Arginine Vasopressin in Advanced Vasodilatory Shock A Prospective, Randomized, Controlled Study

1. Arginine Vasopressin in Advanced Vasodilatory Shock A Prospective, Randomized, Controlled Study Circulation. 2003;107:2313-2319.

2. Vasodilatory shock - siginificantly decreased systemic vascular resistance -> low arterial blood pressure • Sepsis, cardiopulmonary bypass가 필요한 cardiovascular surgery - most frequent cause (any origin of shock -> massive vasodilatation) • Adequate therapy 1) specific treatment of the underlying disease 2) volume resuscitation 3) use of vasopressor

3. Catecholamines - clinically used vasopressor agents of choice - supporting arterial blood pressure + ensuring adequate organ prefusion • Adrenergic hyposensitivity -> a feared complication • Progressively increasing catecholamine therapy -> catecholamine의 사용을 더욱 증가시키는 방향으로 상황을 악화시킬 수 있음 (major adverse side effects의 증가) • 이런 상황에서 mortality는 거의 100%에 가깝다 • 그러므로 catecholamine excess의 상황에서 cardiocirculatory function을 안정화 시킬 수 있는 vasopressor agents의 사용은 큰 이득이 됨

4. Arginine vasopressin (AVP) - potent endogenous vasopressor hormone of the neurohypophysis • Case reports and small clinical trials - continuous infusion of AVP can reverse hypotension in catecholamine-resistant vasodilatory shock • Unfortunately, little is known about possible adverse side effects of AVP used for this indication • In particular, gastrointestinal hypoperfusion (common complication of severe critical illness) may be aggravated by AVP

5. A prospective, randomized, controlled study to evaluate differences in hemodynamic response and organ functions in patients with advanced vasodilatory shock receiving either a combined infusion of AVP and norepinephrine(NE) or NE alone

6. Methods Patients • 48 critically ill patients suffering from vasodilatory shock (cardiovascular surgery, systemic inflammatory response syndrome, sepsis) • MAP < 70 mmHg despite adequate volume resuscitation • NE requirements exceeding 0.5 μg/kg/min • Invasively monitored

7. Fluid loading에 대한 stroke volume의 반응을 보면서 volume resuscitation을 시행 • 반복된 colloid 투여에도 stroke volume이 상승하지 않으면 normovolemia 인 것으로 가정 • Stroke volume이 최대일 때의 PCWP가 further volume resuscitation의 치료 목표치로 사용됨 • stroke volume index < 25 mL/min/m2 or cardiac index < 2 L/min/m2 -> milrinone infusion 시작 (0.3-0.6 μg/kg/min)

8. Study design

9. Study End Points 1) 48시간 동안의 두 군 간 hemodynamics 차이를 조사 2) single-organ function의 변화를 조사

10. Demograpahic data • ASA classification • Admission Dx • ICU에 입원한 후 처음 24시간 동안의 Simplified Acute Physiological Score Ⅱ • Worst clinical and laboratory data -> modified Goris Multiple Organ Dysfuction Syndrome Score를 계산 • Length of ICU stay • ICU mortality

11. Hemodynamics • Heart rate • MAP • Mean pulmonary arterial blood pressure • Pulmonary capillary wedge pressure • Cardiac and stroke volume indices • NE and milrinone requirements (before study entry and at 1, 12, 24, and 48 hours after study entry) • Systemic vascular resistance index • Left ventricular stroke work index (LVSWI) • Systemic oxygen transport index • Systemic oxygen consumption index

12. Incidence and types of new-onset tachyarrhythmias were monitored during the study • Tachyarrhythmias - non sinus rhythm with heart rates exceeding 100 bpm • Twelve-lead ECG examinations and serum troponin I determinations were performed to scan for myocardial ischemia or infarction

13. Single-Organ Functions • Gut mucosal PCO2 (PrCO2) + PrCO2 to arterial PCO2 gradient (Pr-aCO2) -> indicators of splanchnic perfusion • Arterial acid/base status + Arterial lactate concentrations • PaO2/FiO2 quotient • Serum concentrations of creatinine, aspartate aminotransferase, alanine aminotransferase, total bilirubin, and platelet count

14. Results

15. Hemodynamics

16. Significant difference in the incidence of new-onset tachyarrhythmias between groups - 2 of 24 patients (8.3%) receiving AVP -> new-onset tachycardic AF - 14 of 24 NE patients (54.3%) -> new-onset tachycardic AF • No differences in the incidence of myocardial ischemia and myocardial infarction between groups - 2 NE patients -> myocardial ischemia - 1 NE patient -> myocardial infarction • No differences in troponin I values between AVP and NE patients

17. Single-Organ Functions • One patient of the NE group died of total intestinal ischemia and necrosis during the study period

18. Discussion • Combined infusion of AVP and NE -> an effective vasopressor regimen to treat cardiocirculatory failure in patients with catecholamine-resistant vasodilatory shock (higher MAP, cardiac index, stroke volume index, and LVSWI and needed less vasopressor support)

19. AVP-induced intense constriction of peripheral resistance vessels -> significantly higher MAP • In arteriolar smooth muscle cells, stimulation of V1a-receptors -> an increase in cytoplasmatic ionized calcium -> vasoconstriction. • Unlike catecholamine-mediated vasoconstriction, vasopressor effects of AVP -> preserved during hypoxia and acidosis

20. In vasodilatory shock, AVP는 vasodilatation의 pathogenesis와 관련된 several mechanisms에 영향을 줌 1) blockage of ATP-activated potassium channels 2) attenuation of nitric oxide production 3) reversal of adrenergic receptor downregulation

21. Recent investigations에 의하면, patients with vasodilatory shock -> inadequately low AVP serum concentrations • Deficiency of endogenous AVP -> may contribute to loss of vascular tone 1) dysfunction of the baroreceptor reflex 2) inhibition of AVP production 3) depletion of AVP stores during sustained hypotension • Infusion of AVP -> reverse AVP deficiency restore endogenous vasopressor effects

22. Patients receiving AVP -> significantly better myocardial performance • Several mechanisms 1) significantly lower NE dosages (cardiotoxic and proarrhythmic effects) -> lower incidence of tachyarrhythmias 2) attenuate endotoxin- and interleukin-1β-stimulated generation of nitric oxide -> possibly reversing negative inotropic effects of cardiodepressant mediators 3) stimulation of V1a-receptors -> increases intracellular calcium in myocardial cells -> a direct positive inotropic response 4) increased systemic perfusion pressure and selective coronary vasodilatation -> increase myocardial blood flow

23. Significantly lower incidence of new-onset tachyarrhythmias <- significant reduction in NE dosages + improvement of myocardial blood flow • Gastrointestinal perfusion - significantly better - UGI bleeding에서나 catecholamine-resistant hypotension 시 AVP therapy가gastrointestinal blood flow를 현저히 감소시킬 수 있다는 보고와는 상반된 결과 • Bolus injections and high AVP dosages have been applied in these studies <-> AVP dosages in this protocol never exceeded 4U/h • In low dosages, AVP-mediated vasodilatation of the splanchnic vascular bed has been reported

24. Total bilirubin concentrations 증가 • Septic과 postcardiotomy shock에서 total bilirubin의 현저한 증가는 이미 보고되었지만, AVP로 인한 직접적인 hepatic dysfunction에 대해서는 보고된 적이 없음 • Possible mechanisms 1) AVP-mediated reduction in hepatic blood flow 2) direct impairment of hepatocellular function

25. Combined infusion of AVP and NE proved to be superior - Significantly higher blood pressure - Improved cardiac performance - Needed less NE - Reduce cardiotoxic effects of high catecholamine dosages (new-onset tachyarrhythmias) - Gastrointestinal perfusion seemed to be better preserved • 하지만 catecholamine-resistant vasodilatory shock 환자의 mortality와 morbidity에 대한 combined infusion regimen (AVP+NE) 의 장점을 조사하기 위해서는 larger study가 필요함