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Changes in vasopressin use and outcomes in Surgical Intensive Care Unit patients with septic shock
M.I. Lupei, G.J. Beilman, J.G. Chipman, H.J. Mann (Chirurgia, 104 (5): 575-581)

* The results of the study have been presented as a poster at the Chest 2007 annual meeting and published as an abstract in a supplement of Chest Journal.

Vasopressin has become a popular treatment for septic shock, a life-threatening syndrome with a high mortality rate (28-50%) (1,2,3). Treatment of septic shock includes fluid resuscitation, antibiotics, source control, vasopressors, and blood transfusion as needed (4,5). The approach to treatment has notably changed since vasopressin entered into the septic shock arsenal one decade ago (6). Over that time, high doses of vasopressin titrated to blood pressure have trended towards lower and fixed dosages (7). Current guidelines recommend considering vasopressin in patients with refractory shock5. Vasopressin might be superior to norepinephrine alone in less severe septic shock (8).
Hypotension and shock stimulate vasopressin release which declines during the next 96 hours to physiologic, but inappropriately low levels (9). Vasopressin levels at 24 hours were inversely correlated to male sex, admission diagnosis, length of intensive care stay, but not to the incidence of shock (10). The propensity for septic shock may be predicted by the norepinephrine/vasopressin plasma ratio measured early in the disease course (11). Vasopressin treatment improves blood pressure and allows a reduction or discontinuation of adrenergic agents (12,13,14). Vasopressin treatment may also improve urine output and creatinine clearance (7,13). Adverse effects reported with vasopressin include diminished cardiac output, liver function, serum sodium level, platelet count and hepatosplanchnic circulation (13,14).
The purpose of this study is to compare the recent use of vasopressin to our early practice and to assess the benefit and the adverse events related to vasopressin treatment and their impact on survival. The primary end-point was 28-day survival.

Materials and Methods
Setting and study population
The study was conducted in the adult 20 bed Surgical Intensive Care Unit (SICU) of the University of Minnesota Medical Center, Fairview. Patients receiving vasopressin infusion for septic shock were included in the study group. Patients treated between July 2005 and June 2006 were compared to those treated between January 1999 and July 2000 Sepsis and septic shock were defined in conformity with American College of Chest Physicians and Society of Critical Care criteria (15). Patients younger than 18 years, receiving vasopressin for less than an hour, being diagnosed with cardiovascular diseases or having incomplete medical records were excluded from review. Patients with cardio-vascular diseases were excluded in order to minimize the bias of depleted hemodynamic response to vasopressors in these patients. Most of the studies published included cardiovascular patients. We intended to assess the hemo-dynamic response to vasopressin in a septic shock patient population with no history of cardiovascular disease.
Study design
This study is a retrospective, observational, drug utilization chart review of two cohorts separated by 5-7 years. The protocol was approved by the University of Minnesota Institutional Review Board with waiver of informed consent for both included time periods.
Data Collection
The patients were identified through the pharmacy registry and data were abstracted from the electronic and hard copy medical records of both groups. Information included demographic data (age, weight, length of stay in intensive care unit, Surgical Intensive Care Unit and 28-day survival rate), severity of illness score (APACHE II), hemodynamic data (heart rate, mean arterial pressure, systolic blood pressure, diastolic blood pressure, central venous pressure, cardiac output, pulmonary capillary wedge pressure, mean pulmonary artery pressure) and vasoactive drug regimens (drugs, doses, total duration of infusion).
Acute Physiology and Chronic Health Evaluation II (APACHE II) was calculated using information collected during the 24 hours prior to vasopressin infusion. Hemo-dynamic data was summarized from: an average of 4 measurements (-1, -0.75, -0.5, -0.25 hour) for the baseline; of 4 values (0.25, 0.5, 0.75, 1 hour) for the first hour; of 5 measurements (2,4,8,12,24 hours) for the 24 hours; and for end-point infusion, either the value measured at the end of vasopressin treatment if infusion < 24 hours or an average of 5 values recorded between 24 hours and the discontinuation of vasopressin infusion if duration was longer than 24 hours. If hemodynamic data for a time point was not available, an average from the remaining time points in the interval was calculated. Vasoactive drug doses were recorded at the same time points as hemodynamic data.
Data regarding the effect of vasopressin treatment on creatinine clearance, urine output, serum lactate, central venous oxygen saturation (ScVO2), and the occurrence of adverse events reported in the literature as being related to vasopressin treatment (platelet count, INR, bilirubin, transaminase alterations) were recorded for the patients in the 05-06 cohort. The worst value of each parameter in the 24 hours prior to vasopressin treatment and 24 hours after discontinuation of infusion was used. Additional recommended treatments (5) for sepsis administered concomitant with vasopressin infusion were recorded as dichotomous variables (1 if present, 0 if not) for each treatment. These were recorded regardless of the indications or contraindications and included achieving average glycemia <150 mg/dl during vasopressin infusion, administration of low dose corticosteroids, recombinant human activated protein C treatment, and mechanical ventilation with a mean plateau pressure limit of 30 mmHg.
Data are presented as mean ± SD, or percentage, unless otherwise indicated. Continuous variables were compared with the general linear model for repeated measures, paired samples t-test within groups at different time-points, and independent samples t-test between groups when appropriate (2-tailed test). Categorical variables were analyzed with the chi-square nonparametric test. The significant covariates influencing survival were determined through Cox regression analysis. A p value < 0.05 was considered significant for all tests. Statistical analysis was performed using SPSS V14.

Figure 1
Figure 2

A total of 51 patients met study criteria, with 31 patients (21 males and 10 females) in the 05-06 cohort and 20 patients (13 males and 7 females) in the 99-00 cohort. Table 1 and Fig. 1 summarize the patient characteristics of the study population. The APACHE II score was significantly different between groups (Table 1). The vasopressin dose was significantly lower in the 05-06 cohort versus the 99-00 cohort (2.2 ± 1.4 units/hr versus 5.3 ± 6.7 units/hr, p= 0.007) and the intensive care survival rate was significantly higher in the 05-06 cohort (45% versus 15% in the 99-00 cohort, p=0.002) (Fig. 1). By Cox regression analysis the survival function adjusted for APACHE II was significantly different between groups (p = 0.005) (Fig. 2).
Table 2 summarizes the vasoactive drug regimen administered. The number and dosages of other vasoactive drugs did not change with vasopressin infusion in the 05-06 cohort. In the 99-00 cohort only the dose of dopamine significantly decreased within the 24 hours and at the end point of vasopressin infusion (p<0.05). Vasopressin and dopamine dosages were significantly reduced in the 05-06 cohort as compared to the 99-00 cohort (Table 2). Vasopressin was the only vaso-active substance administered in 4 patients in the 05-06 cohort, while in the 99-00 cohort vasopressin was given with another vasoactive drug in all patients.
The mean arterial pressure (MAP) was significantly augmented due to increased systolic blood pressure (SBP) and diastolic blood pressure (DBP) at all time categories compared to baseline in both cohorts. In the 05-06 cohort, MAP increased by 9% within the first hour of vasopressin treatment, 13% within the first 24 hours and 18 % at the end point of infusion (p<0.01), while heart rate (HR) decreased significantly after one hour of vasopressin treatment (by 9% within the first 24 hours and by 15% at the endpoint of infusion) (p<0.01). In the 99-00 cohort MAP increased by 12% in the first hour, 11% within 24 hours and 13% at the end point of infusion (p<0.05). Central venous pressure (CVP), cardiac output (CO), pulmonary capillary wedge pressure (PCWP), and mean arterial pulmonary pressure (MPAP) were not altered during vasopressin administration.
Regarding the adverse events related to vasopressin administration reported in literature, the analysis of the 05-06 cohort revealed that platelet count diminished significantly after vasopressin infusion, but bilirubin, transaminase levels, INR, and serum sodium were not altered (Table 3). Serum lactate level and central venous oxygen saturation did not vary during vaopressin infusion. Neither urine output nor creatinine clearance was improved with vasopressin treatment.
Increased APACHE II, decreased platelet count repeatedly measured during the treatment, decreased creatinine clearance, elevated lactate level and INR values following vasopressin infusion were covariates significantly associated with decreased survival in the 05-06 cohort (p<0.05) (Table 4). Central venous oxygen saturation, urine output, bilirubin, and transaminase levels measured before and after vasopressin infusion did not significantly impact survival in the 05-06 cohort nor did specific sepsis treatments such as tight glycemic control, drotrecogin alpha, and shock doses of corticosteroids.

This retrospective analysis detected a notable change in clinical practice: vasopressin is recently used in more patients with less severe septic shock and in lower dosages than when it was first suggested for treatment of hypotension associated with septic shock. Patients recently treated with vasopressin have a higher survival rate than 8-10 years ago and the vaso-active drug regimens employed over this time frame have changed. Vasopressin administration was followed by a significant MAP elevation in both groups and HR decrease in the 05-06 cohort. Of the parameters reported in literature as being influenced by vasopressin infusion (urine output, cardiac output, liver function, and platelet count), only platelets were significantly reduced after vasopressin administration in our patients. Platelet count prior to and after vasopressin infusion, APACHE II, creatinine clearance, lactate level and INR measured after vasopressin treatment significantly influenced survival.
This is the first study comparing the recent vasopressin use with vasopressin treatment when it was first suggested for the treatment of septic shock. The patients in the 99-00 cohort had significantly higher APACHE II score as compared to the 05-06 cohort. Although studies have reported various severity of illness scores in patients treated with vasopressin treatment for septic shock, there is a trend towards using vasopressin for septic shock in patients with less severe illness over the years (1998-2004) (16,17, 18,19,20). We adjusted only for APACHE II in order to compare survival rates, because other variables that may be confounders are actually used for this severity score calculation. We did not introduce Surviving Sepsis Campaign5 treatment recommendations (tight glycemic control, drotrecogin alpha, shock doses of corticosteroids) in our model considering that in 1999-2000 those recommendations were not released.
The multicenter, randomized trial (VASST study) comparing the outcomes of vasopressin versus norepinephrine treatment in septic shock revealed that vasopressin infusion might be beneficial in patients with less severe septic shock (requiring norepinephrine < 15 µg/min) (8). While the VASST trial was still enrolling patients, our practice already employed to add vasopressin to lower catecholamine doses. The vasopressin, norepinephrine and dopamine doses used recently are lower than 8-10 years ago. This regimen change might be related to the lower severity of illness score in the 05-06 cohort. In our patients the use of vasopressin did not spare the use of other vasoactive agents as reported in literature (6,16,17,18,19). This result might be a consequence of our lower norepinephrine dosage practice compared to other published studies (16,18,21). We also primarily use dopamine as an inotrope, and vasopressin use usually spares the vasopressor effect.
Most published studies showed that vasopressin infusion increases the MAP, but has minimal hemodynamic effect in healthy subjects (7,14,22). The MAP increase mechanisms are various: V1 receptor mediated vasoconstriction, antidiuretic effect via kidney V2 receptor, and corticotropin secretion through pituitary V3 receptor (7,22,23). Vasopressin may enhance the sensitivity of vasculature to adrenergic agents (24). Some publications stated that vasopressin reduces cardiac index (CI) and/or heart rate (HR) (16,17,18,19). The HR and CI might be reduced through the baroreflex control of the heart (25) and peripheral tissue oxygenation (17) or could be related to the vasopressin induced coronary-constriction in high doses (26). We attributed the HR reduction in our 05-06 cohort to the MAP normalization through the baroreflex control of the heart.
Cardiac output did not vary in our study in conformity with a neutral inotropic effect associated with low vasopressin doses (21). PCWP and CVP remained constant during vasopressin administration consistent with other published studies. One retrospective analysis showed that mean pulmonary arterial pressure (MPAP) diminishes with vasopressin treatment16, but most of the human studies found no change with vasopressin infusion in contrast to results from animal studies (27). Our analysis did not show any MPAP alteration in the 05-06 cohort (11 patients).
Some studies reported increased urine output and creatinine clearance with vasopressin treatment (20, 21). Despite the antidiuretic effect mediated by V2 receptors, vasopressin manifests a diuretic effect attributable either to greater efferent arteriole vasoconstriction (28) or down regulation of the V2 receptors (29). Our study revealed no change of urine output in the 05-06 cohort, which might be affected by the high percentage of anuric or oliguric patients (47%) (30). Various studies revealed reduced liver function and platelet count with vasopressin (16,31,32). The liver dysfunction might be a consequence of potent vasopressin gastrointestinal vasoconstriction or hypotensive hepatic injury. The 05-06 cohort laboratory data revealed no liver marker changes with vasopressin administration. The decrease in platelets could be attributed to the septic shock or increased platelet aggregation as in previous studies (31,33). Thrombocytes aggregation is mediated by platelet V1 receptors (34,35) and Von Willebrand factor (36,37).
Decreased creatinine clearance, increased INR, and lactate levels after vasopressin infusion were covariates significantly associated with decreased survival, but not the values assessed before treatment (Table 4). These mean parameters did not significantly vary with vasopressin use (Table 3). While with the t-test the mean values are compared, with Cox regression analysis individual values of each parameter are taken into consideration. We hypothesize that the individual’s creatinine clearance, INR and lactate levels following vasopressin infusion may differentiate each patient’s response to septic shock treatment.
Study limitations include the retrospective evaluation and small sample size that is limited to SICU patients. The potential vasopressin adverse events were not recorded 8-10 years ago, so the effect of current dosing could not be compared. Study strengths include our practice analysis in two different time frames which allowed assessing the change in clinical practice and the ability to assess the impact of several covariates on survival. Despite Surviving Sepsis Campaign recommendations to use vasopressin as a last resort (5), our clinical practice review found that vasopressin was added to lower catecholamine doses and is sometimes used as unique vasopressor therapy. Our change in clinical practice revealed that our practitioners were already using what VASST study demonstrated concomitantly in a large trial.
In conclusion, vasopressin therapy is used in less severe septic shock and at a lower dosage then 8-10 years ago. Vasopressin therapy is added to the treatment of septic shock when doses of other catecholamines are lower as compared to our early practice. The lower dosages are effective in restoring MAP. The recently used vasoactive regimen is not associated with frequent adverse events. Patients treated with vasopressin in the recent years have a higher survival rate than those receiving vasopressin for septic shock in our early practice.

Institution of scientific work
University of Minnesota Medical Center, Fairview Surgical Intensive Care Unit.

Conflict of interest statement
No financial or other potential conflict of interest exists.

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