Results of this retrospective study showed that among patients undergoing open abdominal surgery for NEC, maintaining perioperative blood glucose level in a range of 47 to 150 mg/dL was associated with a shorter postoperative hospital stay. Long duration of tracheal extubation in NICU, long days of antibiotics use and low gestational weight are risk factors for a prolonged postoperative hospital.
Long-term hypoglycemia can lead to profound adverse neurodevelopmental consequences, poor feeding and delays in growth and development, all of which can prolong a patient’s postoperative hospital stay.17 Duckrow 18found that regional cerebral blood flow decreases during chronic and acute hyperglycemia which can cause cerebral hypoxia and has been described as an important risk factor for production of neurologic damage19. A study by Hay11 suggested that prolonged hyperglycemia might have a deleterious effect on lung development, perhaps by inducing hyperosmolarity or triggering oxidative stress. It is well established that the incidence of bronchopulmonary dysplasia increases with decreasing birth weight, and the resultant decreased growth rate and increased oxygen requirements lengthen an infant’s postoperative hospital stay. We has already known that low gestational age is a risk factor for NEC progression.20, 21Another study found that newborns with a lower birth weight and an early stage of NEC were more likely to develop severe NEC. 22 Low perioperative weight is considered to be a type of immature development and to reflect a low adaptive response to stress caused by surgery and anesthesia. Entering into the operation room with endotracheal tube reflects respiratory failure before surgery and postoperative longer days of antibiotics use means severe infection and therefore obviously prolonged neonates’ hospitalization. Our findings in the present study are consistent with those in previous studies. Hence, perioperative glycemic control, preoperative weight, Enter into the operation with endotracheal tube and antibiotics use all have impact on postoperative hospital stay, and also the prognosis of neonates with NEC.
In our study, perioperative glucose monitoring showed that episodes of intraoperative low glucose concentration were more common in poor glycemic control group, whose preoperative glucose delivery rate were lower than that in well glycemic control group though not significant (6.79 ± 1.17 mg/kg/min vs 7.11 ± 1.55 mg/kg/min, p > 0.05). And some of them occurred persistent hyperglycemia during post-operative period(24 hours after surgery). This finding may possibly be due to a decreased responsiveness of β-cells in premature pancreas of preterm neonates. Under stress, derangements in glucose homeostasis may lead to hyperglycemia when glucose infusions exceeding their normal glucose turnover rate due to an immature response to pathoglycemia. Because no standard transfusion protocol was used, our hospital used either 1% or 5% glucose-containing solution or normal saline through the infusion pump to maintain fluid and glucose homeostasis during surgery. However, the hypoglycemia could not be rapidly or excessively corrected, because a rapid correction of hypoglycemia has been reported to be associated with a poor outcome. Studies in an animal model have also demonstrated that higher blood glucose concentrations during recovery from hypoglycemia can worsen neurologic damage, at least in part because of an increased generation of reactive oxygen species.23, 24 Perioperative glycemic fluctuations were more common in poor glycemic control group (SD of blood glucose: 43.78 ± 7.91 mg/dL vs 31.01 ± 8.05 mg/dL, p < 0.001). Patients whose postoperative hospital stay longer than 28 days after had higher SD of blood glucose levels than control (40.26 ± 10.17 mg/dL vs 34.88 ± 9.73 mg/dL, p < 0.001). Glycemic fluctuation can increase the serum levels of chronic inflammatory marker (high-sensitivity C-reactive protein) and lead to an overproduction of free radicals then inducing oxidative stress.25 Fluctuation of blood glucose levels increased hospital stay via influencing wound healing and infection. A large meta analysis looking at over 4000 patients from six studies showed that tight glycemic control does not improve mortality or outcome other than dialysis needs in pediatric intensive care units. The main difference of our study is that our study focused on perioperative period. Perioperative hyperglycemia might be considered as a marker of high stress level. And due to the derangements in glucose homeostasis in critical ill neonates, many of them occurred hyperglycemia after treatment of hypoglycemia. Evans believed that hyperglycemia in the perioperative period is associated with increased morbidity, decreased survival, and increased resource utilization26. Our study is consistent with that. Trying to avoid perioperative hypoglycemia, hyperglycemia and glucose variability may help to optimize patients’ outcome around NEC surgery. It’s not contradictory to the previous study which demonstrated that tight glucose control does not result in a decrease in hospital mortality in pediatric intensive care units27.
Perioperative abundant nutrition is beneficial to attenuate stress response which improve surgical outcome. Low glycogen storage rate, impaired gluconeogenesis and ketogenesis in neonates make them more likely to suffer from hypoglycemia. Carbohydrate loading is necessary to meet the increased energy demands of stressed patients. Several studies focused on perioperative glucose-containing solution. European guideline suggested intraoperative 1-2.5% balanced glucose-containing solution is safe to prevent hypoglycemia and hyperglycemia, but need careful monitoring and management.28 Our study found that pathoglycemia and glycemic variability were common in critically ill neonates and decreasing glucose fluctuation during hospitalization for surgery is important. Little information is available to guide clinicians in how glycemic variability can be reduced but careful glucose monitoring and management may help. Due to deranged glucose homeostasis of neonates and the painful nature of capillary or venous blood testing, noninvasive continuous glucose monitoring may be a good strategy for favourable perioperative blood glucose control. Additional randomized trials are needed to settle the debate about what constitutes a normal neonatal glucose value and the best method of perioperative glucose infusion. Furthermore, new methods for the careful monitoring and control of perioperative glucose levels need to be developed. No definite threshold exists for a normal neonatal blood glucose concentration, mainly because of a lack of data concerning the impact of blood glucose concentrations on the short- and long-term clinical outcomes of neonates.
Our study has several limitations that should be mentioned. Its main limitation is the potential for bias in the inclusion/exclusion criteria due to the study’s retrospective design. Glucose derangements might be a marker of severity of illness, which prejudge the outcome, although there is no statistical significance in gestational age, gestational weight, preoperative CRP and ASA between two groups. Second, although a blood glucose concentration of 47 mg/dL is well-accepted as the threshold for treating hypoglycemia in newborns, there is no evidence that intervention at that threshold is safe or effective.29 However, McKinlay30 found in his prospective study that treatment of neonatal hypoglycemia starting at a threshold of 47 mg of glucose per deciliter was not associated with any subsequent adverse neurodevelopmental outcomes at 2 years. At present, there is no reliable tool that can be used to assess the neurologic state related to a blood glucose concentration in infants. Therefore, clinicians need a pragmatic threshold that indicates when to provide treatment needed to ensure an adequate supply of metabolic fuel for the developing brain during the neonatal transition period. Meanwhile, adverse outcomes have been reported at blood glucose levels > 150 mg/dL, and the threshold for significant neonatal hyperglycemia remains unclear. In this study, we regarded a perioperative glucose concentration in the range of 47 to 150 mg/dL as well glycemic control; however, that definition may not be sufficiently precise. Third, the intervals and frequency of blood glucose tests (24 hours before, during and 24 hours after surgery) were not the same for each patient, although each patient was measured for blood glucose at least five times in total. A few patients may have been mistakenly allocated to the well glycemic control group because an abnormal glucose value was not detected in time due to observation bias. Arterial punctures for blood gas analysis are difficult to perform in all infants in China (similar to any developing country) during surgery. Therefore, various biochemical parameters, such as electrolyte levels, were not included in our analysis because the data were unavailable. We didn’t include patients under 28 weeks because few infants delivered at this gestational age range underwent NEC surgery in our hospital and meanwhile these few infants may cause obvious bias to the LOS due to their extremely immature development. In addition to the retrospective nature of our study, other limitations also exist. As a single-center study, our results should not be extrapolated to patients treated at other centers.
Nevertheless, our results showed that perioperative blood glucose control is necessary for the optimal treatment of neonatal NEC, and has a positive impact on the patient’s postoperative hospital stay and overall prognosis. This study was undertaken to gain a better understanding of glucose monitoring and control in the perioperative period and to broaden the understanding of how hypoglycemia and hyperglycemia, as well as glucose variability, are associated with hospital length of stay in critical ill population. However, these observational findings require further verification in randomized clinical trials.