Literature Review for Vasopressin

Summary of Data for Vasopressin For Cardiac Arrest

Author	Design	Intervention	Comparison	Outcome
Lindner et al. (1997)	Prospective, randomized trial n=40 OHCA	Vasopressin (40 IU), one dose, followed by standard ACLS treatment	Standard ACLS treatment.	Survival to hospital admission: 70 vs. 35% (P = 0.06) and survival to hospital discharge: 40 vs. 15% in the intervention and control groups, respectively (P = NS)
Stiell et al. (2001)	Prospective, randomized trial n=200 IHCA	Vasopressin (40 mg) one dose, followed by standard ACLS treatment	Standard ACLS treatment	Survival to hospital discharge: 12 vs. 14% in the intervention and control groups, respectively (P = NS)
Wenzel et al. (2004)	Prospective, randomized trial n= 1219 OHCA	Two injections of 40 IU of vasopressin followed by additional treatment w/ adrenaline if needed	Standard ACLS treatment	ROSC: 25 vs. 28% (P =0.19) and survival to hospital admission: 36 vs. 31% (P=0.06) in the intervention and control groups, respectively
Grmec et al. 2006	Observational cohort study n= 109 OHCA	Vasopressin 40 IU x 1 after three doses of 1 mg epinephrine Vasopressin 40 IU as first-line therapy	Epineprhine 1 mg every 3 minutes	The rate of restoration of spontaneous circulation (ROSC) with hospital admission, and the 24-hour survival rate were significantly higher among patients in the vasopressin groups (P < 0.05)
Callaway et al. (2008)	Prospective, randomized trial n=325 OHCA	Vasopressin (40 IU), one dose, followed by standard ACLS treatment	One dose saline placebo in addition to standard ACLS treatment	ROSC: 31 vs. 30% and survival to hospital admission: 19 vs. 23% in the intervention and control groups, respectively (P = NS)
Gueugniaud et al. (2008)	Prospective, randomized trial n=2894 OHCA	Epinephrine (1 mg) and vasopressin (40 IU), maximum two doses, followed by standard ACLS treatment	1 mg adrenaline and saline placebo, maximum two doses, followed by standard ACLS treatment	ROSC: 28.6 vs. 29.5% and survival to hospital admission 20.7 vs. 21.3%; in the intervention group and control groups, respectively (P = NS)
Mentzelopoulos et al. (2009)	Prospective, randomized trial n=100 IHCA	Vasopressin (20 IU) + Epinephrine (1 mg) in repeated doses (maximum 5 cycles) + methylprednisolone (40 mg) on the first cycle. Additional adrenaline if needed. Post- resuscitation shock treated w/ hydrocortisone	Epinephrine (1 mg) + saline placebo for maximum five cycles. Saline placebo for patients w/ post- resuscitation shock	ROSC: 81 vs. 52% (P =0.003) and survival to hospital discharge 19 vs. 4% (P=0.02) in the intervention and control groups, respectively
Mukoyama et al. (2009)	Prospective, randomized trial n= 336 OHCA	Vasopressin (40 IU) repeated every 5– 10 min until cumulative dose of 160 IU	Epinephrine (1 mg), repeated every 5 –10 min until cumulative dose of 4 mg	ROSC: 28.7 vs. 26.6% and survival to hospital discharge 5.6 vs. 3.8% in the intervention and control groups, respectively (P = NS)
Carroll et al. (2012)	Prospective intervention vs. historical control group n= 30 IHCA	Vasopressin (0.8 mg/kg), one dose, followed by standard ACLS treatment	Historical control group (pediatric patients in the ICU that received at least two doses of vasopressor medication, but not vasopressin)	24-h survival: 80 vs. 30%, (P = 0.05) and survival to discharge: 60 vs. 25% (P = 0.07) in the intervention and control groups, respectively
Ong et al. (2012)	Prospective, randomized trial n= 727 OHCA	Vasopressin (40 IU), one dose, followed by standard ACLS treatment	Standard ACLS treatment	ROSC: 30 vs. 31% and survival to discharge: 2.3 vs. 2.9% in the intervention and control groups, respectively (P =NS)
Mentzelopoulos et al. (2013)	Prospective, randomized trial n=268 IHCA	Vasopressin (20 IU) + Epinephrine (1 mg) in repeated doses (maximum 5 cycles) + methylprednisolone (40 mg) on the first cycle. Additional adrenaline if needed. Post- resuscitation shock treated w/ hydrocortisone	Epinephrine (1 mg) + saline placebo for maximum five cycles. Saline placebo for patients w/ post- resuscitation shock	ROSC: 83.9 vs. 65.9% (P = 0.005) and neurologically favorable survival 13.9 vs. 5.1% (P =0.02) in the intervention and control groups, respectively
Turner et al. 2014	Prospective, randomized trial n=268 OHCA+IHCA	Vasopressin + Epinephrine	Epinephrine Alone	ROSC: 56% in the vasopressin plus epinephrine group vs 60% in the epinephrine alone group; P = 0.68; odds ratio [OR] = 0.83; 95% CI =0.37-1.85 Survival to hospital discharge did not differ significantly between groups (9% vs 5%; P = 0.46; OR = 1.88; 95% CI = 0.40-8.88). Patients in the vasopressin plus epinephrine group had a significantly higher rate of ROSC compared with patients in the epinephrine alone group (63% vs 37%; P = 0.01; OR = 0.16; 95% CI =0.04-0.69).

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Mentzelopoulos SD, et al. Vasopressin, steroids, and epinephrine and neurologically favorable survival after in-hospital cardiac arrest: a randomized clinical trial. JAMA. 2013

Design

• Randomized, double-blind, placebo-controlled,parallel-group trial
  • September 1, 2008, to October 1, 2010, in 3 Greek tertiary care centers (2400 beds) with 268 consecutive patients

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Primary Outcome

• ROSC for 20 minutes or longer (adjusted to Utstein style) and survival to hospital discharge with favorable neurological recovery (ie, Glasgow-Pittsburgh Cerebral PerformanceCategory [CPC] score of 1 or 2).

Secondary Outcomes

• Arterial pressure during and approximately 20minutes after CPR
• Arterial pressure and central venous oxygen saturation (ScvO2) during days 1 through 10 after randomization
• The number of organ failure–free days during days 1 through 60
• Potentially corticosteroid-associated complications
  • Hyperglycemia,infections, bleeding peptic ulcers, and paresis

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Intervention

• IV Arginine vasopressin 20 IU/CPR cycle upt to 5 cycles
  • IV Epinephrine 1 mg/CPR cycle
  • IV methylprednisolone sodium succinate IV
    • At 4hours after resuscitation, surviving patients in theVSE group with postresuscitation shock received stress-dose hydrocortison(300mg/d for ≤7 days and gradual taper)

Comparison

• IV Epinephrine 1 mg/CPR cycle

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Baseline Characteristics

Characteristic	Control Group (n = 138)	VSE Group (n = 130)
Age, mean (SD), y	62.8 (18.6)	63.2 (17.6)
Male sex, No. (%	88 (63.8)	95 (73.1)
Body mass index, mean (SD)a	25.4 (3.8)	25.8 (4.6)
Hospital stay before the arrest, median (IQR), d	2 (1-6)	5 (1-11)
Cardiovascular comorbidity, No. (%) -Hypertension -Coronary artery disease -Diabetes -Peripheral vascular disease -Cardiac arrhythmia -Valvular heart disease -Cardiac conduction disturbances	77 (55.8) 44 (31.9) 30 (21.7) 24 (17.4) 27 (19.6) 18 (13.0) 6 (4.3)	64 (49.2) 44 (33.8) 34 (26.2) 34 (26.2) 25 (19.2) 21 (16.2) 15 (11.5)
Noncardiovascular comorbidity, No. (%	77 (55.8)	74 (56.9)
Cause of cardiac arrest, No.(%) -Hypotension -Respiratory depression or failure -Myocardial ischemia/infarction -Metabolic -Life-threatening/lethal arrhythmia -Other	51 (37.0) 52 (37.7) 24 (17.4) 21 (15.2) 11 (8.0) 1 (0.7)	61 (46.9) 42 (32.3) 30 (23.1) 11 (8.5) 8 (6.2) 2 (1.5)

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Secondary Outcome Results

Outcome	VSE n [%]	Epinephrine	OR 95% CI	P-Value
ROSC for 20+ minutes	109/130 [83.9%]	91/138 [65.9%]	OR, 2.98 95% CI,1.39-6.40	P = .005
Survival to hospital discharge with favorable neurological recovery	18/130 [13.9%]	7/138 [5.1%]	OR, 3.28 95% CI, 1.17-9.20	P = .02

Secondary Outcome Results

• VSE patients had shorter ALS duration and higher mean arterial pressure during and after CPR compared to the control group.
• VSE patients had no difference in blood gas analysis during and after CPR compared to the control group.
• VSE patients had improved mean arterial pressure and ScvO2 during days 1 through 10 after randomization, compared to the control group
• VSE patients had significantly more neurologic, ventilator, and renal failure–free days, compared to the control group
• The incidence of complications and eventual causes of death among patients who survived >4 h were not significantly different between the two groups

Commentary

• Strengths
  • Multisite study
  • Randomized, double-blind, placebo-controlled, parallel-group trial
  • Readily available medications and ease of administration
  • Author confirms the results of previous study with same drug regimen
  • Vast amount of data during the post-resuscitation phase
• Limitations
  • Small Patient population
  • Lack of sample size analysis
  • Excluded patients that had a life expectancy of <6 weeks
  • Lack of endogenous vasopressin and cortisol levels to test hypothesis
  • In-Hopsital Cardiac arrest which has more favorable results compared to out-of-hospital cardiac arrest

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This is the first data to support that uses a pharmacological combination therapy with vasopressin, steroids, and epinephrine not only increases ROSC but discharge with good neurological outcomes. These results should be confirmed in a large multicenter, multinational randomized controlled trial prior to widespread adoption.