High Neutrophil-To-Albumin Ratio Predicts Postoperative Pneumonia in Aneurysmal Subarachnoid Hemorrhage

doi:10.21203/rs.3.rs-926465/v1

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High Neutrophil-To-Albumin Ratio Predicts Postoperative Pneumonia in Aneurysmal Subarachnoid Hemorrhage

https://doi.org/10.21203/rs.3.rs-926465/v1

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published 07 Apr, 2022

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Background & Aim

: Although there are a variety of risk factors for postoperative pneumonia (POP) in patients with aneurysmal subarachnoid hemorrhage (aSAH), objective and easily accessible biomarkers are still lacking. In this study, we evaluated the relationship between the neutrophil-to-albumin ratio (NAR) and POP in patients with aSAH.

Methods

We retrospectively assessed 395 consecutive patients who underwent clipping or coiling of the aneurysm, analyzed the existing population data and baseline variables of these patients. Patients were divided into POP and did not occur. The recipient operation feature (ROC) curve and logic regression analysis are used to identify independent predictors.

Results

Among the 395 patients, POP occurred in 78(19.7%) in this cohort. Patients with POP had significantly higher NAR than those without (0.31[0.25–0.39] vs 0.23[0.18–0.28]; P < 0.001). Multivariate logistic regression analysis showed that NAR (odds ratio = 2.94; 95% confidence interval, 1.141–7.574; P = 0.026) on admission was independently associated with POP after adjusting for confounders. Besides, the predictive performances of NAR for POP was significantly (AUC [95% CI] 0.775 [0.717–0.832]; P < 0.001).

Conclusions

NAR elevation at admission might be informative for predicting POP in patients with aSAH.

Neurosurgery

Neurology

aneurysm subarachnoid hemorrhage

inflammation

pneumonia

neutrophil

albumin

Aneurysmal subarachnoid hemorrhage (aSAH) represents a devastating and life-threatening type of hemorrhagic stroke.[10, 11, 14] Despite the advancements in the current treatment of intracranial aneurysms, including microsurgery and endovascular coil embolization, both disability and mortality rate of aSAH remain high.[1, 17, 35]

Among patients with aSAH were often accompanied by vasospasm and other non-neurologic complications, including postoperative pneumonia (POP), CVC-associated infections, urinary tract infection and others.[4] Studies have shown that up to 13–37% of patients with aSAH may be impacted POP after surgical treatment.[4, 23, 24] Thus, the current researches are now directed toward finding early risk factors for POP, which might help to identify high-risk patients for aggressive monitoring and therapeutic interventions.

Numerous risk factors of POP have been identified,most of them are based on clinical features including age, aSAH severity, ventilator use, etc.[4, 15, 33] In particular, biomarkers of inflammation has recently gained interest during the last years, such as the neutrophil-to-lymphocyte ratio (NLR).[2] Plenty of evidences have indicated that, as an potential biomarker of inflammation, Neutrophil-to-albumin ratio (NAR) is an independent risk factor for cancers, sepsis, in-stent restenosis undergoing carotid angioplasty and stenting, ST-segment elevation myocardial infarction (STEMI).[3, 12, 25, 30] The mechanistic link between NAR and aSAH, however, remains unstudied. Thus, in the present study, we sought to investigate the relationship between NAR and POP after aSAH, and whether NAR at an early stage may help to identify patients at high risk of POP.[27]

Study Population

We retrospectively reviewed the electronic medical records of 395 patients with aSAH who underwent microsurgery or endovascular coil embolization from December 2016–December 2019 at the Lianyungang College of Nanjing Medical University. Individual patient informed consent for this retrospective study was not required. The Lianyungang First Hospital’s ethics committee approved the study.

Inclusion criteria were as follows:1.age ≥ 18 years, all patients who suffered from first-ever SAH admitted to our hospital within 24 hours after onset; 2.SAH was confirmed by computer tomography (CT), aneurysms were confirmed by computed tomographic angiography (CTA) or digital subtraction angiography (DSA); 3.laboratory investigations were obtained from the first-time examination within 24 h after admission; 4. Surgical clipping or endovascular coiling of the aneurysm was performed. Exclusion criteria were listed as following:1. patients with other possible causes of SAH (eg: craniocerebral trauma,arterio-venous malformation༌hypertensive intracerebral hemorrhage and brain tumors);2.history of connective or autoimmune diseases, uremia, blood system diseases༌malignant tumors, cirrhosis, and chronic lung or heart diseases; 3. patients admitted to hospital with pneumonia; 4.previous use of antibiotics, systemic glucocorticoids, immunosuppressive agents or immunotherapy within 1 month before admission;5. the patient had undergone any type of surgery in the preceding month or acute inflammatory/infectious disease in the past 3 months.

Data Collection

We collected general demographic data for patients, including age, sex, past medical history, radiological data and laboratory results. The severity was classified in accordance with the World Federation of Neurosurgical Societies (WFNS) grade and the amount of bleeding was classified in accordance with the modified Fisher (mFisher) grade. In this study, admission WFNS grade ≥ 3 and mFisher grade ≥ 3 were considered as severe aSAH.

POP was defined as lower respiratory tract infections that occurs within 30 days after operative procedure according to the modified Centers for Disease Control (CDC) and Prevention criteria:[26]1. probable POP could not be diagnosed based on the admission or follow-up chest X-ray, not explained by another diagnosis; 2. proven POP had a confirmed diagnostic change on at least one of the chest X-ray images. For this study, patients with probable/proven pneumonia were considered cases by the modified CDC criteria.[18, 19] All the patients with pneumonia before admission were excluded.

Statistical Analysis

Statistical analysis was conducted using using SPSS version 26.0 (IBM Corporation, Armonk, New York, USA) and MedCalc 9.6.4.0 (Mariakerke, Belgium). The GraphPad Prism 8.0 software (GraphPad Software, La, Jolla, CA, USA) was used for figure production. Non-normally distributed continuous variables were expressed as median (interquartile range) and were compared using the Mann-Whitney U test. Categorical variables were presented as counts (percentages) and were compared by the Pearson chi-square test or the Fisher exact test. All variables with a significant value of P < 0.05 from univariate analysis were entered into a binary multivariate logistic regression model, which was used to determine independent predictors of POP.

We used receiver operating characteristic (ROC) curve, area under the ROC curve (AUC) to determine the predictive value of NAR for POP and optimal cut-off values. Besides, we compared the predictive power of the NAR and conventional markers (eg, age, WFNS grade and NLR) by using Z test. To evaluate the basic characteristics of subjects with a high NAR, we dichotomized the cohort base on the optimal cut-off values of NAR, and compared between high and low NAR groups. P < 0.05 was considered statistically significant.

In total, 395 patients with aSAH were considered in this retrospective analysis, 78 (19.7%) patients had POP after operative treatment (Table 1). The POP group presented with an older age and severe clinical conditions on admission (higher WFNS grade, mFisher grade and intraventricular hemorrhage; Table 1). They also had higher neutrophil, lymphocyte, D-dimer and NLR on admission. Moreover, the POP group had a significantly higher NAR on admission than that of the non-POP group (0.31[0.25–0.39] vs 0.23[0.18–0.28]; P < 0.001;Table 1; Fig. 1A). In addition, patients with severe aSAH (WFNS ≥ 3) exhibited significantly higher NAR levels (0.23[0.22–0.24] vs 0.34[0.31–0.37]; P < 0.001) and higher rates of POP than the others(12.2% vs 52.0%; P < 0.001) (Fig. 1B&1C).

A multivariate logistic regression analysis revealed that NAR (odds ratio [OR] = 2.94; 95% confidence interval [CI], 1.141–7.574; P = 0.026; Table 2) on admission was independently associated with POP after adjusting for confounders. Age (OR = 1.054; 95%CI, 1.019–1.09; P = 0.002), initial WFNS grade (OR = 1.412; 95%CI, 1.067–1.868; P = 0.016) and initial NLR (OR = 1.070; 95%CI, 1.001–1.144; P = 0.048) remained as independent factors of POP. In the ROC curve analysis for predicting POP after aSAH, a NAR of 0.27 was determined to be the cut-off value (AUC [95% CI] 0.775 [0.717–0.832]; P < 0.001; Youden index = 0.41;Figure 2). To compare the predictive power between NAR and conventional markers, we also computed the area under the ROC curve of WFNS grade (95% CI, 0.725 [0.654–0.796]; P < 0.001༛Figure 2) and NLR (95% CI, 0.722 [0.663–0.780]; P < 0.001༛Figure 2). Results showed the predictive performances of NAR were comparable to WFNS grade (NAR vs WFNS grade: Z = 1.587, P = 0.112; Fig. 2) and NLR (NAR vs NLR: Z = 1.335, P = 0.182; Fig. 2).

Beyond this,patients were split into two groups, with high and low NAR groups, according to the best cut-off value of NAR. Patients in the high NAR groups had higher rates of hypertension, higher initial WFNS and higher rates of POP than those in the low NAR group (Table 3).

To our knowledge, no other studies have explored the association between NAR and POP after aSAH. In this study, we found that higher NAR at admission was related to POP in aSAH patients. Interestingly, after adjusting for traditional risk factors such as age, clinical grade,NAR remained an independent factor of POP.

POP is a common condition with possible severe complications following surgical treatment of aSAH patients with 30 days, which directly affects prognosis.[13, 24, 32] Although there are variety of classic predictors of POP,most still is based on clinical parameters including age༌WFNS grade.[4] In recent years, the relevant biomarkers were used to predict the occurrence of POP after aSAH༌such as cerebral lactate and NLR.[2, 20] We suppose that hematology inspection data might be more reflecting and objective subtle changes in patients, especially, when both hematology indicator were administered in combination.

Previous studies have shown that NAR was an inflammatory marker for cancers, sepsis,in-stent restenosis undergoing carotid angioplasty and STEMI,[3, 12, 25, 30] but the underlying mechanisms remain unclear. Studies have shown that neutrophil counts increase as part of the post-stroke immunodepression phenomenon,[8, 21, 29] activated by the sympathetic nervous system and hypothalamic-pituitary-adrenal axis.[7, 9] Serum albumin is not only the most abundant antioxidant in the living body༌but also an inflammatory biomarker that involved in systemic inflammation through high levels of proinflammatory cytokines and growth factors.[5, 16, 22] In fact, studies have shown that albumin therapy can be used to enhance organ function, minimizes complications in aSAH patients, and may lead to a better outcome.[6, 28, 31] We argue that pathological mechanisms of elevated NAR include both an excessive neuroinflammation response indicated by increased neutrophil as well as albumin decrease might resulted in the susceptibility to infection such as POP.

In this study, our results showed that the severity of aSAH could be associated with NAR and POP, the levels of NAR in aSAH patients with higher WFNS grade and mFisher grade were higher than those with lower WFNS grade and mFisher grade. Besides, the incidence of pneumonia in aSAH patients with higher WFNS grade were higher than those with lower WFNS grade. Some of these studies demonstrated a close relationship between POP and severe aSAH.[4, 34]

Furthermore, ROC curves were applied to discriminate between patients with aSAH at risk of POP. We actually observed that NAR was capable of predicting the occurrence of POP significantly. Moreover, its predictive abilities were comparable to the NLR and WFNS grade. Although inflammatory conditions may be dynamically changing during the early acute period, our findings suggest that the NAR may be potent enough to predict POP .

Study Limitations

The present study has a number of limitations which have to be acknowledged. The study is a retrospective single-center analysis which the possibility of selection bias may exist, thus, the generalisation of the results to clinical conditions should be considered with caution. In addition, We further examine whether NAR changed over time are correlated with the onset of POP.

The current study suggests that NAR might be considered as a potent and easily availability biomarker for predicting the occurrence of POP after aSAH. We hope that our study will provide some hints for further clinical trials studying preventive antibiotic therapy and albumin therapy.

Funding: Not applicable

Conflicts of interest: The authors declare no competing interests.

Availability of data and material: Not applicable

Code availability: Not applicable

Ethics approval: The Lianyungang First Hospital’s ethics committee approved the study.

Consent to participate: Individual patient informed consent for this retrospective study was not required.

Consent for publication: Not applicable

Authors' contributions: XZ contributed to the conception of the study; XZ, CW helped the data collection; XZ, AL contributed significantly to analysis and manuscript preparation; XZ, SZ, RL, CW performed the data analyses and wrote the manuscript; XZ, SZ, AL, RL helped perform the analysis with constructive discussions.

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Table 1

Comparison of demographic and clinical data in patients with aneurysmal subarachnoid hemorrhage according to the occurrence of postoperative pneumonia
Characteristics	Non-POP group (n = 317)	POP group(n = 78)	P value
Demographics
Age(years)	61.00(51.00–65.00)	64.00(55.50–69.00)	0.001
Gender (female)	223(70.3%)	51(65.4%)	0.412
Prior medical history
Hypertension	219(69.1%)	63(80.8%)	0.286
Diabetes	17(5.4%)	7(9.0%)	0.05
Admission status
WFNS grade			< 0.001
Grade I	236(74.4%)	29(37.2%)
Grade II	45(14.2%)	10(12.8%)
Grade III	5(1.6%)	3(3.8%)
Grade IV	29(9.1%)	20(25.6%)
Grade V	2(0.6%)	16(20.5%)
Admission CT
mFisher grade			< 0.001
Grade I	33(10.4%)	4(5.1%)
Grade II	244(77.0%)	37(47.4%)
Grade III	14(8.2%)	18(23.1%)
Grade IV	26(8.2%)	19(24.4%)
IVH	60(18.9%)	39(50.0%)	< 0.001
Aneurysm characteristics
Location			0.755
anterior circulation	304(95.9%)	74(94.9%)
posterior circulation	13(4.1%)	4(5.1%)
Size of aneurysm (mm)			0.246
<5	166(52.4%)	33(42.3%)
5–10	140(44.2%)	40(51.3%)
11–25	10(3.2%)	5(6.4%)
>25	1(0.3%)	0(0.0%)
Treatment			0.733
Clip	273(86.1%)	66(84.6%)
Coil	44(13.9%)	12(15.4%)
Lab values on admission
Neutrophil, ×10⁹/L	9.21(7.28–11.30)	12.24(10.16–15.26)	< 0.001
Lymphocytes, ×10⁹/L	0.93(0.64–1.29)	0.84(0.55–1.15)	0.032
NAR	0.23(0.18–0.28)	0.31(0.25–0.39)	< 0.001
NLR	9.86(6.16–15.07)	14.92(11.01–21.87)	< 0.001
Platelet count, ×10⁹/L	206.00(170.50-245.50)	208.00(172.00-265.50)	0.506
D-Dimer, ng/mL	353.00(186.50-680.50)	635.50(264.25-1306.25)	< 0.001
Plasma fibrinogen, ug/mL	2.93(2.56–3.32)	2.88(2.51–3.46)	0.705

Table 2

Parameters related to the occurrence of postoperative pneumonia using multivariate logistic regression analysis in patients with aneurysmal subarachnoid hemorrhage
	Odds ratio	95% confidence interval	P value
Age	1.054	1.019–1.09	0.002
WFNS	1.412	1.067–1.868	0.016
NLR	1.07	1.001–1.144	0.048
NAR	2.94	1.141–7.574	0.026

Table 3

Aneurysmal subarachnoid hemorrhage patients’ demographics and baseline characteristics by the NAR cut-off value.
Characteristics	NAR ≥ 0.27(n = 151)	NAR < 0.27(n = 244)	P value
Demographics
Age(years)	62(51–67)	61.5(52–66)	0.934
Gender (female)	97(64.2%)	177(72.5%)	0.083
Prior medical history
Hypertension	118(78.1%)	164(67.2%)	0.02
Diabetes	9(6.0%)	15(6.1%)	0.94
Admission status
WFNS grade			< 0.001
<Grade III	97(64.2%)	223(91.4%)
≥Grade III	54(35.8%)	21(8.6%)
Admission CT
mFisher grade			< 0.001
<Grade III	100(66.2%)	218(89.3%)
≥Grade III	51(33.8%)	26(10.79%)
IVH	56(37.1%)	43(17.6%)	< 0.001
Aneurysm characteristics
Location			0.028
anterior circulation	140(92.7%)	238(97.5%)
posterior circulation	11(7.3%)	6(2.5%)
Treatment			0.475
Clip	132(87.4%)	207(84.8%)
Coil	19(12.6%)	37(15.2%)
POP	54(35.8%)	24(9.8%)	< 0.001

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High Neutrophil-To-Albumin Ratio Predicts Postoperative Pneumonia in Aneurysmal Subarachnoid Hemorrhage

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Background & Aim

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Materials And Methods

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References

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