My goals during sepsis resuscitation focus largely on the preservation of renal function and maintenance of a reasonable fluid balance (renoresuscitation). The kidney is one of the most fragile organs, which may be rapidly injured by hypoperfusion. Renal failure correlates closely with mortality, participating in a vicious spiral of multi-organ failure. Alternatively, if you can save the kidneys, you’re likely to save the patient too (1).
In this context, any beneficial effect of vasopressin on renal function could be helpful. Vasopressin selectively constricts the efferent arteriole of the glomerulus, which should improve the glomerular filtration rate (2). Until last week, four RCTs had been performed comparing vasopressin vs. norepinephrine, each of which suggested that vasopressin improved renal function. However, the effect of vasopressin on renal function has never been investigated in a large RCT… until now.
Previous studies suggested a synergistic benefit from the combination of hydrocortisone and vasopressin. This is a multi-center RCT using a 2×2 factorial design, to simultaneously evaluate vasopressin, steroid, and their interaction:
408 patients were included in the final analysis, with ~100 patients per group. The primary outcome was the number of kidney failure-free days during the month after randomization. Renal failure was determined using the Acute Kidney Injury Network (AKIN) stage 3 definition, which can be diagnosed by meeting any one of the following criteria:
- Creatinine >3 times baseline
- Creatinine > 4 mg/dL (with an acute increase of at least 0.5 mg/dL)
- Urine output <0.3 ml/kg/hr for 24 hours
- Anuria for 12 hours
- Initiation of dialysis
There was no difference in the primary endpoint (table below). However, patients treated with vasopressin were less likely to require dialysis (25% vs. 35%, p=0.03, fragility index of 2).
This result is a bit of a paradox: no difference in kidney injury, but a difference in dialysis requirement? In general, kidney injury might be expected to be a more sensitive outcome, whereas dialysis requirement is a “harder” outcome (less sensitive, more specific for clinically-relevant kidney failure). Thus, it's surprising that patients treated with vasopressin required dialysis less often, yet had no difference in kidney injury.
Let’s look more closely at the indicators of kidney injury. Besides dialysis, the other determinants of kidney injury are urine output and creatinine. As shown below, patients treated with vasopressin did better in terms of both lower creatinine and higher urine output. Occasionally these differences reached the conventional level of statistical significance (p<0.05, red boxes)(3).
Thus, the paradox deepens. AKIN-3 renal failure is based on creatinine, urine output, and dialysis. Patients treated with vasopressin did better on all three metrics (less dialysis, lower creatinine, higher urine output). How is it possible, then, that there was no difference in AKIN-3 renal failure?
AKIN-3 Renal failure: Endpoint failure?
Like many diseases in critical care, we lack a perfect definition of “kidney injury.” Several definitions exist, with various cutoff values for urine output and creatinine. Using these definitions may yield unexpected results that don't correlate with patient-centered outcomes, including dialysis (previously encountered on the blog here and here).
AKIN-3 renal failure is based on whether patients meet arbitrary binary cutoffs (i.e. creatinine >4 mg/dL or not). There is nothing magical about these cutoff values. When complex patient data is converted into a binary outcome (renal failure = YES/NO), information is lost. For example, most would agree that there is a meaningful difference between a creatinine of 4.1 mg/dL vs. 10 mg/dL. However, according to the AKIN-3 definition, these two creatinine values are identical (“YES”).
Additional problems with using AKIN-3 free days as an outcome include:
- Creatinine values change rapidly in sepsis, making the “baseline creatinine” level somewhat arbitrary (4).
- Based on the pharmacokinetics of creatinine, AKIN-3 may detect renal failure more rapidly in patients with a lower baseline creatinine (Waikar 2009)(5).
- Creatinine and urine output was only measured in the ICU, with the assumption that AKI never occurred after transfer out of the ICU.
AKIN-3 is a composite outcome. The use of composite outcomes is controversial, with a common problem being that they equate outcomes which are unequal. For example, reduction in urine output is generally less worrisome than creatinine elevation (Wlodzimirow 2012). Combining creatinine, urine output, and dialysis leaves us with a mixture of apples, oranges, and bananas.
In summary, the AKIN-3 criteria is a blunt instrument that applies arbitrary cutoff values to creatinine and urine output, and then equates several outcomes to generate a composite. Use of AKIN-3 could easily obscure a signal of benefit from vasopressin. It might be better to examine the raw data directly, evaluating the effect of vasopressin on creatinine, urine output, and dialysis individually.
Does vasopressin improve renal function?
My interpretation of this data is that it provides moderate evidence that vasopressin improves renal function. In isolation, this study isn't definitive. However, this is the fifth RCT comparing vasopressin vs. norepinephrine in sepsis. All five of these studies provide evidence that vasopressin improves renal function (the other four are reviewed here). Altogether, these five studies provide reasonably strong evidence (6).
What is best first-line vasopressor for septic shock?
This is the obvious question, but probably also the wrong question. This question assumes that a single drug is the best treatment for every patient with septic shock. Rubbish. This ignores the enormous heterogeneity that exists among patients with sepsis. It would be equally foolish to ask: what is the first-line antibiotic for septic shock?
Heterogeneity makes it difficult to apply RCT data directly to individual patients. For example, imagine that 50% of patients respond better to norepinephrine, whereas 50% respond better to vasopressin. If these norepinephrine-responders and vasopressin-responders were randomly mixed throughout both study groups, then the study as a whole would be “negative.” Norepinephrine and vasopressin would be equal at the population level, but not at the individual level.
Overall the VANISH trial suggests that vasopressin is a potential front-line vasopressor in septic shock. Other vasopressors which are evidence-supported for use as monotherapy in septic shock are norepinephrine and epinephrine (Myburgh 2008, Annane 2007). The best question might be how to determine which of these is best for any individual patient. The figure below shows some features that might argue for or against vasopressin. Unfortunately, it may be impossible to predict the patient's response to vasopressors based on static hemodynamic variables (e.g. ejection fraction). Empiric titration may be necessary to clinically determine the effect of various agents.
A few considerations may be helpful:
1. Vasopressin probably shouldn’t be peripherally administered
There is increasing comfort regarding the use of peripheral IVs to infuse catecholamine vasopressors. One factor underlying the safety of this approach is that if extravasation occurs, it can be treated by locally injecting a catecholamine antagonist (phentolamine). In contrast, there is no available antagonist to vasopressin. Consequently, studies regarding the safety of peripheral vasopressors have excluded vasopressin (Mayo 2015). For now, it may be wise to avoid peripheral vasopressin (7).
2. Be careful using high doses of vasopressin plus norepinephrine
One problem that I've encountered when combining vasopressin and norepinephrine is that this combination may provide an excessive amount of afterload, impairing perfusion. Dr. Gordon alluded to this issue during his presentation on the VANISH trial at the Critical Care Reviews Meeting, noting that patients who developed digital ischemia were receiving vasopressin plus norepinephrine (8). Increased rate of skin ischemia among patients receiving vasopressin and norepinephrine has been reported previously as well (Dunser 2003).
3. Consider Vepinephrine (vasopressin + epinephrine)
To avoid hypoperfusion, a better combination may be vasopressin plus epinephrine. This combination has some attractive properties:
- Vasopressin counteracts vasodilation and improves renal microcirculation.
- Epinephrine supports cardiac contractility (avoiding hypoperfusion) and stimulates lactate production (which is potentially beneficial).
Vasopressin-epinephrine titration allows for continuous, independent adjustment of afterload and isotropy. Since both of these drugs have been shown to be adequate as monotherapy for sepsis, then arguably any ratio would be OK. In practice, it may be possible to empirically find a ratio which works best for an individual patient (9).
Stress dose steroid basically did nothing in this study. There was no effect on any of twenty-seven outcomes, including mortality and median time to shock reversal. There were trends towards requiring lower doses of vasopressors:
This shouldn't come as a shock. Although steroid in sepsis has been hotly debated, both the benefits and risks have probably been overblown. Low-dose steroid doesn't appear to improve mortality, but neither does it seem to cause superinfection. Steroid seems to reduce vasopressor requirement and might hasten shock resolution. In most cases, steroid probably has little effect.
- Any benefit from immunosuppression is likely to be greatest if started early, before inflammation has spiraled out of control. However, steroid is typically withheld until later in the course of septic shock, when patients have become refractory to vasopressors.
- The level of inflammation varies widely between patients. For example, a normal person may develop sepsis due to hyperinflammation (e.g. sepsis-HLH overlap syndrome). Alternatively, a patient with underlying cardiomyopathy may develop shock without much inflammation. Since steroid is an immunomodulator, it would make the most sense to use it in patients with hyperinflammation (e.g. markedly elevated CRP). Using hypotension as a trigger for steroid makes less sense, because hypotension reflects numerous factors besides inflammation (e.g. cardiac function, autonomic reserve, etc.).
- Compared to norepinephrine, vasopressin caused a reduction in dialysis requirement. Patients in the vasopressin group also had lower creatinine levels and higher urine output.
- There was no difference in the primary endpoint (days free of AKIN-3 renal failure). This could reflect imprecision in the AKIN-3 definition, which is a composite endpoint utilizing arbitrary cutoff values.
- Vasopressin yielded equivalent mortality and complication rates compared to norepinephrine. This supports the use of vasopressin as a front-line vasopressor. It remains unclear which patients might benefit more from vasopressin vs. norepinephrine.
- The conventional application of stress-dose steroids (i.e., for patients with vasopressor-refractory shock) had no impact on patient outcomes.
- VANISH trial
- Renoresuscitation (PulmCrit)
- Vasopressin & renal function 12/2014 (PulmCrit)
- Vasopressor basics (EMCrit)
- Peripheral vasopressors (EMCrit)
- Epinephrine & the benefit of lactate (PulmCrit)
- Epinephrine challenge (PulmCrit)
- Steroid in sepsis 7/2015 (PulmCrit)
- There is no direct prospective evidence supporting renoresuscitation. In practice, this looks much like any high-quality sepsis resuscitation, perhaps with a bit more attention to the kidneys. One exception would patients who with pre-existing chronic anuric renal failure on dialysis, among whom the target blood pressure can often be liberalized a bit.
- My primary reservation about this line of argument is that it's not entirely clear that a short-term improvement in glomerular function rate would correlate with longer-term renal functional outcomes. However, even if this improvement was merely short-term, then avoiding dialysis is still a worthy goal (because dialysis is expensive, invasive, and exposes patients to hemodynamic shifts etc.).
- Given the number of comparisons involved, using a p<0.05 is probably too high. This is useful only as a rough concept of how significant these differences are.
- The AKIN definition requires that volume status be optimized prior to applying these definitions (Mehta 2007). Thus, if the admission creatinine value were utilized as a baseline value, prior to volume resuscitation, this may not technically be valid.
- To illustrate this, let's approximate that if the kidneys stop working completely, creatinine increases by roughly 1-1.5 mg/dL per day. Therefore, if the baseline creatinine is 0.4 mg/dL and the kidneys suddenly shut down, AKIN-3 will occur the next day (serum creatinine will rise above 1.2 mg/dL, which is three times 0.4 mg/dL). Alternatively, if the baseline creatinine is 1.3 mg/dL and the kidneys suddenly shut down, AKIN-3 will occur two days later (the serum creatinine needs rise above 3.9 mg/dL to meet the definition of AKIN-3).
- It should be noted that norepinephrine is not a placebo comparator. In septic shock, norepinephrine typically improves renal perfusion and urine output. Thus, if vasopressin is slightly more effective than norepinephrine, then it may provide a large absolute benefit.
- In fairness, there is only one case report of vasopressin extravasation from a peripheral line causing skin necrosis when utilizing low-dose vasopressin (Bunker 2006). It is possible that peripheral vasopressin is reasonably safe, but currently there is very little evidence about this topic. For now, until patients have a central line, their hemodynamics may be best supported using peripheral catecholamine vasopressors (e.g. norepinephrine or epinephrine).
- Enormous thanks to Dr. Gordon (@agordonICU) and Dr. Sweeney (@CritCareReviews) for creating this and sharing it with the critical care community. This is fantastic material, especially for folks with tight schedules across the pond who otherwise would not be able to hear Dr. Gordon speak.
- Please note that there is no level-I clinical evidence to support this combination.
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