ARE ADMISSION LABORATORY VALUES IN ISOLATION VALUABLE IN PREDICTING SURGICAL OUTCOME IN PATIENTS WITH PERFORATED PEPTIC ULCERS: A RETROSPECTIVE, COHORT ANALYTICAL, OBSERVATIONAL STUDY

Background: Perforated peptic ulcer carries noteworthy mortality, and admission status is a significant prognosticator thereof. Laboratory values are objective and readily available and, therefore, ideal for risk stratification. The objective of the study is to calculate the predictive value of admission laboratory values in patients with perforated peptic ulcers. Methods: A retrospective, cohort analytical, observational study was performed. All patients with surgically confirmed perforated peptic ulcers at Pelonomi Tertiary Hospital from July 2014 to June 2019 were considered. Demographic data and admission laboratory values were collected from hospital and laboratory electronic databases and theatre books. Outcomes measured were in-hospital mortality, ICU admission and length of stay in ICU and hospital. The significance of categorical variables was calculated by Chi-square and Fisher's exact test. Logistic regression analysis considered univariately statistically significant variables. A p-value of < 0.05 was considered statistically significant. 4.36) and creatinine (OR 7.76) were significant in multivariate analysis, and for ICU admission age (OR 1.03), platelet count (OR2.94) and creatinine (OR 6.90). Urea ≥ 10.9mmol/L showed a sensitivity of 70.2% and specificity of 82.1% (AUC 0.79), and creatinine ≥ 109umol/L a sensitivity of 80.9% and specificity of 67.7% (AUC 0.80) in predicting in-hospital mortality. Conclusions: The mortality rate in patients with perforated peptic ulcer disease is still substantial. Admission laboratory values show statistical significance as outcome indicators and are valuable to assist in predicting prognostication. Abnormal high serum creatinine was the strongest single predictor of both mortality and ICU admission.

hypoalbuminaemia, renal failure, and leucocytosis can all be described as part of the sepsis syndrome. 3 The diagnosis of a perforated peptic ulcer cannot be made using laboratory values in isolation, and these values are non-specific. 12 Laboratory values are however, good indicators of organ dysfunction, local and systemic inflammation. They are also used to rule out other pathologies on the differential diagnosis, like acute pancreatitis. 8,18,22 The biggest advantage for the use of laboratory values in risk stratification is that they are objective in nature, routinely done, and readily available. 6 Laboratory values form part of most perforated ulcer and other prognostic scoring systems used currently: (Table 1)

Results:
Over the 5-year study period, we identified 194 patients, of whom 188 met the inclusion criteria. Three patients were excluded due to missing admission laboratory values, two due to confirmed malignancy and one due to surgery for suspicion of PPU without confirmation of perforation. Demographic characteristics showed our patient cohort had a median age of 46 years with a range between 15 and 87 years. The gender distribution showed a male predominance of 134 (71.3%) versus 54 (28.7%) female patients.
The median values and interquartile ranges (IQR) of laboratory variables on admission as well as cases with in-hospital mortality and ICU admission are shown in Table 2. In terms of predicting the two categorical outcomes of in-hospital mortality and ICU admission, abnormal haemoglobin, platelet count, urea, creatinine and potassium were all found to be statistically significant in univariate analysis. Abnormal albumin showed a statistical significance in predicting ICU admission but not in-hospital mortality. The different P-values, as well as the percentage of patients according to outcome categories of in-hospital mortality and ICU admission, are shown in Table 3 Tables 5 and 6.
For in-hospital mortality age (p = 0.0091) haemoglobin (p = 0.0432) and creatinine (p < .0001) were significant in multivariate analysis. For ICU admission, albumin was excluded from the model due to many missing values and no clear independent relation to outcome.
Multivariate analysis significant parameters for ICU admission were age, gender, platelet count and creatinine.    creatinine (p = 0.0055) and albumin (p = 0.0416) to be statistically significant in predicting length of ICU stay. Although all subgroups for these three variables had a median ICU stay of 0 days, some differences were observed regarding 75 th percentiles, and differences were due to differences in ICU admission (as shown in Table 4). Potassium (p = 0.0167) and albumin (p = 0.213) were statistically significant in predicting length of hospital stay.
Patients with low potassium had a median hospital stay of 8 days (IQR 6 to 11 days), those with high potassium levels median stay of 8.5 days (IQR 6 to 11 days) and those with normal potassium levels median hospital stay of 6 days (IQR 5 to 9 days). Patients with low albumin levels had a median stay of 8 days (IQR 6 to 15 days) compared to patients with a normal albumin level who had a median stay of 7 days (IQR 4 to 8 days). These were calculated for patients who did not die in hospital.

Discussion:
The diagnosis of perforated peptic ulcer disease is made using a combination of history, clinical and radiological findings. Surgical intervention with explorative laparotomy, ulcer biopsy, primary repair and omentoplasty is the preferred surgical management of perforated peptic ulcers in our institution. This is followed by post-operative Proton Pump Inhibitor and Helicobacter Pylori eradication therapy.
Our study included all presenting patients in the defined population with no referral selection; therefore, we expected our mortality rate (25%) to be similar to mortality reported in literature (1.3-40%). 2,3,[16][17][18][19][20][21]7,[9][10][11][12][13][14][15] Investigations into risk factors for perforation are complicated by the wide variation in demographics, socioeconomic status, the prevalence of Helicobacter pylori, and medication and substance use in different population groups. 18 Cohorts from other African countries shows a male predominance of 6-13:1 to females. 18 In developing countries, young (predominantly male) smokers make up the most extensive patient group. In contrast, in the developed world, elderly patients (increase in females) with other comorbidities and the associated use of NSAIDs are more commonly found. 8,13,22 Significant inequality in South Africa leads to a broad spectrum of socioeconomic circumstances in our study population, and both these population groups might have been included. 32 Our age distribution, the median of 46 years (range , was similar to other South African study demographics, compared to an older age distribution found in most literature. 21 We had a male predominance (2.48:1), but it was not as high as similar patient groups in South African and other African series and closer to distribution in the rest of literature. 18,21 Our median length of hospital stay of 7 days (range 1-94) was similar to other studies 33,34 .
Perforated peptic ulcers are a multifactor disease, and multiple scoring systems have been suggested and used as outcome predictors. 3 Scoring systems range from simple to complex (combining demographical data, history, vital signs and clinical findings, chosen surgical intervention and management options as criteria), sometimes making practical implementation thereof more difficult. 2,35 The ASA (American Society of Anaesthesiologist physical status classification system) and Boey score are the most commonly used validated scores for patients with perforated peptic ulcers. 22 ICU and other standard surgical scores have also been evaluated in patients with perforated peptic ulcers. 18 Replication of original high positive predictive values of used scores has not always been shown in other study populations, and there is a lack of external cohort validation. 2,18,35 There is still no agreed standard scoring system, and investigation towards an optimal prediction model in terms of outcome for patients with perforated peptic ulcers in today's setting is still not saturated. 6,18 The reason for none of the multiple scoring systems being widely accepted in clinical practice can be due to the complexity, non-specificity or subjective points of these scoring systems. 25 The goals of being easy to calculate, accurate in predicting outcome and being reproducible across diverse populations have not been comprehensively satisfied by any score. 23 Due to the wide rural drainage area of our hospital, a large number of our patients have a late presentation that already falls outside the 24 hour window period at the time of theatre.
Literature from South Africa demonstrates a late presentation in patients with perforated peptic ulcers outside of the 24h window from onset of symptoms. 21 Record bias in terms of pre-hospital data plays a part in retrospective studies. Patient recall bias in terms of medical and complaint history can also be possible. Patients with pre-existing peptic ulcer disease might experience pain or symptoms for some time and are unable to pinpoint exactly when pain is exacerbated. 36 Accurate patient history might not be possible due to the patient's clinical condition (e.g. decrease in level of consciousness, elderly patients), influencing patient medical history in terms of other comorbidities and medication-use at the time of admission. 25 All these risk factors have been questioned due to the lack of objectivity and have been reported to lack sensitivity and specificity. 36 However, these risk factors still form part of scoring systems (PULP score, Mannheim Peritonitis score, Hacettepe score) previously described in the prediction of patient outcome. 15,16 The POMPP score was developed in 2015 as a practical scoring system to assist in calculating mortality risk in patients with perforated peptic ulcers. It indicated age, albumin and urea levels to be three variables that are statistically relevant in multivariate analysis. This new scoring system compared well to ASA, PULP and Boey scoring systems but was found less complex as it only made use of age and two admission laboratory values (albumin and urea). 25 We found urea (p < .0001) to be significant in predicting mortality and ICU admission and albumin (p = 0.0048) to predict ICU admission in univariate analysis.
A model to calculate postoperative risk specifically for emergency surgery (CORES) was developed in Japan in 2012. It uses five preoperative variables: white blood cell count (WCC), platelet count and blood urea nitrogen as laboratory values, and reproducibly predicting postoperative mortality in the validation and multicentre subgroups. It was postulated that the better prediction in the General Surgery patient subset compared to the P-POSSUM score could be due to the inclusion of platelet count, as thrombocytopenia has been shown as a risk factor for mortality in ICU patients and is the most commonly cited manifestation of haematological dysfunction. 30,31 Patients with a high platelet count (>300,000) interestingly also had higher mortality rates demonstrated in the study used to develop the CORES model. 30  We did not find WCC or sodium to be significant variables in our patient group but did find abnormal potassium (p = 0.0008) to be significant in predicting mortality in univariate analysis.  10,25 Knowledge of significant independent risk factors by the surgeon will assist in confident judgement about operative planning and appropriateness. 16 This awareness will also improve patient counselling in terms of risks, possible complications and outcome expectations. Naturally, an individual predictor can't be ascribed to a single patient, but the presence of a significant or more than one risk factor presents a much higher mortality risk in contrast to patients with none. 6 These findings can also be used in combination with other preoperative information or in further prospective studies to develop appropriate prediction and scoring systems for this health care setting or used in different populations as a comparison. Most of the studies available in the literature were done mainly in western and Asian countries. 17 In the era of hand-held devices and smartphones, more complex scoring systems might be easier to calculate at the bedside than before. 23 It might be challenging to develop a universally reproducible scoring system due to geographical variation in age, gender, and presentation patterns. 18 Laboratory values however, have the advantage of being an objective variable not influenced by subjective interpretation and therefore ideal for validation between different patient cohorts and demographic regions. 6 Although the study involved a consecutive cohort, this study's limitation is that it is a retrospective, single-centre study. An advantage is that we had minimal missing data due to consistent laboratory records, which might be more of a problem in future studies using other perioperative variables depending on pre-hospital and hospital records. Laboratory values might be indicators for other underlying factors like chronic disease. Further investigation into causality from the findings in the study might therefore be warranted at a later stage.
Long term outcome after hospital discharge for our patient group was also not assessed.
Logical regression was used to minimize confounding variables. Some of the calculated 95 % Confidence intervals are wide, which indicates low statistical precision. Other reference ranges for abnormal values and definitions or categorizations of demographic variables might have produced different results.

Conclusion
All laboratory values might not be exact in predicting mortality, but we found that routine admission laboratory values do most certainly contribute to building a risk stratification model for this patient group in our health care setting. This study simply questioned whether admission laboratory values in isolation could be trusted to assist with predicting outcomes.
Even though admission laboratory values cannot be influenced in the same way as other risk factors such as for example time to theatre, they play a crucial role in our approach and management of the patient from the time of admission.