High-Dose Norepinephrine Treatment: Determinants of Mortality and Futility in Critically Ill Patients

Abstract

Background Critically ill patients with circulatory shock sometimes need rescue treatment with high doses of norepinephrine, a treatment that may be associated with a poor outcome because of excessive vasoconstriction. Objective To evaluate the outcome of treatment and its determinants in patients with circulatory shock who received high doses of norepinephrine in the intensive care unit and to identify indicators of futility for the treatment. Methods A retrospective study was done on 113 consecutive patients with circulatory shock who received 0.9 µg/kg per minute or greater of norepinephrine during at least 1 hour at any time in the intensive care unit. Data were extracted from the electronic patient data management system according to a predefined checklist. Results A total of 39 patients survived for 28 days after admission to the intensive care unit. The variables independently associated with 28-day mortality in multivariable models included low urine flow, high lactate levels, high organ failure score, high prothrombin time, and need for epinephrine cotreatment. The reason, dose, and duration of norepinephrine administration did not have prognostic significance. Scores greater than 40 on the Acute Physiology and Chronic Health Evaluation II, bicarbonate levels less than 9.0 mEq/L, or receipt of an epinephrine dose of 0.25 µg/kg per minute or greater were associated with 100% mortality. Conclusions Although the cause of shock and treatment with norepinephrine were not predictive of death when high doses of the drug were deemed necessary, rescue treatment with high-dose norepinephrine is futile in patients with severe disease and metabolic acidemia. (American Journal of Critical Care. 2013;22:22-32) HIGH-DOSE 1,2,5,6,9,10,13,15-18 A maximum tolerable dose has not been determined, even though excessive dosing is associated with a risk for extreme vasoconstriction, tissue hypoperfusion, and increased mortality. Consequently, many intensivists do not use doses greater than 100 µg/min or 1.2 µg/kg per minute. 2,5,8,[17][18][19][20][21][22][23] Indeed, use of high doses may be futile (ie, associated with 100% mortality), as reported previously, [17][18][19]21 but currently the indicators for futility of this rescue treatment are unknown. They may vary according to underlying disease, causes of shock, and other factors. Abid et al 19 found that a score greater than 12 on the Sequential Organ Failure Assessment (SOFA) was associated with 100% mortality during (delayed) norepinephrine treatment for shock. Lactate levels may be confounded by the β-adrenergic effects of catecholamines, thereby potentially making the well-known prognostic value of the drugs in shock less helpful during treatment with norepinephrine, which has both α-and β-adrenergic properties. 1,3,5,10,13,23,24 The purpose of our study was to evaluate the outcome of ICU patients who received doses of norepinephrine of 0.9 µg/kg per minute or greater C ritically ill patients in the intensive care unit (ICU) may die of circulatory shock or its se...

Insights and Advances in Multidisciplinary Critical Care: A Review of Recent Research

“…In acute situations, high doses may be necessary as rescue therapy, with the norepinephrine thereby becoming a risk in itself. Independent risk factors for mortality, including norepinephrine dose, were investigated in a retrospective study 3 of 113 patients with circulatory shock treated with at least 0.9 μg/kg per minute. In a multivariable model, the reason, dose, and duration of treatment with norepinephrine were not associated with fatal outcome.…”

Should the norepinephrine maximal dosage rate be greatly increased in late shock?

“…APACHE-II scores of >40, HCO 3 levels <9 mmol/L and epinephrine co-treatment at >0.25 μg/kg/min were associated with 100% 28-day mortality. Other prognostic factors included oliguria, lactate level and prothrombin time 2. In another cohort, an NA flow >3.8 μg/kg/min resulted in 100% mortality (17 of 17 patients) 7.…”

“…The principle of ‘do no harm’ needs to be balanced against the need to rescue blood pressure that would otherwise collapse instantly. The maximal NA dose is not incontrovertibly defined 2 4. Remarkably, the drug information source notes that patients in septic shock may require higher doses.…”

“…In our review, the highest NA flow rate that has been reported in trials in adults is 3 μg/kg/min; yet the highest ‘typical’ value in prescription information is approximately 1 μg/kg/min. Indeed, the drug dosage sections of two of the most widely accessed medical resources worldwide include the following information: (1) “Indication, hypotension, acute dose [weight-based dosing]: 0.02–1 μg/kg/min IV […]; Info: pts w/septic shock may require higher doses.” (Epocrates); and (2) “Sepsis and septic shock (weight-based dosing): Range from clinical trials: 0.01–3 μg/kg/min (Hollenberg, 2004)[…]” (Up To Date) 2 3. The evidence, criteria and reasoning for withholding further escalation of the dose (when the blood pressure continues to respond to increases in NA flow) are poorly described,4 and the relevant clinical data guiding practice are weak.…”

Combining an antiviral with rituximab in EBV-related haemophagocytic lymphohistiocytosis led to rapid viral clearance; and a comprehensive review

“…The shock was treated as septic, and the rate of norepinephrine that was required to maintain a mean arterial pressure >60 mm Hg was exceeded by several times the maximal dosage rate studied in trials10 11 and the maximum reported in the literature, except for one case 12. Inotropes and vasopressors were weaned by the following day.…”