Angiotensin II for the treatment of septic shock in a neutropenic patient with T-cell acute lymphoblastic leukaemia

Abstract

Mortality remains high in septic shock with few new treatment options. Angiotensin II has been recently approved for use in septic shock due to promising results in the ATHOS-3 trial. However, patients with neutropenia were excluded in the trial. This patient population is becoming increasingly common in the intensive care unit as there is an increase in novel biologic therapies and stem cell transplantations for haematological and solid organ malignancies. We present a case of a patient with T-cell acute lymphoblastic leukaemia who received chemotherapy, resulting in neutropenia and septic shock. There was persistent hypotension despite initiating multiple conventional vasopressors. Angiotensin II was attempted with immediate improvement in the blood pressure which resulted in weaning of other vasopressors. This positive haemodynamic response suggests that angiotensin II can successfully be used in neutropenic patients without increasing the overall catecholamine burden of septic shock.

Background

Sepsis affects nearly 1.7 million Americans yearly and is defined as a dysregulated immune response to infection where there is a surge of inflammatory and anti-inflammatory cytokines on exposure to microbial pathogen-associated molecular patterns.¹ Septic shock, a subset of sepsis, has a criterion of serum lactate >2 mmol/L and a need for vasopressors to maintain a mean arterial pressure (MAP) of 65 mm Hg or greater.^{2 3} It is associated with approximately a 56% in-hospital mortality.⁴ Though norepinephrine remains the first-line vasopressor for septic shock, recent research explored promising new agents to be incorporated into clinical practice, such as angiotensin II.^5–7

We report a case using angiotensin II as an adjunct vasopressor in a severely neutropenic patient with septic shock, a patient demographic was excluded in the Angiotensin II for the Treatment of Vasodilatory Shock (ATHOS-3) trial.⁵ Our findings were consistent in that angiotensin II allowed for deescalation of other conventional vasopressors. However, maintaining MAP goals with solely angiotensin II was short lived. Long-term implications with survival, renal function and intensive care unit (ICU) length of stay with angiotensin II use are unknown.

Case presentation

An obese 72-year-old man, with a significant medical history of hypertension, hyperlipidaemia, carotid artery disease, chronic kidney disease stage 4, was admitted to the hospital with new neck lymphadenopathy. He had a family history of coronary artery disease, but no cancer history. He was a former smoker having stopped 25 years prior, but drank one alcoholic drink daily. He was subsequently diagnosed with T-cell acute lymphoblastic leukaemia (T-ALL) and was initiated on daily hyper-CVAD (CVAD includes: cyclophosphamide, vincristine, doxorubicin (Adriamycin) and dexamethasone) along with mesna, methotrexate and cytarabine chemotherapy.

Five days into chemotherapy, the patient developed dyspnoea and rigours. On examination, he was tachypneic with a rate of 28 and febrile with a maximum temperature of 38.6°C. He developed new atrial fibrillation with rapid ventricular response with heart rate into the 150 s. MAP was in the upper 50 s with a collapsible inferior vena cava and hyperdynamic left ventricle on bedside ultrasound, which warranted a fluid bolus. He was still alert and oriented man at this time and was warm to the touch, flushed and diaphoretic. He was using his accessory respiratory muscles to breathe and had bilateral lower lung inspiratory rhonchi. He had a normal abdominal and integumentary examination.

Because of the patient’s presentation and immunocompromised state, we initiated broad-spectrum antibiotics with cefepime and vancomycin after blood cultures were collected. Significant laboratory values at this time showed a bicarbonate of 15 mmol/L, Blood urea nitrogen of 58 mg/dL, creatinine of 1.9 mg/dL (an increase in 0.4 mg/dL from baseline), white cell count of 0.2×10⁹/L and lactic acid of 6.4 mmol/L. An arterial blood gas showed a pH of 7.26, pCO₂ of 39.3 mm Hg and pO₂ of 135.6 mm Hg with the patient requiring a non-rebreather. A chest X-ray was obtained and showed bilateral lower lobe alveolar opacities with a small left pleural effusion (figure 1). Despite 3 L of crystalloids, the patient’s MAP did not improve. His heart rate slightly improved to the low 100 s. The patient was intubated, had central and arterial lines placed and initiated on vasopressors. Our patient’s diagnosis was septic shock as evidenced by his clinical presentation, immunocompromised state, laboratory values and need for vasopressive medications.

Figure 1.

Initial chest radiograph during intensive care unit admission shows areas of increasing opacities at each lung base with a small left pleural effusion.

The patient was initiated on norepinephrine to max dose of 0.3 µg/kg/min and vasopressin 0.04 units/min. He remained hypotensive with a MAP of 55 mm Hg. At this point, angiotensin II was initiated at 20 ng/kg/min, which had an immediate response in his blood pressure (increasing to 167/48 mm Hg; MAP 77 mm Hg). We momentarily weaned norepinephrine and vasopressin. However, we were unsuccessful with down-titrating angiotensin II to 5 ng/kg/min. The angiotensin II dose had to be increased back up to 20 ng/kg/min. Afterwards, we had to supplement the vasopressors with a hydrocortisone bolus of 100 mg and a maintenance dose of 50 mg every 6 hours. Six hours after stopping norepinephrine, we had to restart the medication to a maximum dose of 0.05 µg/kg/min. Within 5 hours, blood cultures grew a Gram-negative anaerobe called Aeromonas. Antibiotics were de-escalated for optimal coverage of his bacteraemia after susceptibilities returned. Following the initial phase of his septic shock, the patient developed multiorgan failure. The patient remained intubated throughout the ICU stay. He required continuous renal replacement therapy starting on day 2 due to oliguric acute kidney injury. An echocardiogram performed on day 4 in the ICU revealed an ejection fraction of 30%, which was normal 10 days prior. Finally, he never returned to consciousness despite stopping all sedating medications.

Outcome and follow-up

The patient suffered from septic shock secondary to Gram-negative bacteraemia likely from a pulmonary source which resulted in multiorgan failure. Along with the multiorgan failure, he was given an extremely poor prognosis from his T-ALL due to his inability to tolerate any further chemotherapy. After 6 days of intense treatment in the ICU, the family requested to transition to hospice care due to his lack of clinical improvement and poor prognosis. The patient expired 1 day after electively entering hospice.

Discussion

Sepsis induces profound vasodilation, capillary leakage and hypovolaemia with clinical studies showing that the renin–angiotensin–aldosterone system (RAAS) is activated in attempts to preserve peripheral vascular resistance and intravascular volume.^{8 9} In theory, angiotensin II would help augment the RAAS’s compensatory mechanisms through vasoconstriction and secretion of aldosterone from the zona glomerulosa of the adrenal cortex. However, angiotensin II also contains thrombotic and proinflammatory effects which can worsen sepsis.^{10 11} Multiple animal models have shown promising results with RAAS blockade in sepsis leading to improved survival, but further research is still warranted.^{12 13} Currently, there appears to be a fine balance for angiotensin II administration.

Angiotensin II was approved by the US Federal Drug Administration in 2017, largely due to the promising results in the ATHOS-3 trial.^{5 14} Angiotensin II effectively increased blood pressure in patients with vasodilatory shock who did not respond to high doses of conventional vasopressors. Its primary endpoint was an increase in MAP of 10 mm Hg from baseline or an increase to at least 75 mm Hg at 3 hours. Our case met those parameters which allowed for complete discontinuation of background vasopressors for at least 6 hours. However, we were unable to maintain MAP goals and deescalate vasopressor requirements with solely angiotensin II for 48 hours as ATHOS-3 did. As aforementioned, because of refractory hypotension, we added norepinephrine and hydrocortisone to our regimen.^15–17 Finally, a prespecified analysis of ATHOS-3 showed that an angiotensin II dose of <5 ng/kg/min was more successful in meeting MAP goals and deescalation of other vasopressors as opposed to >5 ng/kg/min.¹⁸ In the current case, our patient consistently required >5 ng/kg/min. Additional case reports and reviews of the promising use of angiotensin II in vasodilatory shock have been documented elsewhere.^19–25

Our patient’s clinical course progressed very rapidly. We believe that his underlying T- ALL was the impetus of his death, as it is an infiltrative disease responsible for multiorgan failure.²⁶ Additionally, due to his immunocompromised state from hyper-CVAD therapy, he was more prone to infection and subsequent sepsis. Though there are studies that suggest angiotensin II can worsen cancer pathogenesis, it is highly unlikely that our patient expired from the vasopressor.^27–29 ATHOS-3 excluded patients with an absolute neutrophil count (ANC) of less than 1000 per cubic millimetre. When admitted, our patient had an ANC of 891. To the best of our knowledge, our case report is the first that describes angiotensin II effects in a neutropenic patient.

Learning points.

• Angiotensin II is a potent vasopressor, approved in the USA in 2017 for septic or other distributive shock.

• Neutropenic patients may benefit temporarily with angiotensin II for haemodynamic support.

• Angiotensin II offers another mechanism in achieving mean arterial pressure goals in septic shock without adding to the excess catecholamine burden with conventional vasopressors.