There are roughly two strategies for adjusting the intensity of treatment:
- Titrated strategy: Treatment intensity is adjusted to match the severity of the disease.
- Escalation-deescalation strategy: Treatment intensity is increased rapidly to exceed disease severity and gain control of the disease. After the patient improves, treatment intensity is reduced.
The best strategy depends on the situation. A titrated strategy is good for an outpatient with cellulitis: start with cefazolin and broaden antibiotics later if necessary. Septic shock from cellulitis is best treated with escalation-deescalation: start with broad-spectrum antibiotics, then deescalate after the patient responds.
The importance of early escalation in septic shock is generally recognized (e.g. early antibiotics, early resuscitation). However, steroid has traditionally been withheld until the patient was failing to respond to other treatments. This runs contrary to basic principles of sepsis management. The reasons for withholding steroid are two misconceptions:
- Steroid therapy has serious side-effects.
- Only the sickest patients benefit from steroid.
Why delaying steroid therapy doesn't make sense.
Misconception #1: Steroid is very risky and increases infection rates.
A few decades ago, using steroid for sepsis did cause lots of problems, because huge doses were used. We now use much lower doses (equivalent to ~50 mg/day prednisone). Short courses of low-dose steroid are well-tolerated. Such doses are often prescribed to outpatients. If primary care docs are comfortable prescribing this to outpatients with zero monitoring, then we shouldn't be scared of it either.
A common concern regarding steroid is an increased risk of infection. Low-dose steroid is unlikely to exacerbate infection in the absence of tuberculosis or fungal infection. Where the incidence of tuberculosis or fungal infection is low, this is safe. Meta-analysis of prior studies of steroid in sepsis revealed no increase in infection rates (Sligl 2009). The ADRENAL trial confirms this.
Steroid does have side-effects. However, these seem to be fairly minor and tolerable. Hyperglycemia occurs, but it's debatable whether this truly causes harm. Delirium can occur. In the ADRENAL trial, the rate of severe treatment-related adverse events was 4/1835 with steroid vs. 2/1829 with placebo (nonsignificant).
My read on #ADRENAL is that they are indeed harmless
— Scott K Aberegg MD MPH (@medevidenceblog) January 20, 2018
The physiology of sepsis could protect patients from steroid side-effects. Sepsis induces a state of glucocorticoid resistance (Dendoncker 2017). Thus, giving stress-dose steroid to a septic patient should cause fewer side-effects than giving the same dose to a healthy person.
Misconception #2: Only the sickest patients benefit from steroid.
Steroid accelerates shock reversal. This effect is observed across all levels of shock severity. For example the CORTICUS trial, which has been criticized for including patients who weren't that sick, found accelerated shock reversal in all patient subgroups (even the least ill subgroups). Within both ADRENAL and CORTICUS, shock reversal was accelerated among patients on any dose of norepinephrine.
It is conceivable that sicker patients may benefit more. Probably so. However, what the evidence shows is that steroid accelerates shock resolution among septic patient on any vasopressor dose.
— Rob Mac Sweeney (@CritCareReviews) January 19, 2018
Steroid did accelerate recovery in ADRENAL
Some study results may initially appear to contradict each other. The speed of recovery was reported using two types of variables in the manuscript:
- Median time-to-event (e.g. days until extubation)
- Average time free of support (e.g., vent-free days, ICU-free days)
The median time-to-event is significant in every case, but the averages are not:
The reason is simple. An average value is very sensitive to outliers (extreme data points). This causes the standard deviation of the average to be quite high (red boxes above). Large standard deviations make it impossible for differences in the average value to reach statistical significance. That doesn't mean that difference doesn't exist, it just means that this particular statistic isn't powered well enough to detect them (4).
Thus, the average number of support-free days is a noisy variable which can easily obscure clinically meaningful differences. A more sensitive approach to analyzing this data is time-to-event analysis, which was shown in the appendix. Surely enough, highly significant differences are detected:
The overall picture here is simple and clear: steroids accelerate recovery. Shock resolution, extubation, and ICU discharge were all hastened. These differences were highly significant when measured either using the median time-to-event or using hazard ratios.
Using steroid to accelerate recovery is universally accepted.
There is some debate about whether steroid can still be useful, even if it doesn't improve mortality. That's silly. Steroid is widely used to accelerate recovery in many diseases. For example, the use of steroid for COPD exacerbation is universally accepted. RCT evidence shows that steroid doesn't affect mortality in COPD exacerbation, it merely accelerates recovery by one day (Niewoehner 1999). Furthermore, the steroid dose used in sepsis is far lower than steroid doses commonly used for COPD (60-125 mg methylprednisolone q6hr, equivalent to 300-625 mg prednisone/day!). It's illogical to accept the use of steroid for COPD, but not for septic shock.
#Adrenal shows no mortality effect but more rapid shock resolution, reduced ICU LOS, and less transfusion. Unanswered Qs but surely, on the balance of probabilities, the answer is ‘yes' for now?
— Paul Young (@DogICUma) January 19, 2018
Implications for hydrocortisone-ascorbate-thiamine (HAT) therapy
Metabolic sepsis resuscitation with hydrocortisone, ascorbic acid, and thiamine (HAT) remains highly controversial. Until now, the strongest argument against HAT has been concern about side-effects from hydrocortisone (thiamine and ascorbate are water-soluble vitamins with excellent track records for safety)(2). The ADRENAL trial addresses these concerns nicely.
The rationale for using HAT is roughly two-fold:
- HAT might reduce mortality.
- HAT might accelerate recovery.
Whether or not HAT improves mortality is hard to say currently. Numerous RCTs are ongoing, which hopefully will give us a better answer within the next few years.
Regardless, evidence is accumulating that HAT does accelerate recovery from septic shock. Numerous RCTs consistently show that steroid accelerates shock reversal (e.g. CORTICUS and ADRENAL). Likewise, a small RCT found that intravenous ascorbic acid accelerated shock reversal (Zabet 2016). Given that both steroid and ascorbate accelerate recovery when used alone, the combination ought to work quite well (and might even work synergistically)(3). The notorious before-after study by Marik did indeed show that.
Rapid recovery is good for patients and good for the healthcare system. For the patient, this means less time on ventilation, less time in the ICU, and less time with a central line (or avoiding a line entirely)(1). Reducing ICU length of stay is also beneficial for the healthcare system. Hospitals have a limited number of ICU beds. Giving HAT to a patient with mild septic shock won't save that individual's life, but it could save the life of another patient awaiting that ICU bed.
Marik described the use of HAT therapy as immediate, up-front treatment for any patient with septic shock. Nonetheless, most providers using HAT reserve it for a tiny subset of patients with refractory shock who are failing all conventional measures. The ADRENAL trial supports steroid administration for patients with all severities of shock. Once you're willing to accept the concept of steroid administration, the addition of thiamine and ascorbic acid isn't a very large leap of faith. Thus, the ADRENAL trial moves us closer to using HAT broadly for patients with septic shock.
Evolution of sepsis therapy into a front-loaded strategy
Historically, sepsis therapy would start with antibiotics and fluids (figure below). After giving a lot of fluid (customarily four liters), the need for vasopressor would be grudgingly acknowledged. A couple hours delay would ensue to allow for placement of a central line and X-ray confirmation. Later on, if the pressors weren't working, steroid might be added on. This process of treatment escalation might take half a day.
A better approach to septic shock is shown above. Antibiotic, fluid, and peripheral vasopressor are all started immediately. Additional vasopressors are added within minutes if needed. Metabolic resuscitation with hydrocortisone, ascorbate, and thiamine are started immediately, for anyone on vasopressors. As patients improve, vasopressors and metabolic therapy are weaned off. Rapid escalation stabilizes the patient faster, which overall reduces the ICU length of stay. A less fluid-centric strategy avoids volume overload and “ARDS.”
Critical care medicine exists in a perpetual haze of uncertainty. Currently, RCTs are testing HAT therapy. Arguments about steroid will surely rage on forever. However, the above strategy seems congruent with the best available evidence. In an uncertain world, it is acceptable to strike hard, strike fast, and have no remorse.
- The ADRENAL trial showed that stress-dose steroids are fairly safe, have no mortality benefit, and accelerate clinical improvement.
- ADRENAL shows that steroid offers meaningful patient-centered benefit to patients on any dose of vasopressor (not solely patients on high-dose vasopressor).
- Treatment for septic shock involves immediate initiation of numerous therapies to stabilize the patient as rapidly as possible. It makes sense to initiate steroid promptly, rather than withholding it until the patient is failing to respond to high doses of vasopressor.
- Metabolic sepsis resuscitation with hydrocortisone, ascorbic acid, and thiamine remains controversial. By demonstrating the safety and efficacy of hydrocortisone, the ADRENAL study provides indirect support for this combination.
- Fore-runners of this post:
- ADRENAL trial
- Manuscript at NEJM
- Live presentation of results at CCR meeting
- The Bottom Line review – contains all the details of the study
- The Adrenal Trial – Salim Rezaie (Rebel EM
- CC Nerd (Rory Spiegel) – a skeptical view of the ADRENAL trial.
- Why negative trials are generally positive (BMJ, Peter Brindley)
- EM Lit of Note (Ryan Radecki) discusses power & NNT
- End of the roid? Dan Horner at St Emlyns Blog
- For patients with very mild sepsis who need only a very low dose of vasopressor, one strategy is to use peripheral vasopressors (e.g. peripheral phenylephrine) combined with HAT. Such patients can often be weaned off vasopressors promptly, thereby never requiring a central line. A typical scenario where this may be useful is an elderly patient who is DNR and refuses placement of a central line.
- It's generally accepted that 200 mg IV thiamine BID for four days is completely safe. IV ascorbic acid can cause oxalate nephropathy or hemolysis among patients with G6PD deficiency, but these events are reported at higher doses and/or longer durations than used in HAT therapy (6 grams daily for up to four days; Colliou 2017).
- The effect of steroid and ascorbic acid on endothelial function has been shown to be synergistic (Marik 2017). From a theoretical standpoint, the benefit from HAT would be expected to be greater than the sum from each ingredient given alone.
- Looking at event-free days remains important to make sure that time-to-event statistics are generated by accelerating recovery (rather than accelerating death). The fact that trends in event-free days match up with median time-to-event data is reassuring in this regard (as is the fact that there was trend towards reduced mortality among patients treated with steroid). Therefore, event-free days are a very appropriate statistic to include in the manuscript. It's simply a matter that this statistic shouldn't be over-interpreted: absence of a significant difference in the average number of event-free days doesn't exclude a clinically meaningful benefit.
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