|Year : 2019 | Volume
| Issue : 3 | Page : 103-111
Using insulin clamp technique as part of the perioperative care
Department of Surgery, College of Medicine, King Saud University, Riyadh, Saudi Arabia; Department of Oncology, McGill University, Montreal, Quebec, Canada
|Date of Web Publication||1-Jul-2019|
Department of Surgery, College of Medicine, King Saud University, Riyadh - 11472
Source of Support: None, Conflict of Interest: None
Operatively induced inflammation has been the focus of many studies to evaluate the most efficient responses and protocols to be used for its control. Insulin has been characterized with nonmetabolic properties and is used as a preoperative anti-inflammatory agent. We reviewed the published evidence in the past 10 years reporting on the use of glucose–insulin-normoglycemia therapy as a potential anti-inflammatory therapy to improve surgical outcomes about tissue trauma, with the challenges and progress attenuated so far. We also portray our experience in the use of insulin therapy on our liver resection patients as well as the significant knowledge gaps that still exist and the need for a multidisciplinary approach to bridge them.
Keywords: Insulin therapy, liver resection, perioperative inflammation, surgical outcomes
|How to cite this article:|
Hassanain M. Using insulin clamp technique as part of the perioperative care. J Nat Sci Med 2019;2:103-11
| Introduction|| |
Inflammation constitutes a response to a biological insult and is a highly complex, tightly regulated process. Under normal physiological conditions, inflammation provides a restorative and corrective response to invasions of bodily integrity, whether infectious or traumatic. Clinically, surgery-induced inflammation and its associated consequences are difficult to ameliorate., Furthermore, there are some knowledge gaps about surgically induced inflammation. These relate to its biochemical nature, prevention, control, and how to mitigate the associated morbidity and mortality., It is known that surgical trauma triggers inflammation, thereby increasing the risk of organ damage or death in patients. Indeed, advances in surgical techniques such as cardiopulmonary bypass, and extracorporeal membrane oxygenation, are well described in the literature as being sources of additional inflammatory insult. These contribute to postsurgical morbidity and mortality. Since simple, intense exercise is associated with a vigorous inflammatory response, it is hardly surprising that surgical invasion of the musculoskeletal system is a cause of a potentially damaging inflammatory cascade.
Previous clinical approaches to surgery-induced inflammatory responses have involved the use of corticosteroids, aspirin, statins, complement inhibitors, and C1 esterase, a multi-specific inhibitor that is the first component of the complement and contact cascade. However, a meta-analysis of studies examining the effects of steroids in cardiac bypass procedures demonstrated no benefit concerning mortality or cardiac and pulmonary morbidity. Furthermore, preoperative aspirin has been associated with worse reoperation rates, statins have been observed to yield no statistically significant benefit, while complement inhibitors, and C1 esterase inhibitors have been associated with little or no clinical benefit.
These limitations have led to the search for alternative interventions such as the use of the insulin clamp technique. This involves the use of a combination of glucose and insulin to achieve normoglycemia in the perioperative period. Against this background, this paper reviews the current state of knowledge regarding the nonmetabolic properties of insulin, specifically its function as an intraoperative anti-inflammatory agent. To achieve a comprehensive narrative review of the topic focusing on the main objective of the review, the author focused the search on English language literatures published in peer-reviewed journals in the past 10 years and has discussed the following points: surgical stress and its effect on blood glucose, using insulin as a mean of perioperative therapy, and reporting on the surgical outcomes. The review outlines the scope of the problem of perioperative hyperglycemia/insulin resistance, focusing on available evidence for the anti-inflammatory properties of insulin, the potential of insulin clamp to improve surgical outcomes, and some of the clinical and technical challenges associated with insulin clamp therapy.
| Surgical Trauma and Hyperglycemia|| |
Major surgical tissue trauma leads to alterations in carbohydrate metabolism, including increased glucose production and decreased insulin sensitivity, resulting in hyperglycemia and loss of body protein through impaired insulin function. Part of this phenomenon leads to “perioperative diabetes” or “diabetes of injury.” From a biochemical perspective, this may have deleterious consequences due to the linkage between hyperglycemia and sepsis. This explains why organizations, including the Surviving Sepsis Campaign, recommend intensive insulin therapy for all critically ill patients. Biochemically, sepsis-induced hyperglycemia is partly a result of the “fight or flight” response, driven principally by epinephrine (adrenaline), and to a lesser extent by glucagon. However, untreated sepsis overwhelms gluconeogenic stores, leading to hypoglycemia. Sepsis-induced hyperglycemia exerts at least two effects on the immune system. First, plasma hyperglycemia depresses macrophage function. Second, glucose uptake in macrophage-rich tissues remains elevated during the hypoglycemic stages of prolonged sepsis, further depressing macrophage function. These dysfunctions, occurring through sepsis-induced hyperglycemia, are associated with higher morbidity and mortality rates in critically ill patients.
The use of insulin has been attempted as a clinical intervention in sepsis-induced hyperglycemia, with conflicting reports on its effect. The use of insulin has a biochemical basis because it acts as a powerful anabolic and anti-inflammatory agent, suppressing the production of selected cytokines, reversing endothelial dysfunction, and stimulating the production of anti-inflammatory factors. Brunkhorst et al. concluded that severely ill patients with sepsis may not benefit from intensive insulin therapy and that it may increase the risk of hypoglycemia 5 or 6 fold. However, Mesotten and Van den Berghe had earlier reported that intensive insulin therapy reduced intensive care unit (ICU) mortality by more than 40% and also led to a decrease in the number of morbidity factors (including acute renal failure, polyneuropathy, ventilator dependency, and septicemia). In addition, in a classical paper of van den Berghe et al. in 2001, intensive insulin therapy and tight glucose control demonstrated to not only reduce mortality and morbidity but also reduce sepsis-induced organ failure, in critically ill patients, regardless of the history of hyperglycemia or diabetes. Although intensive insulin therapy may significantly increase the risk of hypoglycemia, producing no overall mortality benefit among critically ill patients, some researchers report that it may be beneficial for patients admitted to a surgical ICU. The work of Furnary et al. on the development of specific protocols for intraoperative tight glycemic control was able to report hypoglycemia as a rare event using these procedures. Still, others like Sacks believe that large trials remain the basis on which the question of whether intensive insulin therapy improves the outcomes of selected ICU patients can be unequivocally resolved. Pending the outcomes of such a trial, many hospitals have already implemented refined insulin-infusion protocols and are achieving exemplary glucose control and clinical outcomes although not lowering blood glucose levels below the range of approximately 140–180 mg/dL.
Furthermore, elevated levels of cytokines are released during postoperative catabolism. These trigger systemic inflammatory responses that can result in multiorgan dysfunction and organ failure., Increased circulating concentrations of cortisol, glucagon, and catecholamines also play a major role in perioperative hyperglycemia. They act by suppressing insulin secretion and inhibiting the action of insulin at peripheral sites, causing generalized insulin resistance. Furthermore, the intensity of the surgical trauma that induces perioperative hyperglycemia determines the extent of insulin resistance, suggesting that insulin resistance is an independent marker of surgical stress.
Hyperglycemia is an independent risk factor for poor clinical outcomes. Insulin can be used as a clinical intervention that helps maintain normoglycemia and reduces the mortality and morbidity of critically ill patients. Several studies have shown that even moderate hyperglycemia contributes substantially to morbidity and mortality after various surgical procedures. In one study, patients with elevated blood glucose levels were 2.5 times more likely to suffer adverse outcomes after the 1st postoperative day. Hyperglycemia is associated with poor outcomes, including higher rates of mortality, in patients who have suffered a stroke. In a study of patients admitted for procedures involving cardiopulmonary bypass, a high glucose level independently predicted adverse events, including mortality, in both diabetic and nondiabetic patients. Similarly, in a series of consecutive patients admitted for cardiac procedures at the Mayo Clinic, a 20-mg/dL increase in the mean intraoperative glucose level was associated with an increase of more than 30% in adverse outcomes after adjusting for several confounding factors. Failure to prevent hyperglycemia during cardiopulmonary bypass is associated with adverse cardiovascular and neurological outcomes and increases the risk of renal failure and mortality.,, Hyperglycemia is also a risk factor for poor outcomes following cancer surgery. In a series of patients undergoing surgery for esophageal cancer, increased blood glucose levels correlated with the incidence of postoperative infections. In patients undergoing gastrectomy for cancer, elevated blood glucose levels were associated with increased risks of postoperative morbidity and mortality.
| Clinical Challenges of Managing Surgical Hyperglycemia|| |
The preceding observations raise two important issues in relation to the clinical management of hyperglycemia. The first is the clinical need to mitigate perioperative catabolism, wherein current therapeutic strategies include glycemic control and provision of perioperative nutrition. This is especially important considering the observation that severe intraoperative hyperglycemia is independently associated with postoperative surgical site infection, thereby increasing the risk of poor clinical outcomes postsurgery. The second echoes the observation that blood glucose fluctuates differently in different disease states and gives rise to different clinical outcomes. In a study cohort of critically ill patients, the authors concluded that variation in blood glucose concentration is a significant independent predictor of mortality. According to them, decreasing the variability in the plasma glucose level constitutes an important aspect of glucose management. Similarly, Yoo et al. recently reported that perioperative glucose variability is independently associated with an increased risk of postoperative acute kidney injury in liver transplantation recipients. Since inaccurate blood glucose measurement adversely affects glycemic control and may result in direct harm to patients, the continuous monitoring of plasma glucose of patients has been suggested as a means to overcome this problem. This will help obtain glucose values that are representative of the actual glycemic state; these values can then be used to shape interventions according to specific clinical scenarios.
| Insulin as an Anti-Inflammatory Molecule|| |
Maintaining tight control of blood glucose levels in the perioperative period is not only difficult but also some data suggest that it is no longer be recommended. Two large European trials that evaluated the use of continuous insulin drips in the critical care setting were terminated early because of the unacceptably high rates of severe hypoglycemia observed., In addition, a randomized controlled study of intraoperative continuous insulin versus standard therapy showed no beneficial effects on outcomes in patients undergoing cardiac surgery. Similarly, the Normoglycemia in Intensive Care Evaluation and Survival Using Glucose Algorithm Regulation Trial reported a high incidence of severe hypoglycemia and increased mortality associated with intensive insulin therapy. Although Zornow noted that the beneficial effects of avoiding hyperglycemia can be offset by the risk hypoglycemia, some recent evidence shows that continuous insulin infusions using a computerized method can help achieve optimal glycemic control in patients after undergoing cardiac surgery.
Notwithstanding these difficulties, some successes have been reported in studies that aimed to achieve tight glucose control in surgical patients. The Leuven study was a randomized controlled trial of intensive insulin therapy versus conventional glucose control. This study showed that intensive therapy, aiming to maintain blood glucose at a level that did not exceed 110 mg/dL, substantially reduced mortality in critically ill patients., In our previous study, insulin was observed to have an anti-inflammatory effect: in brain-dead donors, high-dose insulin therapy decreased the concentration of pro-inflammatory cytokines such as interleukin (IL)-6 and monocyte chemoattractant protein-1, increased the concentration of anti-inflammatory cytokines such as IL-10, and preserved normoglycemia. A post hoc analysis of the Leuven study suggested that the mortality rate during the first 5 days of being admitted to an ICU was not affected by tight glucose control. This finding suggests that the deleterious effects of hyperglycemia/insulin resistance may occur before admission to ICU, more specifically during the perioperative period. It is for that reason that some researchers recommend starting the intensive insulin therapy in the operating room before the initiation of surgery.
| Is Insulin Anti-Inflammatory and Pro-Inflammatory?|| |
Several lines of evidence suggest that insulin can exert anti-inflammatory effects, reducing the damage that occurs through surgical stress. Insulin has been shown to reduce endothelial damage, an effect that can reduce the incidence of organ failure and death. In rats, insulin suppressed the inflammatory cascade unleashed by endotoxins. Insulin has also been shown to possess anti-inflammatory properties, manifested by lowered levels of pro-inflammatory cytokines, acute-phase proteins, and adhesion molecules. Finally, the hormone has been shown to exert anti-thrombotic and anti-atherogenic effects.,,
While insulin can exert anti-inflammatory effects, in certain contexts, it can act in a pro-inflammatory capacity. In animal models of diabetes, for example, insulin has been shown to restore anti-microbial, pro-inflammatory functions that had been lost as a result of the disease. Anjos-Valotta et al. examined the role of insulin in modulating the inflammatory cascade in alloxan-induced diabetic rats. The animals were exposed to inflammatory stress in the form of tumor necrosis factor-alpha (TNF-α). Increased inflammatory responses were observed, including leukocyte migration and expression of adhesion molecule ICAM-1. Administration of insulin inhibited the pro-inflammatory effects of TNF-α.
de Oliveira Martins et al. studied the effects of insulin on lipopolysaccharide-induced lung injury in diabetic rats. The investigators found that immune responses to lipopolysaccharides were blunted at baseline in the experimental rats compared with controls, suggesting that the diabetic state decreased the animals' response to an infectious insult. Administration of insulin before lipopolysaccharide administration restored the animals' immune responses to those of nondiabetic rats. Using the same animal model, the investigators demonstrated that diabetic rats exhibit deficiencies in immune responses at the level of pro-inflammatory gene transcription and that insulin restored expression of these genes to normal levels.
Insulin may directly or indirectly enhance the ability of macrophages to perform their anti-microbial functions. In this regard, Costa Rosa et al. showed that the phagocytic activity of macrophages is lower in diabetic rats than in healthy rats but that insulin restored phagocytic activity to normal levels. In patients with type II diabetes, insulin contributed to the mediation of some of the chronic inflammatory features of the disease. Overweight and obese patients are known to suffer from hyperinsulinemia, insulin resistance, and chronic low-grade inflammation. Manowsky et al. studied the effects of insulin on isolated macrophages. They showed that insulin itself induced the production of pro-inflammatory cytokines such as IL-1 β and IL-8 and that expression of these cytokines contributed to insulin resistance. Further, they showed that this effect was especially pronounced in the liver, a finding that is consistent with the well-known increased level of insulin in the portal-hepatic circulation. Together, these results suggest that insulin possesses both pro-inflammatory and anti-inflammatory properties, depending on the biological context.
| Surgical Use of Insulin|| |
The nonmetabolic importance of insulin and the value of perioperative normoglycemia have spurred some investigators to investigate the effects of insulin administration in surgical cases. Some of such studies used high-dose insulin perioperatively for patients undergoing cardiopulmonary bypass.,, Certainly, these studies concluded that perioperative normoglycemia was difficult to attain at best and was likely impossible. Indeed, optimal glucose control is difficult to achieve, largely because of the complex interaction between glucose metabolism and neuroendocrine and inflammatory changes induced by extracorporeal circulation.
| Insulin Clamp Therapy|| |
One clinical approach that has been used to address the problem of surgery-induced hyperglycemia is glucose–insulin–potassium clamp therapy. Despite an almost 40-year history of implementation, insulin clamp has yielded inconsistent results. The Hinge trial in patients undergoing aortic valve replacement surgery demonstrated a significant reduction in the incidence of postoperative low cardiac output states and the need for inotropic support. Similarly, Lazar reported improved cardiac function indices with the use of insulin clamp therapy. In patients undergoing cardiac bypass, both Quinn et al. and Shim et al. demonstrated decreased myocardial enzyme release. However, previous research had shown no benefit.
| the Insulin Clamp Therapy|| |
Carvalho et al. introduced a preemptive strategy of glycemic control, employing a hyperinsulinemic-normoglycemic clamp. The technique would later become known as “glucose and insulin administration while maintaining normoglycemia therapy.” This involves infusing insulin at a constant rate while intravenous glucose is simultaneously titrated to clamp the blood glucose concentration at a specific level. The rate of insulin infusion is at a level at which suppression of endogenous glucose production and optimization of glucose use by both diabetic and nondiabetic individuals would be obtained. Importantly, insulin therapy is initiated before the typical surge of counterregulatory hormones that typically occurs during cardiopulmonary bypass and gives rise to insulin resistance. This can be thought of as a metabolic preconditioning effect. The features of insulin clamp therapy that differentiates it from others include as follows: (a) use of a standardized, fixed, high dose of insulin (5 mU/kg/min), (b) early administration of insulin, at anesthesia induction, and (c) titration of glucose to a preset level (4–6 mmol/L). Insulin clamp therapy has been used in specific clinical scenarios including cardiac surgery as well as liver resection and transplantation.
Haider et al. published their work on insulin clamp therapy, emphasizing some of the beneficial effects of perioperative insulin administration and myocardial protection. Albacker et al., demonstrated that perioperative high-dose insulin administration blunted postoperative cytokine surges and protected the myocardium in patients undergoing cardiac bypass surgery. Sato et al. reported that patients undergoing cardiac procedures using the insulin clamp protocol maintained normoglycemia. Lending clinical support to this, Schricker et al. reported that preserving intraoperative normoglycemia by intravenous insulin and glucose may prevent the impairment of both short- and long-term memory function after cardiac surgery.
Hassanain et al. adapted the insulin clamp method for patients undergoing major hepatectomy. Their investigation was partly inspired by the problematic nature of liver resection and the vulnerability of the liver glycogen depletion due to preoperative fasting. They modified the insulin clamp protocol to “preload” the liver through diet modification and preoperative glucose infusion. Patients treated with the modified insulin clamp protocol demonstrated reduced postoperative liver dysfunction, maintained normoglycemia, and had improved liver glycogen content, compared with patients treated using standard therapy. Finally, insulin clamp has been shown to be of benefit about the protein breakdown that characterizes surgical stress. Specifically, Hatzakorzian et al. reported that insulin clamp decreased whole-body protein breakdown and synthesis in patients undergoing cardiac artery bypass grafting surgery. [Table 1] presents a summary of the major methodological milestones and findings on insulin clamp therapy.
| Selected Challenges of Insulin Clamp|| |
The Leuven study, which showed that maintaining the blood glucose level at approximately 110 mg/dL substantially reduced mortality in critically ill patients, holds some promise for the future exploratory research. Acute rejection of transplanted organs from brain-dead donors remains a serious impediment in transplant medicine. About this, insulin clamp may have some clinical value based on its possible capacity to help mitigate the inflammatory storm surrounding brain death. This optimism has some credence from results of experimental studies of rabbits, wherein increasing an intravenous glucose infusion while strictly maintaining normoglycemia was reported to be safe for neuronal integrity and did not substantially affect glial cells in the frontal cortex during a prolonged period of critical illness.
Just as insulin clamp therapy reduced the inflammatory consequences of perioperative inflammation in patients undergoing cardiac and liver surgery, similarly the technique can be usefully applied to other types of surgery in diabetic and nondiabetic patients.,,,, A recent review pointed out the enduring phenomenon of “stress hyperglycemia” during surgery and its adverse consequences. A recent meta-analysis studied the effects of tight glucose control on rates of surgical site infection. The results suggest that intensive blood glucose control in the perioperative period reduces the incidence of surgical site infection without a significant increase in the frequency of serious adverse events. A systematic review of studies looking at risks for anastomotic leaks after major colon surgery found that both diabetes and hyperglycemia were correlated with an increased risk of postsurgical anastomotic leaks. This suggests that insulin clamp therapy is clinical of potential benefit to patients undergoing surgery for colon cancer and inflammatory bowel disease.
The routine use of insulin clamp is, however, complicated by some factors, including the frequency of blood sampling required to adjust the glucose infusion rate. This problem is closely tied to the inadequacies of disposable glucose probes used in subcutaneous sensors to detect glucose values in the hypoglycemic range and how different kinds of probes give different results. Furthermore, these probes used for glycemic monitoring are prone to experience inaccuracies, namely, due to the interference to certain drugs used not only in the ICU but also intraoperatively. A computerized closed-loop glycemic control system developed in a Japanese hospital setting may help to overcome this technical challenge, to reduce the workload of ICU nurses, and to decrease incidents related to the management of blood glucose levels according to manual conventional venous infusion insulin therapy.
In these settings, regular insulin is administered intravenously in almost all patients following several available algorithms for dose adjustment which not only to quantify monitoring of glucose levels but also to minimize nursing burden. Few automated protocols exist aiming to achieve the latter, including the Yale protocol as well as the Leuven protocol while using continuous glucose monitoring aiming to also avoid hypoglycemia. In the Leuven protocol, treatment starts if blood glucose exceeds 110 mg/dl and aims to maintain it between 80 and 110 mg/dl. Whole-blood sugar measurements are taken on intervals of 1–4 h and the insulin dose, set at a maximum of 50 IU/h, is adjusted accordingly., In the Yale protocol, now modified, the target blood glucose levels are between 80 and 120 mg/dl. The infusion is initiated with 1 IU of regular insulin per 1 cc 0.9% NaCl per infusion pump with an increase of 1 IU/h. The threshold for starting IV insulin is set at 180 mg/dl. The doses of infusion are calculated as such: if initial blood glucose is between 181 and 299 mg/dl, the number should be divided by 100 (rounded to nearest unit) to get the initial drip rate. If initial blood glucose is more than 300 mg/dl, the same calculation stands, however, bolus insulin should be administered. Blood glucose is checked hourly until stable and then can be checked on intervals of 2–4 h.
Continuous glucose monitoring would replace frequent static glucose measurements, thereby making the practice of insulin clamp safer and available to more patients. In September 2016, the Food and Drug Administration in the US approved a hybrid closed-loop system for the use in patients with type I diabetes. The device permits continuous blood glucose monitoring with simultaneous insulin adjustment. Devices such as these are likely to smooth the process for similar devices to be used in different contexts, such as in the operating theater. Adoption of insulin clamp would require multidisciplinary team education that would need to include anesthesiologists and surgeons, all working to translate the results of successful clinical studies into clinical practice.
Another challenge to the adoption of insulin clamp is the history of mixed success in trials of tight glucose control in the ICU setting. This often raises some concerns about hypoglycemia and its associated negative clinical consequences. While this source of apprehension is understandable, surgical teams may proceed with more confidence using the continuous blood-glucose monitoring systems referenced above.
| Future Directions and Persistent Knowledge Gaps|| |
Knowledge about the role of insulin as an inflammatory modulator continues to grow. However, there remain substantial gaps in our knowledge of the role that hyperglycemia, insulin, and regulatory hormones play in the mechanisms of inflammatory damage in response to surgical trauma and the prevention thereof. Since the extent of surgical trauma appears correlated with the amount of inflammation triggered, efforts have been made to reduce this through minimally invasive surgery. Whereas, such approaches produce an overall lower inflammatory burden on the patient, the specific effects of minimally invasive surgery on glucose metabolism remain to be studied.,
Some of the barriers to the implementation of insulin clamp therapy are of an engineering nature. The devices and protocols needed present problems that could best be solved by the collaborative efforts of bioengineers, surgeons, and anesthesiologists. This collaborative approach promises the highest likelihood of developing delivery and monitoring devices that can be adapted for patients at risk of uncontrolled inflammatory events in ICU and the surgical suite.
The insulin clamp technique is also clinically relevant in other types of surgery, in diabetic and nondiabetic patients. The technique can also be usefully applied in the field of organ transplantation, partly because of promising results from liver donor studies and partly because of the little attention (if any) that carbohydrate management and insulin therapy currently receive in transplantation medicine., The capacity of the insulin component of insulin clamp to induce anti-inflammatory cytokines such as IL-6 that can make hepatocytes become susceptible to mitogenic stimuli and move from the G0 phase into the G1 and S phase of the cell cycle suggests the potential application of the technique as adjunctive therapy in liver transplantation.
A recent retrospective analysis reported that insulin therapy might not be beneficial for organ preservation. This, combined with the gap in existing knowledge, underscores the need for some clinical caution. Since insulin clamp has potential benefits about transplantation medicine, one way to ethically address this uncertainty is obtaining consent before commencing infusions coincident with, or immediately before, declaration of brain death and conducting more clinical research.
In our ICU experience, where the rate of glucose drip and rate change percentages to that drip are used (rather than units of insulin drip changes), we have found that there are some technical challenges associated with the adoption of insulin clamp. These include the use of the clamp's sliding scale and avoiding other glucose-containing infusions during insulin clamp therapy. The possibility of the latter occurring is due to the high number of intravenous drips that patients in the ICU may be received simultaneously. Another challenge that was faced when applying the clamp is the insulin resistance variability between patients; this created a learning curve challenge in reaching the normoglycemic clamp status. The preoperative insulin resistance status is yet another gap in our knowledge, adjusting the insulin dose and therapy plans according to the preoperative insulin sensitivity have not yet been explored in the literature. Based on these clinical challenges, an important learning outcome from this review is the need for continuous training and retraining of nursing and other clinical staff that administers insulin clamp therapy. In addition, reaching a steady state during GIN therapy may be demanding and may take a long time in some patients; this requires that the blood glucose level of such patients should be regularly tested once they are transferred to the ICU.
For the promise of insulin clamp therapy to take its full clinical realm, the recent developments in automated insulin delivery pumps are essential. We hope to see further involvement of multidisciplinary teams to develop algorithms that can respond to changes in blood glucose and adjust the input of insulin accordingly. This could open a window to patient-specific protocols with the potential of further optimal outcomes.
Manuscript writing and publication support were provided by Editage (www.editage.com).
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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