Angiotensin II in septic shock

In patients with vasodilatory shock on high-dose vasopressors, intravenous administration of angiotensin II increased blood pressure and consequently allowed catecholamine dose reduction when compared to placebo at 3 hours of therapy. Level of evidence: 1B (Randomised controlled trial with a low risk of bias)

Appraised by: Samuel N Denham and Tomasz Torlinski

Citation: Khanna A, English SW, Wang XS, et al. Angiotensin II for the treatment of vasodilatory shock. N Engl J Med 2017; 377: 419–430.

Lead author: Bellomo; [e-mail]

Three-part clinical question:

Patients: Adult patients with clinical features of high-output shock requiring a total catecholamine dose equivalent to >0.2 mcg/kg/min of noradrenaline to maintain mean arterial pressure (MAP).

Intervention: Patients were randomised by computer to receive either an infusion of angiotensin II (intervention group) or of placebo (control group) in addition to their existing vasopressors.

Outcomes: Primary outcome was the number of patients at 3 h in whom MAP increased to >75 mmHg or by 10 mmHg from baseline without an increase in baseline vasopressors. Secondary outcomes were decrease in Sequential Organ Failure Assessment (SOFA) score (total and cardiovascular component alone), all-cause mortality at 7 and 28 days and adverse event rates.

Study design:

International multicentre, double-blinded randomised controlled trial with modified intention to treat analysis, industry sponsored.

Study patients:

Inclusion criteria: Patients of 18 years or older who had clinical features of high-output shock (Central venous oxygen saturation >70% and central venous pressure >8 mmHg OR cardiac index > 2.3 L/min/BSA) and who required a total catecholamine dose equivalent to >0.2 mcg/kg/min of noradrenaline for >6 and <48 h to maintain a MAP of 55–70 mmHg. All patients had received at least 25 ml/kg of IV fluids in the preceding 24 h and had an arterial line, central venous catheter and urinary catheter in situ.

Exclusion criteria: Patients with acute coronary syndrome, more than 20% body surface area cutaneous burns, bronchospasm, liver failure, mesenteric ischemia, active bleeding, aortic aneurysm, neutropenia, venoarterial ECMO and high-dose steroids.

A total of 404 patients met the study criteria during the trial period and were assessed for eligibility to participate. Of these, 344 were randomised (172 to each group).

Study groups: The 172 patients in the treatment group were commenced on 20 ng/kg/min of angiotensin II in addition to their existing vasopressors. This dose was adjusted over 3 h to increase the MAP >75 mmHg up to a maximum dose of 200 ng/kg/min. Their existing vasopressors were not increased other than for safety. If this occurred, then the patient was deemed a non-responder to the trial intervention. From 3 to 48 h, the doses of angiotensin II and existing vasopressors were titrated to achieve a MAP of 65–75 mmHg. Patients in the control group followed the same protocol with the placebo drug.

Results:

The demographics and APACHE II scores of the study groups were well matched.

The primary outcome (MAP > 75 mm Hg) was achieved in significantly higher proportion of patients in treatment group with NNT = 2, see Table 1.

There was no difference in total SOFA score between the groups at 48 h; however, the cardiovascular component of the SOFA score decreased significantly in the treatment group (−1.75 versus −1.28, p = 0.01). There was no difference in the incidence of serious adverse events.

EBM questions:

Do the methods allow accurate testing of the hypothesis? Yes. This international multicentre doubled blinded randomised controlled trial allows testing of the hypothesis; however, one may question if the primary outcome measure of increase in MAP is clinically meaningful.

The inclusion criteria for the study called for patients to have received at least 25 ml/kg of IV fluids in the preceding 24 hours. This is in contrast to the surviving sepsis bundle recommendations of 30 ml/kg. ¹

Table 1.

Results.

Outcome	Time to outcome	CER	EER	RRR	ARR	NNT
MAP response	3 h	0.234	0.699	−199%	−46.5%	2
	95% Confidence intervals			−240% to −157%	−56.2% to −36.8%	2 to 3
Death	7 days	0.348	0.288	17%	6%	ns
	95% Confidence intervals			−12% to 46%	−4.2% to 16.2%
Death	28 days	0.538	0.460	14%	7.8%	ns
	95% Confidence intervals			−6% to 35%	−3.1 to 18.7%

Control group = placebo, experimental group = angiotensin II. RRR and ARR are negative for MAP response as the intervention increases rather than decreasing the outcome frequency.

ARR: absolute risk reduction; CER: control event rate; EER: experimental event rate; NNT: number needed to treat; RRR: relative risk reduction.

The study definition of ‘high dose vasopressor’, which was defined as >0.2 mcg/kg/min of noradrenaline or the equivalent is in contrast to previous studies looking at the use of vasopressin in this patient group which used a dose of >0.5–0.6 mcg/kg/min to define refractory shock.^2,3

Do the statistical tests correctly test the results to allow differentiation of statistically significant results? Yes. Appropriate statistical tests were used to analyse the results. However, the sample sizes are quite small, and it is underpowered to detect mortality differences or rare adverse events.

Are the conclusions valid in light of the results? Yes. There is a statistically significant increase in blood pressure in the treatment group compared with the control group. However this is the only conclusion which may be drawn from the results of this study.

Did any results get omitted and why? Yes. The previously published study protocol ⁴ detailed the recording of several additional exploratory endpoints – serum creatinine, serum lactate, urine output, time on ventilator, ICU length of stay and the SOFA score breakdown by organ. However these endpoints are not reported in the published manuscript.

Did the authors suggest areas for further research? Yes. The authors acknowledge the need for larger trials with a longer duration of patient follow up in order to study the effects of angiotensin II on mortality and to look for any rare or long-term side effects of its use.

Did the authors make any recommendations based on the results and were they appropriate? No. The authors did not make any specific clinical recommendations for the use of angiotensin II other than to state the conclusions of the study.

Is this study relevant to my clinical practice? Yes. Vasodilatory shock is possibly the most common shock state seen within the ICU. The risks of high dose catecholamine use are well known and some patients remain refractory to their use. Angiotensin II, which works via a non-catecholamine pathway may be of clinical benefit, however its place within the ICU is yet to be fully determined.

What level of evidence does this study represent? 1B. A randomised control trial with narrow confidence intervals. The study was also double blinded.

What grade of recommendation can I make based on this result alone? B. The only statistically significant endpoint from this study is an improvement in blood pressure. No improvement in any clinically meaningful outcome was demonstrated. Further larger studies will be required to investigate this in more detail.

What grade of recommendation can I make when this study is considered alongside other available evidence? B. As angiotensin II is new to the market and has only recently gained FDA approval, there is limited evidence for its clinical use. In particular there is little evidence for any improvement in mortality, length of ICU stay or reduction in organ failure.

Should I change my practice based upon these results? No. This single study in isolation does not yet justify a change in clinical practice, and this would not yet be possible anyway due to the unavailability of this drug in the UK. However, it may represent an important development in future once further trials have been performed.

Should I audit my own practice based upon these results? No. No clear standard of practice in the management of these patients was suggested by this study.