similar among the two groups. 90% of patients had solid malignancies, and 67% of patients had metastatic disease. Within the VKA group, INR was estimated to be therapeutic 46% of the time, subtherapeutic 30% of the time, and supratherapeutic 24% of the time. Within the six-month follow-up period, symptomatic VTE occurred in 8.0% of the dalteparin group and 15.8% of the VKA group (HR 0.48, 95% CI 0.30-0.77, p=0.002; NNT = 12.9). The Kaplan-Meier estimate of recurrent VTE at 6 months was 9% in the dalteparin group and 17% in the VKA group. 6% of the dalteparin group developed major bleeding versus 6% of the VKA group (p = 0.27). 14% of the dalteparin group sustained any type of bleeding event versus 19% of the VKA group (p = 0.09). Mortality at 6 months was 39% in the dalteparin group versus 41% in the VKA group (p = 0.53).

In summary, treatment of VTE in cancer patients with low-molecular-weight heparin reduced the incidence of recurrent VTE relative to the incidence following treatment with vitamin K antagonists. Notably, this reduction in VTE recurrence was not associated with a change in bleeding risk. However, it also did not correlate with a mortality benefit either. This trial initiated a paradigm shift in the treatment of VTE in cancer. LMWH became the standard of care, although cost and convenience may have limited access and adherence to this treatment.

Until recently, no trial had directly compared a DOAC to LMWH in the prevention of recurrent VTE in malignancy. In an open-label, noninferiority trial, the Hokusai VTE Cancer Investigators demonstrated that the oral Xa inhibitor edoxaban (Savaysa) was noninferior to dalteparin with respect to a composite outcome of recurrent VTE or major bleeding. The 2018 SELECT-D trial compared rivaroxaban (Xarelto) to dalteparin and demonstrated a reduced rate of recurrence among patients treated with rivaroxaban (cumulative 6-month event rate of 4% versus 11%, HR 0.43, 95% CI 0.19–0.99) with no difference in rates of major bleeding but increased “clinically relevant nonmajor bleeding” within the rivaroxaban group.

Further Reading/References:
1. CLOT @ Wiki Journal Club
2. CLOT @ 2 Minute Medicine
3. UpToDate, “Treatment of venous thromboembolism in patients with malignancy”
4. Hokusai VTE Cancer Trial @ Wiki Journal Club
5. “Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism,” NEJM 2017
6. “Comparison of an Oral Factor Xa Inhibitor With Low Molecular Weight Heparin in Patients With Cancer With Venous Thromboembolism: Results of a Randomized Trial (SELECT-D).” J Clin Oncol 2018.

Summary by Duncan F. Moore, MD

Image Credit: Westgate EJ and FitzGerald GA, CC BY 2.5, via Wikimedia Commons