A 52-year-old woman presents to the emergency department with a 1–2-day history of fever, right flank pain, and nausea. Vital signs are: temperature 39.1°C (102.4°F), heart rate (130 beats/min), respiratory rate (22 breaths/min), and blood pressure (70/40 mm Hg). She has right costovertebral angle tenderness. Laboratory findings are: WBCs 15 × 10/μL, creatinine 1.9 mg/dL, and lactate 3.5 mmol/L. Urinalysis reveals many WBCs and few RBCs. CT reveals right hydronephrosis with an obstructing ureteral stone. She receives 2 L of lactated Ringer solution and is started on norepinephrine and broad-spectrum antibiotics. Blood and urine cultures are pending. Urology plans intervention once the patient is stabilized. Despite increasing norepinephrine to 0.25 µg/kg/min, blood pressure remains low at 80/50 mm Hg. Which of the following is the most appropriate next step? Titrate norepinephrine upward to maintain mean arterial pressure of 65 mm Hg. Add vasopressin. Add stress-dose steroids only. Add vasopressin and stress-dose steroids. CLINICIAN COMMENTS This patient presents with the classic symptomatology of septic shock secondary to obstructive uropathy. Her clinical condition is rapid declining as evidenced by the continuing hypotension (despite an initial fluid bolus), lack of response/minimal response to norepinephrine, and an elevated lactate level. At this dose of norepinephrine of 0.25 ug/kg/min, in my practice, I would prioritize rapid correction of hypotension. To this effect, I would initiate vasopressin, if need use angiotensin II and use stress-dose steroids with the goal of decreasing the reliance on high doses of catecholamine monotherapy to achieve a blood pressure response. While the definition of high-dose vasopressors is highly debatable, a range from upward of 0.2 mcg/kg/min to greater than 2–3 µg/kg/min of norepinephrine base equivalents is prevalent in literature (1–3). High-dose catecholamines are associated with poor outcomes (4). Considering that this patient has needed rapid escalation of norepinephrine without any blood pressure response, she could be regarded as a nonresponder to catecholamines and alternatives such as vasopressin may be considered and that change should be considered early in the evolution of shock. While considering initiation of vasopressin, I would repeat a point of care ultrasound and get a rapid estimation of inferior vena cava diameter and respirophasic variation along with an estimate of cardiac function. If indicated, another fluid bolus would be administered based on the echo findings. Vasopressin use practice patterns are extremely heterogeneous and vary across institutions and geography (5). One aspect is the early initiation in terms of timing of onset of septic shock, and the other is at a lower dose of norepinephrine equivalents of other background vasopressors. The Vasopressin and Septic Shock (VASST) trial was a landmark effort to compare norepinephrine and vasopressin in septic shock and did demonstrate marginal benefit to early initiation of vasopressin at norepinephrine of less than 15 µg/min (6). However, this benefit was tested in the Vasopressin vs Norepinephrine as Initial Therapy in Septic Shock (VANISH) trial and could not be replicated, where early and primary use of vasopressin did not improve clinical outcomes compared with primary use of norepinephrine (7). More recently, the work from the Optimal Vasopressin Initiation in Septic Shock (OVISS) trial investigators, a machine learning initiative using external validation in more than 10,000 patients, demonstrated that vasopressin initiation based on the model was earlier relative to shock onset (median interquartile range (IQR), 4 hr 1–8 hr vs. 5 hr 1–14 hr), and at lower norepinephrine doses (median IQR, 0.20 µg/kg/min 0.08–0.45 µg/kg/min vs. 0.37 µg/kg/min 0.17–0.69 µg/kg/min) compared with clinicians’ actions. Following the OVISS model’s rules was seen to benefit with patient centric outcomes (8). Early multimodal therapy for vasopressors goes one step further, and in our practice, we support this initiative to choose multiple different mechanism vasopressors at a very early stage of management of shock and titrate and de-escalate based on a clinical response (9). For this patient, from the choices listed above, I would select D) add vasopressin and stress-dose steroids. The evidence for steroids is driven by the results of the ADRENAL trial that demonstrated a blood pressure response and a catecholamine sparing response (10). I use hydrocortisone 50 mg IV every 6 hours or 100 mg IV every 8 hours, at least during the time when my patient is on two or more vasopressors or at greater than 0.2–0.3 µg/kg/min of norepinephrine monotherapy. I come off steroids once my patient has established a clear trajectory for hemodynamic stability, as evidenced by a consistent decrease in vasopressor requirements. For short bursts of steroids, I do not use a taper while coming off. The multimodal approach to vasopressors, would suggest that biomarkers should drive the choice of a vasopressor specific to patient need (4). Even though not listed in the choices for the question above, in my practice, and as part of my approach, I would consider using angiotensin II early in such patients. The evidence supporting angiotensin II is limited, although it is an appropriate option with septic shock not responsive to traditional vasopressors or high doses of catecholamines. Especially in a population with high renin shock, which is the case in most patients with septic shock, there is benefit for angiotensin II for patient centric outcomes (11). A decrease in catecholamine burden with a mechanistic approach that uses different though synergistic pathways for a vasoactive response may be beneficial as well. A critical element in the decision-making process at this stage with the introduction of vasopressin and or angiotensin II is continuously ascertaining the presence of a euvolemic status and ruling out a low cardiac output state or significant cardiac dysfunction with a point of care ultrasound. While using vasopressors that need escalation, in my practice I routinely reaccess tissue perfusion with lactate. The recent compelling evidence of a capillary refill time (CRT) guided personalization of vasopressor and fluid therapy does offer an option to the clinician to access peripheral perfusion and an easy surrogate for microcirculatory adequacy (12). This is a practice I would strongly consider, and at some stage after initial resuscitation, would be okay dropping blood pressure targets to a mean arterial pressure (MAP) of 60–65 mm Hg if CRT is adequate. Again, while all of this is being done, repeat a check for euvolemia and cardiac contractility with point of care ultrasound and give an additional bolus of fluid as allowable. The evolution of septic cardiomyopathy is often subtle and difficult to recognize. Persistent hypoperfusion and a decline in cardiac output/cardiac index in the setting of euvolemia and increasing vasopressor needs would necessitate an inotrope at this stage. PHARMACIST COMMENTS This patient has septic shock that is minimally responsive to increasing doses of vasopressors and requires urgent stabilization for source control surgery. To better appreciate the state of the clinical situation, I would first evaluate the patient’s vascular access. Peripheral infusion of vasopressors has been found to be generally safe, although, I would prefer a vein in or above the antecubital fossa (13). A recent study identified no infiltrative or extravasation events in patients receiving peripheral vasopressin concomitantly with at least one other peripheral vasopressor (14). Thus, absence of a central venous catheter would not influence my choice of next action in this patient requiring immediate hemodynamic stabilization. Next, I would clarify the patient’s current vasopressor exposure by confirming that the norepinephrine dose is expressed in its base (i.e., molecular) form to aid applicability of evidence and decision-making (15). While I do not consider norepinephrine to have a ceiling dose, in my practice, I prefer to leverage multiple vasoconstricting mechanisms to maximize the chances of hemodynamic response and minimize catecholaminergic side effects. While in vitro and animal studies suggest a linear dose-response relationship, in patients with septic shock, the incremental increase in MAP to norepinephrine tends to decline as doses get higher (16). Thus, in the immediate resuscitation period, I would D) add vasopressin and stress-dose steroids to stabilize the patient for source control surgery. To do so, I would prioritize rapid blood pressure correction by initiating vasopressin at 0.03 U/min and titrating up to 0.06 U/min as needed. Higher doses of vasopressin have been shown to be more effective than lower doses in reversing hemodynamic failure in patients with norepinephrine-refractory septic shock (17). Vasopressin doses up to 0.06 U/min have been used in several randomized trials and are generally tolerated, but I would monitor for digital ischemia (18,19). As an adjunct, I tend to add stress-dose steroids at the same time as the second vasopressor. While mortality outcomes have been mixed, corticosteroids may increase sensitivity to vasopressors, reduce their overall duration, lessen time in intensive care, and may reduce the need for renal replacement therapy (20,21). While various hydrocortisone dosing schema in the 200–300 mg/d range have been reported in the literature, I use 50 mg every 6 hours in my practice. Recent observational data suggest less frequent dosing at the same total daily dose may produce equivocal outcomes with economic benefits and could be considered depending on local resources (22). During treatment, I would monitor for and treat hyperglycemia and aim to discontinue corticosteroids in the recovery phase of shock as vasopressor requirements demonstrate a clear downward trajectory.
Khanna et al. (Fri,) studied this question.