Nonfunctioning pituitary adenomas (NFPAs), which account for 14%–54% of all pituitary adenomas, lack evidence of hypersecretion of hormones and generally present with symptoms related to mass effect.1,2 NFPAs are primarily treated by transsphenoidal surgery, and endoscopy appears to have been the most important technique over the past 3 decades.3 There are numerous studies reporting the finding that both endoscope and microscope are safe and effective.4–6 These complication rates in transsphenoidal surgery are relatively low; however, they can still be significant. In clinical decision-making, it is important to identify patients with an increased risk of postoperative complications and intervene in time before surgery. In other specialties, malnutrition has been shown to be closely linked to clinical symptoms and complications.7–11 Serum albumin is the classic biomarker to evaluate nutritional state; however, hypoalbuminemia is a relatively nonspecific outcome caused by many different disease processes, and debate exists on how well it reflects malnutrition.12–14 Currently, prealbumin and retinol-binding protein (RBP), whose production highly depend on adequate nutritional intake, are more preferred because of their shorter half-life, reflecting more rapid changes of the nutritional state, especially during the perioperative period.11,15 In addition, several researchers have reported that prealbumin and RBP, as nutritional markers, are effective for evaluating malnutrition, even for outcomes after surgery.16,17
The prognostic nutritional index (PNI) was originally proposed to assess perioperative immunonutritional status and surgical risk in patients undergoing gastrointestinal surgery. Now it is also used for other perioperative nutritional status evaluations. The PNI has been reported to be associated with therapeutic efficacy and to predict postoperative infection.7 In addition, the PNI may help predict invasive and refractory NFPAs.18
At present, there is no research on the relationship between nutritional parameters and the complications of pituitary surgery. In the current study we collected information regarding preoperative prealbumin, RBP, PNI, and postoperative laboratory findings, to identify the usefulness of preoperative nutritional markers as predictors of postoperative complications of transsphenoidal surgery in NFPAs.
Methods
Patients and Data Collection
Data were collected from the electronic medical record system of Shandong Provincial Hospital. The inclusion criteria were as follows: 1) older than 18 years of age; 2) first diagnosis of NFPAs and transsphenoidal surgery in our hospital; and 3) available data, including clinical, hormonal, and radiological adenoma characteristics. A total of 429 patients with nonfunctioning adenoma who underwent transsphenoidal surgery in our hospital between January 2015 and July 2020 were enrolled in the research. The median follow-up time was 34.0 months.
The PNI was calculated using the following formula: PNI = serum albumin g/L + 5 × total lymphocyte count (109/L).
Definition of Postoperative Complications
Diabetes insipidus (DI) was defined as presenting the following symptoms within 14 postoperative days: 1) serum sodium concentration > 145 mmol/L; 2) urine volume > 3 L/24 hours; 3) urine specific gravity < 1.003; 4) plasma osmolality > 300 mOsm/kg; and 5) response to desmopressin. Hyponatremia was defined as a serum sodium concentration < 135 mmol/L or serum osmolality < 280 mOsm/kg within 14 postoperative days.1,19–21 Serum sodium concentration, urine volume, urine specific gravity, and plasma osmolality were measured on the 1st, 7th, 14th, 90th, and 180th days after surgery.
Hormonal assessment was performed before the operation and on the 3rd day after surgery. Cortisol level (8 am) < 171 nmol/L and adrenocorticotropic hormone (ACTH) (8 am) < 7.2 pg/ml established the diagnosis of ACTH deficiency. Central hypothyroidism was defined as free thyroxine (FT4) < 12.0 pmol/L and thyroid-stimulating hormone (TSH) < 0.27 µIU/ml. Growth hormone (GH) deficiency was defined as a peak serum GH concentration below 3 ng/mL and a serum insulin-like growth factor–I (IGF-I) concentration below the normal range in patients with and without the insulin-induced hypoglycemia test. Estrogen levels < 0.05 ng/ml (in females) or testosterone levels < 0.06 ng/ml (in males) and with a low follicle-stimulating hormone/luteinizing hormone (FSH/LH) level indicated central hypogonadism.22,23
The following criteria were used to define intracranial infection. 1) Definitive infection—the organisms were cultured from CSF leakage. 2) Potential infection—fever (> 38°C), headache, stiff neck, meningeal signs, cranial nerve signs, or irritability; increased white blood cell count; increased protein level; and/or decreased glucose level in the CSF; and/or a positive blood culture result. If infection was present, a full course of antibiotics was administered.24,25 CSF leakage was defined as CSF rhinorrhea found during or after surgery, and bleeding was defined as postoperative bleeding at the surgical site.
Statistical Analysis
Data are presented as mean ± SD or median (interquartile range [IQR]) values for continuous variables, and categorical variables are presented as the frequency (%). The baseline characteristics were analyzed with univariate binary logistic regression analyses. A logistic regression algorithm was used to develop the classification model. Univariate logistic regression analysis was performed to identify the correction factor of postoperative complications. The p values < 0.100 or commonly considered clinically significant were then submitted to a multivariable logistic regression analysis. The discrimination performance of prealbumin and RBP for predicting postoperative complications in NFPAs was assessed by generating the receiver operating characteristic (ROC) curve, and the area under the ROC curve (AUC) was used to evaluate the classification performance. All analyses were performed using SPSS (version 21.0; IBM Corp.) and GraphPad Prism 8. A p value < 0.05 was considered statistically significant.
Results
Patient Characteristics
A total of 429 patients met the inclusion criteria of this study. We divided them into two groups—patients with and those without postoperative complications—and the baseline characteristics of the study population are presented in Table 1. Among these patients, 188 (43.8%) procedures were performed with postoperative complications and 241 (56.2%) were performed without complications. In all, the preoperative prealbumin level was 247.2 (205.0, 289.9) mg/L, the RBP level was 37.1 (30.0, 44.2) mg/L, and the PNI was 53.5 (49.8, 57.6). The preoperative prealbumin level was 233.8 (194.6, 277.3) mg/L in the group with complications and 253.3 (215.9, 299.0) mg/L in the group with no complications. The preoperative RBP level was 38.9 (28.4, 43.3) mg/L in the complications group and 37.7 (30.6, 45.6) mg/L in the no complications group. The preoperative PNI was 53.4 (49.6, 58.4) mg/L in the complications group and 53.5 (50.0, 57.2) mg/L in the no complications group.
Preoperative characteristics at baseline, stratified by complications, in patients with NFPA
| Overall | Complications | p Value | ||
|---|---|---|---|---|
| Yes | No | |||
| Total pts, no. (%) | 429 (100.0) | 188 (43.8) | 241 (56.2) | |
| Age in yrs, median (IQR) | 56 (46, 63) | 62 (57, 66) | 65 (60, 70) | 0.598 |
| Sex, no. (%) | 0.103 | |||
| Male | 209 (48.7) | 99 (23.1) | 110 (25.6) | |
| Female | 220 (51.3) | 89 (20.7) | 131 (30.5) | |
| Diabetes, no. (%) | 30 (7.0) | 17 (4.0) | 13 (3.0) | 0.164 |
| Prealbumin level in mg/L, median (IQR)* | 247.2 (205.0, 289.9) | 233.8 (194.6, 277.3) | 253.3 (215.9, 299.0) | 0.002 |
| RBP level in mg/L, median (IQR)* | 37.1 (30.0, 44.2) | 38.9 (28.4, 43.3) | 37.7 (30.6, 45.6) | 0.017 |
| PNI, median (IQR)* | 53.5 (49.8, 57.6) | 53.4 (49.6, 58.4) | 53.5 (50.0, 57.2) | 0.464 |
| Surgery type, no. (%) | <0.001 | |||
| MTSS | 234 (54.5) | 83 (19.3) | 151 (35.2) | |
| ETSS | 195 (45.5) | 105 (24.5) | 90 (21.0) | |
| Preop tumor characteristics | ||||
| Max diam of tumors in cm, median (IQR) | 2.7 (2.2, 3.1) | 2.7 (2.2, 3.2) | 2.6 (2.1, 3.0) | 0.020 |
| Cavernous sinus invasion, no. (%) | 230 (53.6) | 110 (25.6) | 120 (28.0) | 0.073 |
| Suprasellar extension, no. (%) | 362 (84.4) | 154 (35.9) | 208 (48.5) | 0.215 |
| Sellar floor disruption, no. (%) | 284 (66.2) | 128 (29.8) | 156 (36.4) | 0.466 |
Diam = diameter; ETSS = endoscopic transsphenoidal surgery; max = maximum; MTSS = microscopic transsphenoidal surgery; pts = patients.
Per SD increment.
Table 1 shows a significant correlation between preoperative prealbumin, RBP, and postoperative complications (p = 0.002, 0.017). However, PNI was not found to have a strong statistical difference with surgical complications in the current study (p = 0.464). The incidence of complications after microscopic transsphenoidal surgery was higher than that of endoscopic transsphenoidal surgery (p < 0.001). In addition, patients with complications had a larger tumor diameter (p = 0.020). Other detailed patient characteristics are shown in Table 1.
Association Between Preoperative Serum Nutritional Markers and Postoperative Complications
We explored the associations by categorizing preoperative prealbumin and RBP into quartiles and using quartile 4 as a reference (Table 2). Compared to quartile 4, after full adjustments for the confounders (model 3), the prealbumin level in quartile 1 was significantly associated with complications, with a value of 1.804 (95% CI 1.023–3.183, p = 0.041). Similarly, after full adjustments for the confounders (model 3), the RBP level in quartile 1 was also significantly associated with a value of 1.962 (95% CI 1.105–3.485, p = 0.021). In addition, the p value for the trend has been reported (Table 2).
Association of the preoperative prealbumin and RBP with postoperative complications in patients with NFPA
| Postop Complications | ||||||
|---|---|---|---|---|---|---|
| Model 1 | Model 2 | Model 3 | ||||
| OR (95% CI) | p Value | OR (95% CI) | p Value | OR (95% CI) | p Value | |
| Prealbumin | ||||||
| Quartile 1 | 1.960 (1.132–3.394) | 0.016 | 1.941 (1.117–3.375) | 0.019 | 1.804 (1.023–3.183) | 0.041 |
| Quartile 2 | 1.269 (0.730–2.207) | 0.398 | 1.264 (0.724–2.207) | 0.409 | 1.129 (0.636–2.003) | 0.679 |
| Quartile 3 | 1.246 (0.716–2.167) | 0.437 | 1.219 (0.698–2.128) | 0.486 | 1.042 (0.586–1.852) | 0.888 |
| Quartile 4 | Reference | Reference | Reference | |||
| p for trend | 0.002 | 0.002 | 0.006 | |||
| RBP | ||||||
| Quartile 1 | 2.035 (1.173–3.528) | 0.011 | 2.043 (1.173–3.558) | 0.012 | 1.962 (1.105–3.485) | 0.021 |
| Quartile 2 | 1.609 (0.919–2.818) | 0.096 | 1.630 (0.927–2.867) | 0.090 | 1.691 (0.943–3.032) | 0.078 |
| Quartile 3 | 1.631 (0.933–2.850) | 0.086 | 1.664 (0.949–2.919) | 0.076 | 1.513 (0.847–2.701) | 0.162 |
| Quartile 4 | Reference | Reference | Reference | |||
| p for trend | 0.013 | 0.016 | 0.021 | |||
Model 1: adjusted for age and sex; model 2: model 1 + adjusted for maximum diameter of tumors and cavernous sinus invasion; model 3: model 2 + adjusted for surgical type, duration of surgery, and surgeon experience.
A total of 26 (6.1%) patients had CSF leakage during or after surgery (Table 3). Postoperative DI occurred in 27 (6.3%) patients, of whom 2 (0.5%) developed permanent DI. There were 65 (15.2%) cases of postoperative hyponatremia, 14 (3.3%) cases of postoperative surgical site bleeding, and 11 (2.6%) cases of postoperative intracranial infection. Prolactin (PRL) deficiency after surgery occurred in the largest number (59, 13.8%), followed by ACTH (53, 12.4%). GH/IGF-I deficiency occurred in the smallest number, accounting for only 3.5%.
Postoperative complications in patients with NFPA
| No. (%) | |
|---|---|
| CSF leakage | 26 (6.1) |
| DI | 27 (6.3) |
| Transient | 25 (5.8) |
| Permanent | 2 (0.5) |
| Hyponatremia | 65 (15.2) |
| Bleeding | 14 (3.3) |
| Intracranial infection | 11 (2.6) |
| Postop hypopituitarism | |
| ACTH | 53 (12.4) |
| FSH/LH | 48 (11.2) |
| TSH | 46 (10.7) |
| GH/IGF-I | 15 (3.5) |
| PRL | 59 (13.8) |
In addition, we analyzed associations between preoperative prealbumin, RBP, and different complications by using multivariate binary logistic regression (Table 4). After adjusting for the corresponding confounding factors, prealbumin level was still significantly correlated with postoperative DI (multivariable adjusted OR per SD increment, 0.591; p = 0.001), hyponatremia (OR per SD increment, 0.636; p = 0.003), and intracranial infection (OR per SD increment, 0.443; p = 0.029). RBP level was also significantly correlated with hyponatremia (OR per SD increment, 0.736; p = 0.038) and intracranial infection (OR per SD increment, 0.452; p = 0.026).
Multivariate logistic analysis of the association between nutritional markers and complications in patients with NFPA
| Prealbumin | RBP | |||
|---|---|---|---|---|
| Adjusted OR (95% CI), per SD Increment* | p Value | Adjusted OR (95% CI), per SD Increment† | p Value | |
| CSF leakage | 1.019 (0.671–1.548) | 0.929 | 0.997 (0.648–1.532) | 0.988 |
| DI | 0.591 (0.428–0.816) | 0.001 | 0.858 (0.560–1.314) | 0.482 |
| Hyponatremia | 0.636 (0.472–0.857) | 0.003 | 0.736 (0.550–0.984) | 0.038 |
| Bleeding | 1.083 (0.618–1.899) | 0.780 | 0.918 (0.525–1.606) | 0.765 |
| Intracranial infection | 0.443 (0.214–0.919) | 0.029 | 0.452 (0.224–0.910) | 0.026 |
| Postop hypopituitarism | ||||
| ACTH | 0.759 (0.559–1.030) | 0.077 | 0.780 (0.575–1.058) | 0.110 |
| FSH/LH | 0.745 (0.539–1.028) | 0.073 | 0.904 (0.660–1.238) | 0.529 |
| TSH | 0.838 (0.631–1.145) | 0.267 | 0.930 (0.682–1.266) | 0.643 |
| GH/IGF-I | 1.242 (0.753–2.048) | 0.395 | 1.247 (0.774–2.009) | 0.364 |
| PRL | 0.794 (0.597–1.056) | 0.113 | 0.808 (0.605–1.079) | 0.148 |
SD increment in prealbumin group = 64.7 mg/L.
SD increment in RBP group = 11.7 mg/L.
The ROC analyses (Fig. 1) were used to assess the sensitivity and specificity of the prealbumin and RBP to predict overall postoperative complications. The results showed that prealbumin was better than RBP in predicting complications (AUC 0.749 vs 0.678). In order to explore the possibility that prealbumin or RBP combined with clinical characteristics could be better predictions of complications, we constructed a different model and compared its predictive value with the models respectively integrating the two markers (intracranial infection [Fig. 2 upper panel] and hyponatremia [Fig. 2 lower panel]) and clinical characteristics. The establishment of our model is based on clinical experience, and the combination of model and prealbumin showed a better sensitivity and specificity for intracranial infection prediction with an AUC of 0.794, and for hyponatremia prediction with an AUC of 0.677. Model and RBP showed relatively weak sensitivity and specificity for intracranial infection prediction with an AUC of 0.738, and for hyponatremia prediction with an AUC of 0.643. The model combined with prealbumin was not ideal for the prediction of DI, and we have provided the result in Supplemental Fig. 1.
The prediction model in overall complications.
Discussion
Many studies have shown that a low preoperative prealbumin or RBP level is related to postoperative complications or prognosis. However, similar studies were rarely carried out in postoperative patients with pituitary adenomas.11
In our study, univariate analysis (Table 1) showed that there was a significant difference in preoperative prealbumin and RBP levels between the complication group and the no complication group. Our results (Table 2) showed that prealbumin and RBP were closely associated with complications in quartile 1, after full adjustment for confounding factors. However, these associations were not found for complications in quartiles 2 and 3. This may indicate that only the prealbumin or RBP values below a certain level will be a risk factor for postoperative complications. Moreover, the increase of preoperative prealbumin and RBP level was a major protective factor regarding postoperative DI (excluding RBP), hyponatremia, and intracranial infection in the cohort of patients with NFPAs who underwent transsphenoidal surgery (Table 4).
Both prealbumin and RBP present better predictive value for overall complications—however, the predictive effect of prealbumin is better than that of RBP (Fig. 1).
Intracranial Infection
Intracranial infections are uncommon but serious complications that can result in increased morbidity and mortality, length of stay in the hospital, and costs. The incidence of intracranial infection is approximately 0.3%–8.9%.24 In our study we found that higher preoperative levels of prealbumin and RBP may be associated with a lower risk of postoperative intracranial infection (Table 4). In addition, prealbumin or RBP level combined with clinical characteristics may better predict the occurrence of postoperative intracranial infection, as indicated by ROC (Fig. 2 upper). Serum prealbumin and RBP are markers of both malnutrition and systemic inflammatory response syndrome (SIRS), and malnutrition or SIRS may be the cause of postoperative intracranial infection.26 Malnutrition may cause depression of the immune system, which can reduce the patient’s defense against pathogens after surgery.27 In addition, malnutrition may lead to delayed wound healing in patients undergoing surgery, which also increases the risk of postoperative infection.27 SIRS can also be manifested as intracranial infection, but this syndrome has not been found in our cohort. Prealbumin is a negative acute-phase reactant, and its serum level can fluctuate with malnutrition and SIRS. Therefore, during the perioperative period, nutritional support may help reduce the probability of postoperative intracranial infection.
The prediction model in intracranial infection (upper panel) and hyponatremia (lower panel). Upper: Model including age, sex, diabetes, and duration of surgery. Lower: Model including age, sex, and maximum diameter of tumors.
Hyponatremia
Hyponatremia is the most common complication after transsphenoidal pituitary surgery, and it is the reason for hospital readmission.28 Postoperative hyponatremia is usually caused by syndrome of inappropriate antidiuretic hormone, and rarely by cerebral salt-wasting syndrome.28,29 In the present study, the increase of preoperative prealbumin and RBP levels were protective factors regarding hyponatremia, but their value in predicting postoperative hyponatremia is limited (AUC 0.677, 0.643). However, the currently available literature cannot fully support our findings. The pathophysiological mechanism of postoperative hyponatremia is not clear, but it is generally considered to be due to the change of antidiuretic hormone (ADH) release from ADH-secreting neurons in posterior pituitary cells after surgery.30 We speculate that surgery may cause the dysfunction of ADH-secreting neurons, and malnutrition may prolong or even block the recovery of these neurons. However, this view needs the support of further research.
Diabetes Insipidus
The course of postoperative DI may be transient, persistent, or triphasic.28 In our cohort, 27 patients had postoperative DI, of whom only 2 (0.5%) had permanent DI. Due to the insufficient number of cases of permanent DI, we performed multivariate binary logistic regression analysis on the data related to DI. Our results show that the increase of preoperative prealbumin rather than RBP is a protective factor regarding postoperative DI. Similarly, we also analyzed the value of prealbumin in predicting postoperative DI by ROC, but the results were not statistically significant. We have provided the result in Supplemental Fig. 1. The cause of postoperative DI is usually pituitary stalk transection caused by the interruption of blood supply or edema after pituitary surgery, which can block the transport of ADH from the hypothalamus to the posterior pituitary.31 Therefore, endogenous ADH release will be reduced. Transient DI then resolves when there is recovery of blood supply or edema. If there is no recovery, there may be persistent or triphasic DI. A low prealbumin level may aggravate edema or decrease blood supply, which may prolong the transection of the pituitary stalk. More seriously, the pituitary stalk transection cannot recover if it is in a state of edema or ischemia for a long time. This view also needs the support of further research.
Conclusions
Together, both prealbumin and RBP have a certain predictive value for postoperative intracranial infection or hyponatremia in NFPAs, and the value of predicting intracranial infection is better than that of predicting hyponatremia. Low prealbumin or RBP concentrations are associated with the higher risk of postoperative complications, especially for intracranial infection. Further work is required to determine whether preoperative nutritional intervention could result in a substantive decrease in complications. In addition, it should be noted that the association between nutritional markers and postoperative complications in other types of pituitary adenomas needs further research.
Acknowledgments
This work was supported by National Natural Science Foundation of China (81970685, 81000323) and Key Research and Development Plan of Shandong Province (2016GSF201007).
Disclosures
The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.
Author Contributions
Conception and design: Song. Acquisition of data: Song, Qiu, Wang, Zhang, Qi. Analysis and interpretation of data: Song. Critically revising the article: Feng, Qiu. Approved the final version of the manuscript on behalf of all authors: Feng. Statistical analysis: Song.
Supplemental Information
Online-Only Content
Supplemental material is available online.
Supplemental Fig. 1. https://thejns.org/doi/suppl/10.3171/2022.9.FOCUS22211.
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