Systemic Inflammatory Response Syndrome Combined with Pre- and Postoperative White Blood Cell Ratio Is a Better Criterion to Identify Septic Shock Patients After Flexible Ureteroscopic Lithotripsy

Abstract

Objective:

To find out a better criterion to identify septic shock patients after flexible ureteroscopic lithotripsy (FUL).

Materials and Methods:

In total, 2364 patients who underwent the FUL procedure were enrolled in the study. The demographics and preoperative results of laboratory tests of the patients were collected. The postoperative white blood cell (WBC), systemic inflammatory response syndrome (SIRS), and quick sequential (sepsis-related) organ failure assessment score (qSOFA) were assessed 2 hours after FUL. The predictive efficacy was measured by sensitivity, specificity, positive and negative predictive value, and area under the receiver's operating characteristic curve (AUROC).

Results:

A total of 15 (0.63%) patients developed septic shock. There were 86 (3.64%) patients who were SIRS positive and 69 (2.92%) patients who were qSOFA positive. The pre- and postoperative WBC ratios in septic shock patients and normal patients were 2.50 ± 1.55 and 0.69 ± 0.24, respectively (p < 0.001). For sensitivity and negative predictive value, all reached 100%. For specificity, qSOFA was 97.70%, SIRS was 96.98%, and SIRS combining pre- and postoperative WBC ratio (the new criterion) was 99.79%. The new criterion had statistically significant higher specificity than SIRS or qSOFA (p < 0.001 for both), but when comparing SIRS and qSOFA, it had statistically insignificant specificity (p = 0.142). For positive predictive value, qSOFA was 21.73%, SIRS was 17.44%, and the new criterion was 75%. qSOFA and SIRS had similar AUROC (0.989 for qSOFA and 0.985 for SIRS), both lower than the new criterion (AUROC: 0.999).

Conclusions:

SIRS combined with pre- and postoperative WBC ratio has a much better specificity and positive predictive value than SIRS or qSOFA alone. It has 99.79% specificity and 75% positive predictive value, and as high as 100% sensitivity and negative predictive value.

Introduction

Flexible ureteroscopic lithotripsy (FUL) is widely used for renal and upper ureteral stones. FUL is much safer than percutaneous nephrolithotomy (PCNL), with a lower complication rate.¹ Although postoperative septic shock rate is low, it is still a severe complication that may lead to death. It was found that 38 (0.3%) patients developed urosepsis after FUL in a study of 11,185 patients.² Mortality rate was as high as 20% to 40% once urosepsis occurred after FUL.^3,4 Cindolo et al. reported in their survey that four patients died from sepsis shock in six fatal cases after FUL.⁵

Historically, most studies on the criteria of the urosepsis were based on systemic inflammatory response syndrome (SIRS), which was established in 1991. The Sepsis-3 definition and criteria were introduced as sequential organ failure assessment score (SOFA) and quick sequential (sepsis-related) organ failure assessment score (qSOFA) in 2016,⁶ to replace the SIRS criterion. Yaghoubian and colleagues have reported that qSOFA was superior to SIRS when predicting septic shock after PCNL.⁷ However, the result showed that positive predictive value was 13% for qSOFA, which suggests that only 13% qSOFA positive patients had septic shock. This is still quite unsatisfying in clinical practice, since it might cause overtreatment and waste of intensive care unit (ICU) resource. Also, there is a lack of publications evaluating the validity of these criteria to predict septic shock after FUL. In this study, we aimed to find out the better criteria for identifying the septic shock patients after FUL.

Methods

Patients

A total of 2364 patients enrolled in the study underwent the FUL procedure for renal and upper ureteral stones between October 2015 and July 2018. The study was approved by the ethics committee of Shanghai General Hospital. We excluded patients with end-stage renal disease, severe cardiac or lung disease, malignant tumor, and immunodeficiency status. Patients' characteristics, including age, gender, medical history, stone characteristics such as stone size and location, and laboratory tests, including complete blood count (CBC), C reactive protein (CRP), procalcitonin (PCT), interleukin 6 (IL-6), midstream sample of urine culture (MSSU), and urine white blood cell (WBC), both pre- and postoperatively, were obtained from the electronic medical records. The stone size was measured by an experienced endourologist in the axial diameter from CT scan.

Preoperative

The preoperative blood tests were performed on the day before the operation. The MSSU was performed in the out-patient department. The FUL procedure would be postponed in patients with positive preoperative urine cultures until reculture was negative after sensitive antibiotics were used for treatment. And a dose of antibiotic was used 30 minutes before the FUL procedure.

FUL procedure

All of the patients underwent FUL. The ureteral access sheath (COOK Medical) was routinely used and the irrigation rate was 50 mL/min. Stones were fragmented using holmium:YAG laser lithotripsy and removed using a basket (COOK Medical). In the end of the operation, a 4.7F Double-J ureteral stent (Bard, USA) was placed. The duration of the operation was recorded.

Postoperative

Body temperature, blood pressure, heart rate, respiratory rate, and the Glascow Coma Scale (GCS) were measured 2 hours after the operation. The blood sample was obtained 2 hours after the surgery.

Septic shock was defined as the need for vasopressors to maintain a mean arterial blood pressure >65 mm Hg and a suspected urinary tract infection.⁷ The hypotension should not have any other possible reasons, for example, anesthesia-related hypotension. If so, the patients were recognized as “septic shock patients.” Otherwise the patients were recognized as “normal patients.”

SIRS positive was defined as meeting two or more of the following criteria: temperature >38.5°C or <36°C,;heart rate >90 beats/min respiratory rate >20 breaths/min or PaCO₂ <32 mm Hg, and WBC >12 × 10⁹/L or <4 × 10⁹/L or >10% bands.

qSOFA positive was defined as meeting two or more of the following criteria: respiratory rate >22 breaths/min, altered mentation (decrease in GCS), and systolic blood pressure <100 mm Hg.⁶

Statistical analysis was performed on the SPSS 25.0 platform, and p < 0.05 (two-tailed) was considered as statistically significant. Descriptive analysis was performed to demonstrate the distribution patterns of patients' demographics and stone characteristics. Data with normal distribution were recorded as the means ± standard deviations. The chi-square test was used to check the differences in proportions for categorical data, whereas continuous variables were processed using independent sample t-tests. Sensitivity, specificity, and positive and negative predictive values were used to measure the efficacy of the criteria. The area under the receiver's operating characteristic curve (AUROC) was used to recognize the comprehensive predictive value of the criteria.

Results

A total of 2364 patients were enrolled in the study. The demographics are described in Table 1. Among them, 15 (0.63%) patients had postoperative septic shock. A total of 1613 (68.23%) patients were male. The average age of the patients was 51.67 years old. The culture results of septic shock patients are listed in Table 2.

Table 1.

Demographics of the Patients

Index	Septic shock patients	Normal patients	p
Number	15	2349	—
Gender			<0.001
Male	3	1610
Female	12	739
Age (years)	55.00 ± 13.90	51.65 ± 13.47	0.338
BMI (kg/m²)	23.83 ± 2.81	24.58 ± 3.24	0.368
Side			1.000
Left	3	1302
Right	10	1008
Bilateral	2	39
Location			0.804
Renal	10	1495
Ureter	5	954
Stone size (mm)	14.23 ± 8.85	9.33 ± 5.76	0.050
Preoperative
Body temperature (°C)	37.01 ± 0.63	36.72 ± 0.24	0.091
Glucose (mmol/L)	5.90 ± 1.76	5.58 ± 1.67	0.455
Blood WBC ( × 10⁹/L)	12.02 ± 8.49	6.51 ± 1.91	0.025
Neutrophil percentage (%)	72.0 ± 14.6	61.1 ± 8.7	0.012
Urine WBC (+∼4+)	2.40 ± 1.68	2.10 ± 1.13	0.301
Operation time (minutes)	38.33 ± 29.20	36.17 ± 20.53	0.779
Postoperative
2 hours blood WBC ( × 10⁹/L)	6.33 ± 5.45	7.10 ± 2.49	0.612
Neutrophil percentage (%)	72.4 ± 13.0	69.8 ± 12.0	0.463
Pre- and postoperative ratio	2.50 ± 1.55	0.69 ± 0.24	<0.001
SIRS			<0.001
Positive	15	71
Negative	0	2278
qSOFA			<0.001
Positive	15	54
Negative	0	2295

qSOFA = quick sequential (sepsis-related) organ failure assessment score; SIRS = systemic inflammatory response syndrome; WBC = white blood cell.

Table 2.

Culture Results of Septic Shock Patients

Patient No.	Urine culture	Blood culture
1	Escherichia coli	/
2	Negative	Negative
3	Escherichia coli, Candida albicans	Enterococcus faecium
4	Negative	/
5	Escherichia coli	/
6	Negative	Negative
7	Escherichia coli	/
8	Negative	Negative
9	Negative	Negative
10	Negative	/
11	Escherichia coli	Escherichia coli
12	Negative	Negative
13	Negative	/
14	Citrobacter freundii	Negative
15	Candida tropicalis	Negative

There were 86 (3.64%) patients who were SIRS positive and 69 (2.92%) patients who were qSOFA positive. SIRS and qSOFA had identified all the septic shock patients correctly. However, both have a poor positive predictive value (17.44% and 21.73%, respectively) (Table 3).

Table 3.

Sensitivity, Specificity, and Negative and Positive Predictive Values of Quick Sequential (Sepsis-Related) Organ Failure Assessment Score, Systemic Inflammatory Response Syndrome, and Systemic Inflammatory Response Syndrome Combined with Pre- and Postoperative White Blood Cell Ratio (the New Criterion)

	qSOFA	SIRS	The new criterion
Total number positive (%)	69 (2.92%)	86 (3.64%)	20 (0.85%)
Sepsis	15	15	15
Sensitivity	100.00%	100.00%	100%
Specificity	97.70%	96.98%	99.79%
AUROC (95% CI)	0.989 (0.984–0.993)	0.985 (0.979–0.991)	0.999 (0.998–1.000)
Negative predictive value	100.00%	100.00%	100%
Positive predictive value	21.73%	17.44%	75%

AUROC = area under the receiver's operating characteristic curve; CI = confidence interval.

Interestingly, we found out that all of the septic shock patients had a lower postoperative WBC than preoperative WBC, but few normal patients had. Therefore, we defined “pre- and postoperative WBC ratio” as the ratio of preoperative and postoperative WBC. If the ratio is >1, it suggested that preoperative WBC is higher than postoperative WBC. We found out that the pre- and postoperative WBC ratio in septic shock patients is 2.50 ± 1.55, but is 0.69 ± 0.24 in normal patients (p < 0.001). Therefore, we combined the pre- and postoperative WBC ratio and SIRS, which may have a better efficacy. Those patients whose pre- and postoperative WBC ratio is >1 and SIRS positive were considered as septic shock patients.

For specificity, qSOFA was 97.70%, SIRS was 96.98%, and SIRS combined with pre- and postoperative WBC ratio was 99.79%. The new criterion had statistically significant higher specificity than SIRS or qSOFA (p < 0.001 for both), but SIRS and qSOFA had statistically insignificant specificity (p = 0.142). For positive predictive value, qSOFA was 21.73%, SIRS was 17.44%, and SIRS combined with pre- and postoperative WBC ratio was 75.00%. For sensitivity and negative predictive value, all reached 100% (Table 3).

AUROC was used to recognize the comprehensive predictive value of the three criteria. We found out that qSOFA and SIRS had similar AUROC (0.989 [95% confidence interval, CI: 0.984–0.993] for qSOFA and 0.985 [95% CI: 0.979–0.991] for SIRS), whereas SIRS combined with pre- and postoperative WBC had highest AUROC of 0.999 (95% CI: 0.998–1.000) (Fig. 1).

FIG. 1.

ROC curve of the SIRS, qSOFA, and SIRS combined with pre- and postoperative WBC. qSOFA, quick sequential (sepsis-related) organ failure assessment score; ROC, receiver's operating characteristic; SIRS, systemic inflammatory response syndrome; WBC, white blood cell.

Discussion

We established a new criterion for identifying septic shock patients after FUL in this study. The combination of SIRS and pre- and postoperative ratio has some advantages. It has higher specificity and especially positive prediction value. In comparison of the new criterion, SIRS, and qSOFA, the positive predictive value is 75%, 17.44%, and 21.73%, respectively. That means that among four patients who met the new criterion, three of them are septic shock, but only one out of five qSOFA positive patients is septic shock. It is a huge step forward in identifying septic shock patients. Sepsis was the most expensive condition treated in the United States. It costed ∼$23.7 billion (6.2% of aggregate costs) for all hospitalizations in 2013.⁸ Septic shock is one of the most severe complications after FUL. To reduce the urosepsis and septic shock after FUL, many studies worked on the risk factors and the predictive signs of urosepsis and septic shock after FUL. Most of the studies used the SIRS as the criterion of urosepsis and septic shock. However, the use of SIRS to identify sepsis and septic shock was “unanimously considered to be unhelpful” by the task force who introduced qSOFA criteria.⁶ Many studies showed that most (93%, 88.4%, and 68%) patients in ICU met two or more SIRS criteria.^9
–11 SIRS was considered as “sensitive but not sufficiently specific.” Therefore, a more specific criterion was needed for better screening the potential sepsis and septic shock patients. Many patients met the SIRS criterion but never had sepsis and septic shock. It also helps to cut the expense of the patients who were treated as sepsis patients but never had sepsis.

The qSOFA was considered as a quick tool to identify sepsis and septic shock patients, and in some researches, it performed better than SIRS.^4,12 However, we have to emphasize that it also has limitations. For example, in a patient with heart failure or large pulmonary embolism, qSOFA may be >2, but there is no sepsis or septic shock. And some septic shock patients who presented with hypoxemia, renal failure, coagulopathy, or hyperbilirubinemia may have qSOFA <2 points.¹² Therefore, the qSOFA can be used for bedside screening, but still not a gold standard for sepsis or septic shock. Yaghoubian et al. have reported that qSOFA was superior to SIRS to predict septic shock after PCNL.⁷ However, the efficacy of qSOFA is still not satisfying. The positive predictive value is only 13% in Yaghoubian's study and 21.73% in our study.

In a prospective cohort study including 1535 sepsis patients in an emergency department in Norway, 108 patients had sepsis but only 33 (30.1%) met qSOFA criterion. As for the 26 patients who died within 7 days, only 4 (15.4%) had a qSOFA ≥2. In addition, only 8 (11.9%) out of 68 patients who died within 30 days met the qSOFA criterion.¹³ It is a shocking finding, which may suggest that qSOFA had a serious lack of sensitivity. Many previous researches recommend that the early diagnosis and treatment is vital for the sepsis and septic shock patients.¹⁴ Every hour's delay of treatment leads to a 6% rise of mortality rate.¹⁵

Some sepsis experts regard SIRS not a criterion for sepsis, but when infection is presented or suspected, it is a sign of life-threatening organ dysfunction. Therefore, the patients with high SIRS score should be considered as a high risk of mortality. Abandoning the SIRS was recognized as encouraging waiting rather than early and aggressive treatment.¹⁶ We admit that SIRS has a poor specificity and positive predictive value, which needs amendments. When combined with the pre- and postoperative WBC ratio, the new criterion has much higher specificity and positive predictive value. Also, the new criterion can be performed as early as 2 hours after FUL and easy to perform. All the required data in the new criterion can be retrieved easily.

In a previous research by Wu and coworkers, postoperative WBC <2.85 × 10⁹/L was suggested as a predictor after ureteroscopic lithotripsy. This criterion has 92.7% specificity and 95.9% sensitivity.¹⁷ However, this conclusion is based on upper urinary tract endoscopic lithotripsy, which included ureteroscopic lithotripsy, FUL, and PCNL, but not specified in FUL. Also, the cutoff is set at an absolute figure as 2.85 × 10⁹/L. The validity of the model may be affected by patient's baseline WBC. In our research, only 5 out of 15 patients who had septic shock had a 2-hour postoperative WBC lower than 2.85 × 10⁹/L. It might lead to a large scale of missing diagnoses. A WBC ratio may perform better than an absolute figure, since it can eliminate the variance of baseline.

Although septic shock after FUL has low morbidity (<1%), it has fatal outcome. Since some of the hospitals discharge the patients several hours after the FUL procedure, we recommend the urologists may perform a CBC test 2 hours after the FUL, in the postanesthesia care unit or in the day-care ward. If the SIRS combining pre- and postoperative WBC ratio criterion shows negative, the patients can be discharged safely since the criterion has 100% sensitivity and negative predictive value. Otherwise, the patients were highly suspected septic shock patients. More tests and monitoring should be applied. A CBC test is quickly reported and costs little, but it can help identifying septic shock patients and reduce the mortality rate.

Our study is the first to focus on the criterion of septic shock after FUL, which may suggest a better criterion for screening and monitoring the potential urosepsis patients after FUL. A better criterion for identifying the potential urosepsis patients can help to improve the outcome and reduce the mortality of the patients who received FUL.

There are some limitations in our study. First of all, it is a single-center study, which may have selection bias. Second, only 15 (0.63%) patients presented with urosepsis after FUL, most patients were safe and sound after FUL. The small ratio of the urosepsis patients vs total patients may influence the result. It is a retrospective study, some potential bias may be present. Further prospective study is recommended to verify the result. And whether the new criterion could be extended to other procedures, such as PCNL and ureteroscopic lithotripsy, can be validated in a future research.

Conclusion

We introduced a new criterion combined with SIRS and pre- and postoperative WBC ratio, which had a much better specificity and positive predictive value than SIRS or qSOFA alone in predicting septic shock patients after FUL. It has 99.79% specificity and 75% positive predictive value, and as high as 100% sensitivity and negative predictive value.

Footnotes

Author Disclosure Statement

The authors declare that they have no competing interests.

Funding Information

The study was supported by grants from Science and Technology Commission of Shanghai Municipality (Grant No. 19441909400) and Shanghai Hospital Development Center (Grant No. SHDC12016226).

Abbreviations Used

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