ABSTRACT
Objectives:
The influence of chronic liver disease (CLD) on emergent neurosurgical outcomes in patients with spontaneous intracerebral hemorrhage (ICH) remains unclear. CLD is usually associated with coagulopathy and thrombocytopenia, which contribute to a high rebleeding rate and poor prognosis after surgery. This study aimed to confirm the outcomes of spontaneous intracranial hemorrhage in patients with CLD after emergent neurosurgery.
Materials and Methods:
We reviewed the medical records of all patients with spontaneous ICH from February 2017 to February 2018 at the Buddhist Tzu Chi Hospital, Hualien, Taiwan. This study was approved by the Review Ethical Committee/Institutional Board Review of Hualien Buddhist Tzu Chi Hospital (IRB111-051-B). Patients with aneurysmal subarachnoid hemorrhage, tumors, arteriovenous malformations, and those younger than 18 years were excluded. Duplicate electrode medical records were also removed.
Results:
Among the 117 enrolled patients, 29 had CLD and 88 did not. There were no significant differences in essential characteristics, comorbidities, biochemical profile, Glasgow coma scale (GCS) score at admission, or ICH sites. The length of hospital stay (LOS) and length of intensive care unit stay (LOICUS) are significantly longer in the CLD group (LOS: 20.8 vs. 13.5 days, P = 0.012; LOICUS: 11 vs. 5 days, P = 0.007). There was no significant difference in the mortality rate between the groups (31.8% vs. 28.4%, P = 0.655). The Wilcoxon rank-sum test for liver and coagulation profiles between survivors and the deceased revealed significant differences in the international normalized ratio (P = 0.02), including low platelet counts (P = 0.03) between survivors and the deceased. A multivariate analysis of mortality found that every 1 mL increase in ICH at admission increased the mortality rate by 3.9%, and every reduction in GCS at admission increased the mortality rate by 30.7%. In our subgroup analysis, we found that the length of ICU stay and LOS are significantly longer in patients with CLD who underwent emergent neurosurgery: 17.7 ± 9.9 days versus 7.59 ± 6.68 days, P = 0.002, and 27.1 ± 7.3 days versus 16.36 ± 9.08 days, P = 0.003, respectively.
Conclusions:
From our study’s perspective, emergent neurosurgery is encouraged. However, there were more prolonged ICU and hospital stays. The mortality rate of patients with CLD who underwent emergent neurosurgery was not higher than that of patients without CLD.
KEYWORDS: Chronic liver disease, Emergent neurosurgery, Intracranial hemorrhage
INTRODUCTION
Spontaneous intracranial hemorrhage (ICH) accounts for approximately one-fifth of all types of stroke and is a major global health problem with different expressions worldwide but with a significant impact in different countries [1,2]. Evidence has shown that the presence of coagulopathy resulting from chronic liver diseases (CLDs), such as liver cirrhosis, alcoholic liver disease, and viral hepatitis, could theoretically predispose to bleeding and precipitate the severity of ICH [3-5]. Extensive lobar hemorrhages or hematomas may lead to life-threatening cerebral or brainstem herniation, which may require life-saving emergency surgical evacuation [6]. CLDs are well-documented as the primary mortality factors for trauma, laparotomy, and cardiothoracic surgery [7]; however, there is a lack of studies on the outcomes of emergent neurosurgical procedures. One retrospective study by Chen et al. found that patients with liver cirrhosis had rebleeding and mortality rates as high as 63.2% after emergent neurosurgery for traumatic brain injury [8]. However, a study of a population suffering from spontaneous ICH who underwent emergent neurosurgical procedures remains desired. Hence, our study focused on the emergent neurosurgical outcomes of spontaneous intracranial hemorrhage in patients with CLD to fill this knowledge gap.
MATERIALS AND METHODS
We reviewed the medical records of all patients with spontaneous ICH from February 2017 to February 2018 at the Buddhist Tzu Chi Hospital, Hualien, Taiwan. This study was approved by the Review Ethical Committee/Institutional Board Review of Hualien Buddhist Tzu Chi Hospital (IRB111-051-B). Patients with aneurysmal subarachnoid hemorrhage, tumors, arteriovenous malformations, and those younger than 18 years were excluded. We collected a database on each patient’s characteristics, including age, sex, biochemistry profile including aspartate aminotransferase, alanine aminotransferase (ALT), creatinine, bilirubin, albumin, prothrombin time, international normalized ratio (INR), platelet count, hepatitis B virus, and hepatitis C virus (HCV). The Glasgow coma scale (GCS) was used to evaluate neurological status and severity on admission. The ICH site was classified, and once ICH involved more than two regions, the location was determined as the location where the hematoma was largest on computed tomography. ICH volume was calculated based on the first CT scan using the following formula: volume = (A × B × C)/2 (cm3). A is the maximum diameter in centimeters, and B is another maximum diameter 90° angle to A in centimeters. C is the total number of 2.5-mm axial slices. The primary outcomes of this study were overall mortality and length of intensive care unit stay (LOICUS). The secondary outcomes were the length of hospital stay (LOS) and hematoma volume. Student’s t-test is used for the analysis of independent continuous variables and Chi-square test is used for the analysis of independent categorical variables. Wilcoxon rank-sum test is used for nonparametric statistics. All statistical calculations were performed using SPSS version 25.0, and statistical significance was set at P < 0.05.
RESULTS
Essential demographic characteristics [Table 1] among the 117 enrolled patients included the following: 29 patients had CLD and 88 patients did not and 96% of the CLD cases were diagnosed with hepatic viruses, 62% with hepatitis B, 24% with hepatitis C, and 10% with both. There were no significant differences in the baseline characteristics, comorbidities, coagulation profile at admission, or liver profile at admission. The most common ICH site was the putamen, followed by the thalamus, subcortex, and cerebellum, similar to CLD and non-CLD (P = 0.388). In addition, there was no statistically significant difference in the GCS score under 12 (P = 0.68), and the ICH volume in the CLD group was calculated as 28.64 ± 25.81 mL, compared with the non-CLD group calculated at 23.05 ± 21.11 mL, which was not statistically different (P = 0.478). Nevertheless, the LOS and LOICUS were significantly longer in the CLD group (LOS: 20.8 vs. 13.5 days, P = 0.012; LOICUS: 11 vs. 5 days, P = 0.007). There was no significant difference in the mortality rate between the groups (31.8% vs. 28.4%, P = 0.655). In search of predictors for mortality, we performed the Wilcoxon rank-sum test for the liver profile of ALT, coagulation profile of platelet counts, and INR between survival and death [Table 2] and logistic regression for age, sex, hypertension, diabetes mellitus, ICH volume at admission, and GCS at admission [Table 3]. We noted significant differences in the INR (P = 0.02) and low platelet counts (P = 0.03) between survivors and the deceased. Multivariate analysis of mortality found that every 1 mL increase in ICH at admission increased the mortality rate by 3.9%, and every reduction in GCS at admission increased the mortality rate by 30.7%.
Table 1.
Essential demographic characteristics (n=117)
| CLD (n=29) | Non-CLD (n=88) | P | |
|---|---|---|---|
| Age, medium (Q1-Q3) | 63 (47-79) | 65 (41-79) | 0.688 |
| Sex, male (%) | 14 (48.3) | 50 (56.8) | 0.423 |
| Comorbidity (%) | |||
| Hypertension | 20 (69.0) | 51 (57.6) | 0.292 |
| Diabetes mellitus | 4 (13.8) | 27 (30.7) | 0.074 |
| HBV | 18 (62.0) | 0 (0.0) | - |
| HCV | 7 (24.0) | 0 (0.0) | - |
| HBV + HCV | 3 (10.0) | 0 (0.0) | - |
| Other liver disease | 1 (4.0) | 0 (0.0) | - |
| GCS <12 at admission (%) | 17 (58.6) | 40 (45.6) | 0.68 |
| Coagulation profile at admission | |||
| Platelet count (103) | 201±15.4 | 197±8.9 | 0.83 |
| PT (s) | 14.2±1.90 | 11.6±0.46 | 0.072 |
| INR | 1.36±0.17 | 1.43±0.32 | 0.795 |
| Liver profile at admission | |||
| AST, units/L | 61.2±22.8 | 43.6±5.58 | 0.292 |
| ALT, units/L | 31.1±4.79 | 45.4±9.91 | 0.416 |
| Total bilirubin, mg/dL | 1.28±0.24 | 1.23±0.27 | 0.924 |
| ICH volume at admission (mL) | 28.64±25.81 | 23.05±21.11 | 0.478 |
| ICH site (%) | |||
| Putamen | 11 (29.3) | 26 (29.5) | 0.388 |
| Thalamus | 6 (20.7) | 13 (14.8) | |
| Subcortex | 4 (13.8) | 35 (39.8) | |
| Cerebellum | 0 (0.0) | 7 (8.0) | |
| Brainstem | 4 (13.8) | 5 (5.7) | |
| Intraventricular | 4 (13.8) | 2 (2.2) | |
| Length of ICU stay (day) | 11 | 5 | 0.007** |
| Length of hospital stay (day) | 20.8 | 13.5 | 0.012** |
| Mortality (%) | 7 (31.8) | 25 (28.4) | 0.655 |
**P<0.05 is considered statistically significant. ALT: Alanine aminotransferase, AST: Aspartate aminotransferase, CLD: Chronic liver disease, HBV: Hepatitis B virus, HCV: Hepatitis C virus, ICH: Intracranial hemorrhage, ICU: Intensive care unit, PT, Prothrombin time
Table 2.
Biochemistry profile between survivors and the deceased
| Survivor (n=86) | Deceased (n=31) | P | |
|---|---|---|---|
| ALT (Q1-Q3) | 24.5 (15-51.25) | 20 (13.5-40) | 0.42 |
| Platelet count (Q1-Q3) | 192.5 (154.5-239.25) | 199 (151.5-236) | 0.03** |
| INR (Q1-Q3) | 1.01 (0.98-1.05) | 1.03 (0.98-1.11) | 0.01** |
**P<0.05 is considered statistically significant. Wilcoxon rank-sum test is used for nonparametric statistics. ALT: Alanine aminotransferase, INR: International normalized ratio
Table 3.
Logistic regression for prediction of mortality
| Univariate | Multivariate | |||
|---|---|---|---|---|
|
|
|
|||
| OR (95% CI) | P | OR (95% CI) | P | |
| Age | 0.997 (0.966-1.029) | 0.834 | 0.969 (0.925-1.015) | 0.183 |
| Sex, male | 0.813 (0.322-2.05) | 0.661 | 0.548 (0.144-2.085) | 0.553 |
| HTN | 1.375 (0.512-3.691) | 0.527 | 1.249 (0.341-4.569) | 0.742 |
| DM | 1.899 (0.658-5.483) | 0.236 | 1.337 (0.328-5.446) | 0.692 |
| ICH volume at admission | 1.035 (1.012-1.059) | 0.003** | 1.039 (1.014-1.065) | 0.002** |
| GCS at admission | 0.709 (0.612-0.822) | <0.001** | 0.693 (0.567-0.847) | <0.001** |
**P<0.05 is considered statistically significant. CI: Confidence interval, DM: Diabetes mellitus, GCS: Glasgow coma scale, HTN: Hypertension, ICH: Intracranial hemorrhage, OR: Odds ratio
In our subgroup analysis of patients who underwent emergent neurosurgery [Table 4], we found that the length of ICU stay and LOS are significantly longer in patients with CLD who underwent emergent neurosurgery: 17.7 ± 9.9 days versus 7.59 ± 6.68 days, P = 0.002, and 27.1 ± 7.3 days versus 16.36 ± 9.08 days, P = 0.003, respectively. There was no significant difference between mortality rates; however, mortality rates in patients with CLD were three times lower than those in patients without CLD (10% vs. 36.2%, P = 0.132).
Table 4.
Patients underwent emergent neurosurgery (n=32)
| CLD (n=10) | Non-CLD (n=22) | P | |
|---|---|---|---|
| GCS on admission | 10.6±3.77 | 9.59±4.40 | 0.536 |
| Volume of ICH (mL) | 39.43±32.17 | 27.36±18.59 | 0.295 |
| Length of ICU stay (day) | 17.7±9.9 | 7.59±6.68 | 0.002** |
| Length of hospital stay (day) | 27.1±7.3 | 16.36±9.08 | 0.003** |
| Mortality (%) | 10 | 36.3 | 0.132 |
**P<0.05 is considered statistically significant. CLD: Chronic liver disease, GCS: Glasgow coma scale, ICH: Intracranial hemorrhage, ICU: Intensive care unit
DISCUSSION
Spontaneous ICH is life-threatening and sometimes overlooked due to the similarities of neurological deficits caused by hepatic encephalopathy [9]. Most cirrhotic patients who developed spontaneous ICH were sent to the emergency room for resuscitation and admitted to the neurosurgery wards for surgical intervention [7].
Neurosurgeons intuitively believe that patients with a history of CLD have a high risk of bleeding, which may be attributed to decreased platelet count and function, decreased levels of clotting factors, fibrinogen abnormality, and Vitamin K deficiency [8,10,11]. The most significant concern for emergent neurosurgery is whether the procedure causes secondary hemorrhage and worsens the patient’s outcome than nonperformance of the procedure [12]. Our preliminary study showed consistent results in that there were statistically significant differences in the INR (P = 0.02) and low platelet counts (P = 0.03) between survivors and deceased patients, which indicates that increasing values at admission correlate with higher mortality rates. Accordingly, platelet, Vitamin K, and fresh-frozen plasma transfusions are advised to decrease the risk of coagulopathy before surgery [13,14]. We hope that preoperative prophylactic management can reduce surgical complications and postoperative re-bleeding rates.
Patients with CLD have a longer ICU stay and length of hospital stay, regardless of whether they undergo emergent neurosurgery. In our hospital’s experience and published literature, difficulty in ventilator weaning and ventilator-associated pneumonia are reasons for extended intensive care unit stay [15]. Moreover, patients with alcoholic liver disease may have longer hospital stays because of alcohol withdrawal syndrome [16]. Previous studies [Table 5] reported a high mortality rate in patients with CLD who underwent emergent neurosurgical procedures [7,8,11]. Our study focuses on patients without a history of cancer, showing the least mortality rate. Moreover, we believe that we are the first study to compare the outcome of patients with and without the CLD who underwent emergent neurosurgery. There was no significant difference in the volume of ICH and GCS scores at admission and the overall mortality rate between patients with and without CLD. However, multivariate analysis of mortality found that every 1 mL increase in ICH at admission increased the mortality rate by 3.9%, and every reduction of GCS at admission increased the mortality rate by 30.7%. Paradoxically, in our subgroup analysis, we found that the mortality rate of patients with CLD who underwent emergency neurosurgery was three times lower than that of patients without CLD. Although there was no statistically significant difference, it may encourage neurosurgeons not to hesitate in the decision-making of life-saving neurosurgical procedures for patients with CLD.
Table 5.
Comparison of mortality rate with literature of emergent neurosurgery
| Author | Year | Patients (n) | Reason for surgery | Etiology of CLD | Mortality rate (%) |
|---|---|---|---|---|---|
| Huang et al. [11] | 2008 | 36 | SICH | Viral hepatitis alcoholic cirrhosis HCC | 47 |
| Chen et al. [8] | 2012 | 44 | SICH | Viral hepatitis alcoholic cirrhosis HCC | 22.7 |
| Chang et al. (This study) | 2022 | 32 | SICH | Viral hepatitis alcoholic cirrhosis | 10 |
CLD: Chronic liver disease, HCC: Hepatocellular carcinoma, SICH: Spontaneous intracranial hemorrhage
Limitation
This was a single-center study. We retrospectively collected information from electronic medical records. Hence, the study might underestimate the number of patients with CLD due to errors in ICD codes or misdiagnosis. In addition, our study was limited by the annual records and number of patients of interest.
CONCLUSION
From our study’s perspective, emergent neurosurgery is encouraged. However, there were more prolonged ICU and hospital stays. The mortality rate of patients with CLD who underwent emergent neurosurgery was not higher than that of the patients without CLD.
Financial support and sponsorship
This study is funded by the Buddhist Tzu Chi Medical Foundation, Hualien Tzu Chi Hospital, Hualien, Taiwan (TCMF-CWP-109-01).
Conflicts of interest
There are no conflicts of interest.
REFERENCES
- 1.Schmahmann JD. Vascular syndromes of the thalamus. Stroke. 2003;34:2264–78. doi: 10.1161/01.STR.0000087786.38997.9E. [DOI] [PubMed] [Google Scholar]
- 2.van Asch CJ, Luitse MJ, Rinkel GJ, van der Tweel I, Algra A, Klijn CJ. Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: A systematic review and meta-analysis. Lancet Neurol. 2010;9:167–76. doi: 10.1016/S1474-4422(09)70340-0. [DOI] [PubMed] [Google Scholar]
- 3.Parikh NS, Navi BB, Kumar S, Kamel H. Association between liver disease and intracranial hemorrhage. J Stroke Cerebrovasc Dis. 2016;25:543–8. doi: 10.1016/j.jstrokecerebrovasdis.2015.11.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Caldwell SH, Hoffman M, Lisman T, Macik BG, Northup PG, Reddy KR, et al. Coagulation disorders and hemostasis in liver disease: Pathophysiology and critical assessment of current management. Hepatology. 2006;44:1039–46. doi: 10.1002/hep.21303. [DOI] [PubMed] [Google Scholar]
- 5.Boehme AK, Esenwa C, Elkind MS. Stroke risk factors, genetics, and prevention. Circ Res. 2017;120:472–95. doi: 10.1161/CIRCRESAHA.116.308398. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.de Oliveira Manoel AL. Surgery for spontaneous intracerebral hemorrhage. Crit Care. 2020;24:45. doi: 10.1186/s13054-020-2749-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Chen CC, Huang YC, Yeh CN. Neurosurgical procedures in patients with liver cirrhosis: A review. World J Hepatol. 2015;7:2352–7. doi: 10.4254/wjh.v7.i21.2352. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Chen CC, Hsu PW, Lee ST, Chang CN, Wei KC, Wu CT, et al. Brain surgery in patients with liver cirrhosis. J Neurosurg. 2012;117:348–53. doi: 10.3171/2012.4.JNS111338. [DOI] [PubMed] [Google Scholar]
- 9.Ferenci P. Hepatic encephalopathy. Gastroenterol Rep (Oxf) 2017;5:138–47. doi: 10.1093/gastro/gox013. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Prelipcean CC, Fierbinteanu-Braticevici C, Drug VL, Lăcătuşu C, Mihai B, Mihai C. Liver cirrhosis-procoagulant stasis. Rev Med Chir Soc Med Nat Iasi. 2011;115:678–85. [PubMed] [Google Scholar]
- 11.Huang HH, Lin HH, Shih YL, Chen PJ, Chang WK, Chu HC, et al. Spontaneous intracranial hemorrhage in cirrhotic patients. Clin Neurol Neurosurg. 2008;110:253–8. doi: 10.1016/j.clineuro.2007.11.010. [DOI] [PubMed] [Google Scholar]
- 12.Mendoza-Avendaño M, Ramírez-Carvajal A, Barreto-Herrera I, Muñoz-Báez K, Ramos-Villegas Y, Shrivastava A, et al. Approach to emergent neurotrauma-related neurosurgical procedures in patients with hepatic disease. Indian J Neurotrauma. 2021;18:133–7. [Google Scholar]
- 13.Youssef WI, Salazar F, Dasarathy S, Beddow T, Mullen KD. Role of fresh frozen plasma infusion in correction of coagulopathy of chronic liver disease: A dual phase study. Am J Gastroenterol. 2003;98:1391–4. doi: 10.1111/j.1572-0241.2003.07467.x. [DOI] [PubMed] [Google Scholar]
- 14.Dezee KJ, Shimeall WT, Douglas KM, Shumway NM, O'malley PG. Treatment of excessive anticoagulation with phytonadione (vitamin K): A meta-analysis. Arch Intern Med. 2006;166:391–7. doi: 10.1001/.391. [DOI] [PubMed] [Google Scholar]
- 15.Wu D, Wu C, Zhang S, Zhong Y. Risk factors of ventilator-associated pneumonia in critically III patients. Front Pharmacol. 2019;10:482. doi: 10.3389/fphar.2019.00482. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.García ML, Blasco-Algora S, Fernández-Rodríguez CM. Alcohol liver disease: A review of current therapeutic approaches to achieve long-term abstinence. World J Gastroenterol. 2015;21:8516–26. doi: 10.3748/wjg.v21.i28.8516. [DOI] [PMC free article] [PubMed] [Google Scholar]