What's the Deal with the Vitamin C in the ICU?

I am noticing more physicians using Vitamin C and thiamine infusion along with steroid for patients with sepsis in the ICU. At first glance, the obvious issues are small sample study, retrospective study, and all patients at one hospital.

NPR's take

Another good one...

Another report

Need More Studies

He wants there to be a comprehensive study, and he said that Stanford University has expressed some interest. But he said it will be difficult to fund because it uses drugs that have been on the market for decades: “We are curing it for $60. No one will make any money off it.”

It will be interesting to see where this leads... if anywhere. But, in the meantime, a little Vitamin C never hurt anyone, right?

Sepsis and Septic Shock Guidelines

One of the main guidelines in sepsis is the Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock from 2012 (updating the 2008 guidelines).

Pocket Guide

Key recommendations and suggestions:

• Early quantitative resuscitation of the septic patient during the first 6 hrs after recognition (1C)
• Blood cultures before antibiotic therapy (1C)
• Imaging studies performed to confirm a potential source of infection (UG)
• Administration of broad-spectrum antimicrobials therapy within 1 hr of recognition of septic shock (1B) and severe sepsis without septic shock (1C) as the goal of therapy; reassessment of antimicrobial therapy daily for de-escalation, when appropriate (1B)
• Infection source control with attention to the balance of risks and benefits of the chosen method within 12 hrs of diagnosis (1C)
• Initial fluid resuscitation with crystalloid (1B) and consideration of the addition of albumin in patients who continue to require substantial amounts of crystalloid to maintain adequate mean arterial pressure (2C) and the avoidance of hetastarch formulations (1C)
• Initial fluid challenge in patients with sepsis-induced tissue hypoperfusion and suspicion of hypovolemia to acheive a minimum of 30 mL/kg of crystalloids (more rapid administration and greater amounts of fluid may be needed in some patients) (1C)
• Fluid challenge technique continued as long as hemodynamic improvement, as based on either dynamic or static variables (UG)
• Norepinephrine as the first-choice vasporessor to maintain mean arterial pressure >/= 65 mm Hg (1B)
• Epinephrine when an additional agent is needed to maintain adequate blood pressure (2B)
• Vasopression (0.03 U/min) can be added to NE to either raise MAP to target or to decrease NE dose but should not be used as the initial vasopressor (UG)
• Dopamine is not recommended except in highly selected circumstances (2C)
• Dobutamine infusion administered or added to vasopressor in the presence of a) myocardial dysfunction as suggested by elevated cardiac filling pressures and low cardiac output, or b) ongoing signs of hypoperfusion despite acheiving adequate intravascular volume and adequate MAP (1C)
• Avoiding use of IV hydrocortisone in adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability (2C)
• Hemoglobin target of 7-9 g/dL in the absence of tissue hypoperfusion, ischemic coronary artery disease, or acute hemorrhage (1B)
• Low tidal volume (1A) and limiation of inspiratory plateau pressure (1B) for acute respiratory distress syndrome (ARDS)
• Application of at least a minimal amount of positive end-expiratory pressure (PEEP) in ARDS (1B)
• Higher rather than lower level of PEEP for patients with sepsis-induced moderate or severe ARDS (2C)
• Recruitment maneuvers in sepsis patients with severe refractory hypoxemia due to ARDS (2C)
• Prone positioning in sepsis-induced ARDS patients with a PaO2/FIO2 ratio of </= 100 mm Hg in facilities that have experience with such practicees (2C)
• Head-of-bed elevation in mechanically ventilated patients unless contraindicated (1B)
• A conservative fluid strategy for patients with established ARDS who do not have evidence of tissue hypoperfusion (1C)
• Protocols for weaning and sedation (1A)
• Minimizing use of either intermittent bolus sedation or continuous infusion sedation targeting specific titration endpoints (1B)
• Avoidance of neuromuscular blockers if possible in the septic patient without ARDS (1C)
• A short course of neuromuscular blocker (no longer than 48 hours) for patients with early ARDS and a PaO2/FIO2 < 150 mm Hg (2C)
• A protocolized approach to blood glucose management commencing insulin dosing when two consecutive blood glucose levels are > 180 mg/dL, targeting an upper blood glucose </= 180 mg/dL (1A)
• Equivalency of continuous veno-venous hemofiltration or intermittent hemodialysis (2B)
• Prophylaxis for deep vein thrombosis (1B)
• Use of stress ulcer prophylaxis to prevent upper gastrointestinal bleeding in patients with bleeding risk factors (1B)
• Oral or enteral (if necessary) feedings, as tolerated, rathern than either complete fasting or provision of only IV glucose with the first 48 hrs after a diagnosis of severe sepsis/septic shock (2C)
• Addressing goals of care, including treatment plans and end-of-life planning (as appropriate) (1B), as early as feasible, but within 72 hours of intesive care unit admission (2C). 

Should you be recommending a proton pump inhibitor (PPI) or H2-receptor antagonist (H2RA) for stress ulcer prophylaxis in critically ill patients?

We know that PPIs are better than H2RAs at raising intragastric pH, but we don’t know whether this higher pH value translates to superior clinical outcomes.  In fact, there is some debate whether a higher pH could actually cause problems, like nosocomial pneumonia or Clostridium difficile infection.  Given that clinically important GI bleeding has been associated with a high mortality rate (48.5% vs. 9.1% in non-bleeders), it seems that selecting the best agent for stress ulcer prophylaxis is an important decision. This hotly-debated topic, reinvigorated by the 2012 Surviving Sepsis Campaign Guidelines’ grade 2D recommendation in favor of PPIs, has again been examined with a recent meta-analysis by Alhazzani et al published in the March 2013 issue of Critical Care Medicine.

Actual .pdf of meta-analysis.

Of course, this is not the first meta-analysis to examine the topic.  In fact, three other meta-analyses have been published since 2009.  Here, here, and here. Naturally, the authors of this most recent meta-analysis claim that their statistical analysis was superior, they included more relevant trials, and they excluded more inappropriate trials to make this analysis a more pure, scientifically-valid view of the data.

This meta-analysis combined 14 randomized controlled trials with 1,720 total patients.  The analysis concluded that PPIs were associated with a reduction in clinically important upper GI bleeding (1.2% vs. 6.4%, NNT 19, RR 0.36, p=0.002) and overt upper GI bleeding (3.8% vs. 15.7%, NNT 9, RR 0.35, p<0.0001).  There was no difference in nosocomial pneumonia, ICU mortality, or ICU length of stay.

Is it time for famotidine and ranitidine to hang up their hat in the ICU?  The evidence from this meta-analysis appears compelling at first glance, but diving deep into the manuscript reveals some troubling issues.

First, the included trials were not comparing similar treatments of H2RAs.  Some trials used continuous infusions, some used once daily dosing, and one did not report dose at all.  It is scientifically questionable to pool a variety of different H2RAs with different dosing strategies together into a single group and categorize the treatments as being the same.

Second, the included trials did not have consistent definitions for “clinically important bleeding” and “overt bleeding”.  Some trials used very strict definitions where bleeding had to be confirmed with EGD, others has very loose criteria (eg, hemodynamic instability not explained by other causes), and some did not even provide definitions.  Indicative of the questionable criteria, 5 of the 12 included trials had an event rate of 0% in both arms, whereas one trial had an event rate as high as 31%.

Third, one must question whether the endpoint of “clinically important bleeding” is a surrogate or a clinically relevant outcome.  Given the questionable definitions and criteria used, a firm endpoint like ICU mortality would be a definitive approach to concluding a victor.  Unfortunately, there was no difference in ICU mortality demonstrated in this meta-analysis (17.5% PPI vs. 21.2% H2RA, p=0.91).

Given the paucity of high-quality data examining PPIs versus H2RAs for stress ulcer prophylaxis, it can be extremely temping to favor meta-analyses to find an answer to this compelling question.  The fallacy in this approach, however, is that you cannot take a multitude of poor-quality trials (many with fewer than 50 patients in the H2RA arm) and somehow combine the data into a valid, reliable, unbiased manuscript on which you base your clinical practice.

So how should we interpret this meta-analysis?  In my view, until better quality evidence comes out, there is no proven difference in the prevention of stress ulcer prophylaxis between PPIs and H2RAs.  The decision should be made based on formulary considerations (cost and availability), formulation considerations (ability to be crushed), the patient’s history of using a particular agent prior to admission, and potentially drug interactions (although I believe the PPI/omeprazole debate has not been concluded).

Sean P. Kane is a critical care clinical pharmacist and the author of ClinCalc.com -- an evidence-based website with clinical tools and calculators for medical professionals.

Nexium photo:  Photo credit: License Some rights reserved by Rennett Stowe