Effect of HUK on the outcome of ruptured intracranial aneurysm

Abstract Objective To evaluate the clinical efficacy of Human Urinary Kallidinogenase (HUK) on the outcome of patients with ruptured intracranial aneurysm. Methods This was a prospective, open‐label study. At the Department of Neurosurgery in our hospital, 127 patients were treated and operated due to ruptured intracranial aneurysm in the period 2015–2016. After surgery, all the patients received basic treatment and 70 patients received additional HUK treatment (HUK group) according to their willing. In detail, 0.15 PNA unit of HUK injection plus 100 ml saline in intravenous infusion was performed, with once a day for 14 consecutive days. The modified Rankin Scale (mRS) scores and favorable mRS rates (mRS 0–1) were analyzed 3‐month after the treatment. Results No difference was shown in the basic characteristics between the two groups (p > 0.05). Favorable mRS rate in the HUK group (71.43%) was significantly higher than that in control group (50.88%, p < 0.05). In addition, 3‐month death rate was significantly lower in the HUK group. Delayed ischemic stroke rate was similar between the two groups. Conclusion HUK can reduce morbidity and mortality of patients with ruptured intracranial aneurysm after surgery.


| INTRODUC TI ON
Intracranial aneurysm is still a challenging health problem. Of all cerebrovascular accidents, it ranks the third, just behind ischemic stroke and hypertensive intracerebral hemorrhage. The incidence varies widely among populations; with an overall incidence about 9-20 per 100,000 (Steiner et al., 2013). 30-day mortality rate with conservative treatment is over 40% (Korja et al., 2013). About onethird of patients left with an untreated aneurysm will die from recurrent bleeding within 6 months after recovering from the first bleeding (Lantigua et al., 2015;Pakarinen, 1967;Phillips, Whisnant, O'Fallon, & Sundt, 1980). Vasospasm, hydrocephalus, delayed ischemic deficit and other complications occur in a short or long time after intracranial aneurysm rupture will make the prognosis worse.
Human Urinary Kallidinogenase (HUK) is a glycoprotein extracted from urine of healthy men and has been widely used in the acute ischemic stroke. Numerous clinical trials have proved its efficacy (Zhang, Tao, Liu, & Wang, 2012) and have revealed that it can selectively dilate arterioles in the ischemic area, enhance angiogenesis and neurogenesis, increase regional cerebral blood flow, inhibit apoptosis and inflammation, promote glial cell migration, and improve neurological deficits after acute ischemic stroke (Ling

| Study design
This was a single-center, prospective, open-label study. Patients' baseline characteristics were obtained from our database system, and patients were divided into two groups according to the treatment they decided to receive: 70 cases in the HUK group and 57 cases in the control group. Baseline characteristics included gender, age, comorbidities, size of ruptured aneurysm, aneurysm location, Hunt-Hess scale score on admission and surgical methods. mRS scores and mortality rates at 3 months were obtained by telephone follow-up. Patients' baseline characteristics, favorable mRS score rate (mRS score 0-1), and 3-month mortality rate were also compared.

| Statistical analysis
Categorical variables were reported as number or percentage; continuous variables fitting the normal distribution were expressed as mean ± standard deviation (SD), whereas median (1st to 3rd quartile, interquartile ratio) was used for nonfitting variables.

| Baseline characteristics of all the patients
We finally included 79 patients in HUK group and 58 patients in control group. There were 28 males and 51 females in the HUK group, with an average age at 53.97 ± 10.35 years old. The mean value of preoperative SBP is 142.81 ± 24.25, and preoperative DBP is 88.18 ± 14.56. Among them, 30 cases (37.97%) had hypertension, one case had previous subarachnoid hemorrhage and one case had diabetes mellitus. 70 patients had ruptured aneurysm, two cases had cerebral infarct. The mean maximum size of aneurysm was 5.73 ± 2.78 mm. In the control group, there were 28 males and 30 females with an average age at 52.32 ± 10.49 years old. 30 (51.72%) cases with hypertension, two cases had previous subarachnoid hemorrhage and one case had diabetes mellitus and mean maximum size of aneurysm was 5.24 ± 2.37 mm. The mean value of preoperative SBP is 143.17 ± 20.88, and preoperative DBP is 87.78 ± 14.11. 57 patients had ruptured aneurysm, two cases had cerebral infarct. We found no significant differences in age (p = 0.361), gender (p = 0.131), hypertension (p = 0.109), SAH history (p = 0.574), mean maximum size of aneurysm (p = 0.318). All the baseline clinical and demographic characteristics of participants were presented in Table 1. Aneurysm variables in ruptured participants and Hunt-Hess scale score on admission were presented in Table 2 and Table 3.

| Outcomes and safety of HUK
In this study, 50 patients in the HUK group (71.43%) and 29 patients in the control group (50.88%) got favorable mRS score (mRS score 0-1), patients in HUK group had a higher ratio of good outcomes (p = 0.018). Four patients (7.02%) died within 3 month in the control group while no patient died in the HUK group,the mortality of HUK group was significant lower than that of control group (p < 0.0001).
However, no statistically significant difference was found between the two groups in delayed ischemic stroke, with one patient in the HUK group (1.43%) and two patients in the control group (3.51%) respectively (Table 4, p > 0.05). In addition, no adverse effect was reported in the HUK group.

As a state category I new drug approved by China's State Food
and Drug Administration (CFDA), HUK has been widely used for acute ischemic stroke treatment in China with 87% efficacy rate (Emanuelia & Madeddu, 2003). Clinical researches showed that HUK could improve patients' neurological deficits effectively and safely after acute ischemic stroke (Ding et al., 2007). HUK involves in many physiological and pathological functions, however, whether it can improve the prognosis of patients with ruptured intracranial aneurysm has not been studied. Our study found that HUK promoted good recovery in ruptured intracranial aneurysm, suggesting that HUK had the potential of regulating inflammation, coagulation and vasospasm in these patients.  Juvela & Siironen, 2006;Juvela, Siironen, & Kuhmonen, 2005;Lanzino et al., 1993). Hyperglycemia results in an increase in nuclear factor κB (NF-κB) binding, which leads to increased production of inflammatory cytokines and chemokines, such as tumor necrosis factor (TNF) and monocyte chemoattractant protein (MCP-1) (Dhindsa et al., 2004). Zhao and his colleagues (Zhao et al., 2003) found that a continuous supply of kallikrein (kinin in vivo) can suppress oxidative stress, thus protecting the cardiovascular, renal and central nervous systems against hypertension and associated type 2 diabetes. On the other hand, using of thromboprophylaxis in ruptured intracranial aneurysm is challenging because of the risk of rebleeding. The kallikrein-kinin system not only takes part in coagulation, it also promotes fibrinolysis (Moreau et al., 2005). Thus, conduction of HUK may regulate coagulation and fibrinolysis after intracranial aneurysm rupture.
Although did not reach a statistical difference, our study showed an extremely low rate of delayed ischemic stroke in aneurysm rupture patients (1.43%) 3-month after surgery, indicating the possible mechanism of the good clinical efficacy of HUK.
No side effect of hypotension, the most common adverse event of HUK, was reported in the HUK group, which proved the safety of HUK in the application of aneurysm rupture patients.
HUK could reduce morbidity and mortality of patients with ruptured intracranial aneurysm. Inflammation and coagulation regulation, glucose metabolism improvement and selective arterioles dilation might be it potential mechanism.

| CON CLUS ION
HUK successfully reduce 3-month morbidity and mortality of patients with ruptured intracranial aneurysm.

CO N FLI C T O F I NTE R E S T
There is no conflict of interest in this research.