Category: Articles

Substance use disorder has been a significant issue within the medical profession throughout history. It is recognised as an important issue of concern, particularly due to its associated mortality, morbidity and social consequences. Although a substantial body of literature addresses this issue amongst doctors, there is little discussion focusing on medical students. This review summarises the existing literature available on the epidemiology, common  presenting  features,  management,  legal  implications and mandatory notification requirements of substance abuse in the medical student. Limited evidence suggests concerning levels of hazardous alcohol use exists in medical students, however alcohol and drug use is not comparatively higher than the general student population. While early detection is optimal for harm prevention, signs and symptoms of substance abuse are subtle and easily missed. Prevention and early intervention is critical, and it is important for students to recognise possible signs of substance abuse  in  their  colleagues,  as  the  biggest  barrier  to  treatment is   denial.   Once   detected,   current   evidence   from   Physician Health Programs suggests a service to manage the student’s multidisciplinary  care,  follow  up  and  return  to  study  obtains the best outcome. As a chronic medical condition that carries significant risk of harm to the impaired student – and potentially to patients – all health professionals should be aware of this issue and their mandatory reporting obligations.

Introduction

Substance use disorder (SUD) amongst doctors is an issue of significant concern. It is estimated the lifetime prevalence of substance abuse in Australian doctors is approximately 8%. [1] There is limited literature or discussion, however, addressing this issue in the context of the most junior members of the profession, medical students. The university experience is often coupled with alcohol use and occasionally with casual illicit drug use, but this is, to some extent, accepted, perhaps as part of youthful exuberance, experimentation or a rite of passage. [2] For some, however, this substance use may manifest as, or progress to, substance abuse: a pattern of drug or alcohol use that is detrimental both to the individual and to society. [3] For the substance-abusing medical student, there is a wide scope for serious implications personally, professionally and with the public.

This article aims to highlight the importance of this topic and provide information  on  the  concept  of  substance  use  disorder,  common signs  of  substance  abuse,  management,  reporting  requirements and legal implications. It also addresses why it is imperative there is awareness for this issue in medical students to prevent serious health consequences and risk to the public.

Terms within this article

Substance use disorder or substance abuse: A chronic condition characterised by a pathological pattern of behaviours related to substance use, manifesting as two or more symptoms of: impaired control of drug use; social impairment at work, school or home; risky use; tolerance or withdrawal. [4]

Substance   dependence:   An   inability   to   control   substance   use, despite problems caused by use. [5] This may manifest physically or psychologically with tolerance or withdrawal. Dependence and drug abuse are not separate entities within the Diagnostic and Statistical Manual 5 (DSM-5), however these terms are prevalent in the cited literature.

Impairment: A physical or mental impairment, disability, condition or disorder (including substance abuse or dependence) that detrimentally affects, or is likely to detrimentally affect, a practitioner’s capacity to practise the profession. [6]

How common is student substance abuse?

There  is  little  recent,  comprehensive  data  on  student  substance abuse, with most studies occurring in the 1980s-1990s and concerning rates of use rather than abuse. [5] Furthermore, prevalence studies are hindered by surveys requiring self-reporting of abuse and varied case definitions. With these limitations, the available data on student substance use is summarised below.

Alcohol use and abuse

Use of alcohol in the general student population is common, with consumption occurring in approximately 96% of Australians aged 18-21 years. For medical students in particular, international studies have indicated that rates of lifetime alcohol usage range between 62.3% and 98.1%. [2,5,7-11] Male medical students have higher levels of intake compared to females and hazardous alcohol use is significantly higher in those with high levels of psychological distress. [12] The BeyondBlue study of medical students and doctors found concerning rates of moderate-risk (21%) and high-risk (4%) drinking amongst medical students in Australia. [12] Moderate risk is classed as a hazardous intake level and high risk is associated with harmful drinking patterns, as assessed by the World Health Organisation Alcohol Use Disorders Identification Test (AUDIT). [12] This level of drinking, however, appears low in comparison to the general university population, which has an approximately 8.1% rate of harmful drinking. [12,13]

Internationally, 50% of medical students in the UK consumed above the recommended amount. [8] Using the CAGE questionnaire (Table 1),  22.4%  of  junior  Turkish  medical  students  and  52.5%  of  Irish medical students were found to be CAGE positive. [10,11] Of medical students who drink, 60.5% of men and 72.2% of women engaged in binge drinking, with 36.8% of men and 58.2% of women suggesting that their performance had been affected at least one day in the past month by alcohol consumption. [8] While the BeyondBlue study noted that drinking levels decreased with age, other data suggests that as students progress through their clinical years and beyond, a greater number of students drink, and drink more heavily. [10,14]

Drug use

Rates of illicit substance abuse in medical students appear comparable to, or less than that of, the general population, with data falling between 3-10%. [17] BeyondBlue reports show low rates, with 10.2% of students engaged in illicit drug use 2-3 times a month, and 0.5% 1-6 times a week. [12]

Drugs of abuse may be recreational, for example cannabis or stimulants, or prescription, such as benzodiazepines, opiates or propofol. Amongst junior students, the most common drug of abuse is cannabis and is often likely to be the first used before medical school. [2,8,14] Other illicit or prescription drugs are less common, however alcohol and cannabis might be considered gateway drugs to these. In one study, those who used cannabis were more likely to be drinking heavily than non-users and those who used illicit drugs had also used cannabis. [14] It is reported that medical students are increasingly being offered illicit drugs, and more are accepting them. [11] Abuse of illicit drugs, such as cocaine, or prescription drugs, such as benzodiazepines, was more likely to occur once at university. [2]

Notably, as students progress to become doctors, patterns of drug abuse change with increasing rates of prescription drug abuse. [5,10] Drugs of choice vary by medical specialty as to what is easiest to obtain; for example, anaesthetists have high rates of propofol and opiate abuse, whereas other specialties such as psychiatrists are more likely to abuse benzodiazepines. [1,18,19].

Recognition of substance abuse

Signs  of  substance  abuse  are  both  subtle  and  varied,  and  can  be easily missed. They are often disguised by the affected practitioner. Denial is common, and often it is the person with the disorder that is last to acknowledge a problem. [20] Early detection can prevent the development of significant harm. Table 2 lists possible emotional, social and physical signs of alcohol or drug abuse.

Reporting requirements

The impaired physician is a concept defined under national law as a physical or mental impairment, disability, condition or disorder (including substance abuse or dependence) that detrimentally affects, or is likely to detrimentally affect, a practitioner’s capacity to practise the profession. [6] For a student, the impairment must detrimentally affect, or be likely to detrimentally affect, the student’s capacity to undertake clinical training. This means impairment is defined by a student’s reduced capacity to learn, a quite broad definition. For a notification to the Australian Health Practitioner Regulation Agency (AHPRA) to be made, however, there must be a belief that their impairment could cause public harm, for instance intoxication at work. [6,23]

Two forms of notification can be made to AHPRA. [6] Mandatory notifications compel  practitioners  or  education  providers  to  make a notification if they form a reasonable belief that a student has an impairment that may place the public at substantial risk of harm in the course of their clinical training, or are practising whilst intoxicated with alcohol or drugs. Voluntary notifications about a student can be made by anyone if they form a reasonable belief that a student has an impairment that may cause public harm.

Consequences  of  notification  may  include  the  suspension  of  a student’s registration, the imposition of conditions of practice, further health assessment, and possible long-term impacts on their ability to continue their studies and future registration (depending on expert advice in each case). [6,23] For students, it is important to recognise the possible future career consequences of alcohol or drug abuse.

Management of the impaired student

Treatment  of  impairment  is  both  complex  and  individualised  and there is no standard protocol for treating impaired medical students. Treatment may be managed by the student and their treating team, or may be arranged by AHPRA or the medical board as a result of a notification.  Individual  medical  school  impairment  policies  likely vary and are not reviewed here. A majority of reviewed American school policies require direct referrals for management of suspected substance abuse cases, and one third forego disciplinary treatment for those impaired students who self-refer to promote seeking early intervention. [5] Depending on the substance(s) involved, treatment may include features such as inpatient treatment and detoxification, 12 step programs or use of therapeutic agents (e.g. naltrexone). [3]

Referral to a long-term support program with a specific focus on doctors’ health is optimal. Within Australia, available services and models of support vary from state to state. Most states offer a Doctor’s Health Advisory Service telephone counselling service, with support offered by experienced practitioners. [24] The Victorian Doctors’ Health Program (VDHP) offers the only full-time physician health program (PHP) of its kind in Australia. It is confidential, independent of AHPRA and open to both doctors and medical students. [25] PHPs were pioneered in the United States to assist in the rehabilitation of impaired physicians. They do not directly provide treatment but provide evaluation and diagnosis, facilitation of formal addiction treatment, on-going confidential support, case management, biochemical and workplace monitoring,  and  return-to-work support  as  required  on a case-by-case basis. [25,26] A core component is an individualised care contract lasting up to five years to ensure compliance with the appropriate treatment plan devised. This may include a case manager, psychiatrist, addiction specialist, psychologist, general practitioner or social worker. Ongoing peer support is also recommended through a facilitated Caduceus collegial support group open to medical practitioners and students with substance abuse issues, and has been shown to play an important role in recovery. [1] The VDHP offers three types of programs of different levels of support, ranging from intensive case management to wellbeing and support programs and long term follow up, depending on what is required in each case and the phase of recovery. These programs are successful, with studies consistently demonstrating success rates of 75-90% after five years for American physicians treated through PHPs. [27,28] Preliminary data from the VDHP program indicates similar Australian five-year success rates. [25]

The evidence-based success of these programs suggests that similar services should be available for all doctors. However, cost is a significant issue. The average American state PHP costs USD$521,000 annually to manage between 65 to 75 physicians per year, primarily paid for by an additional $23 charge to licensing fees, whilst formal treatment costs are covered by health insurance and personal physician contributions. [27] It is important to note that some PHPs produce better outcomes than others and that implementation should replicate published successful models and be followed with outcome evaluations. [29,30]

Further to specific services available to doctors, there is a wealth of support available through the pastoral support and wellbeing services of universities that can be accessed in a student capacity. One proactive university  even developed and successfully implemented an Aid for the Impaired Medical Student program to oversee medical student recovery management, although little has been published on this recently. [31]

Fighting the “conspiracy of silence”

Boisaubin and Levine discuss the concept of a “conspiracy of silence” where the impaired physician, his/her colleagues, friends and family have a tendency to dismiss their suspicions and suppress their concerns, with a belief that the physician is fine, or capable of solving his/her issues. [32] They state “denial is the most consistent hallmark of this disease process, for both colleagues and the susceptible physician.” This is a key barrier to treatment, and only increases with professional advancement in a medical culture of not admitting weakness, let alone acknowledging the presence of a medical condition laden with stigma. Participants in the VDHP substance use programs were most likely to have been referred by colleagues, employers or treating doctors, compared to self-referral or referral from regulatory bodies. [1] This demonstrates the importance of students and educators being aware of the signs of substance abuse in others, and knowing the options available to assist.

Future implications

There is little data about the risks of student substance abuse, but death or near fatal overdose is the presenting symptom in 7-18% of doctors. [33] Alarmingly, recent data demonstrates anaesthetists abusing propofol have a 45% mortality rate. [19] Substance abuse is also often coupled with psychiatric morbidity and stress-related disorders. Harm to patients is a real risk, either indirectly through impairment of capacity and decision making, or directly, such as in the well-publicised case of the fentanyl-abusing doctor spreading Hepatitis C to women undergoing pregnancy terminations. [34]

There is no clear longitudinal data to demonstrate whether substance abuse as a student is associated with substance abuse as a doctor. This article does not enter the debate as to whether impairment due to substance abuse as a student should preclude a student pursuing a career intimately associated with a range of drugs of abuse, such as opiates. Without prescribing rights, students are more limited in their access to the wide range of substances, compared with their qualified colleagues. It was noted that, of those surveyed in an evaluation of the VDHP Caduceus program, substance abuse issues began in medical school for 16% of the respondents. [1] Furthermore, the diagnosis of alcohol abuse is commonly delayed, often for years, and can start with patterns of high risk drinking.

Conclusion

In conclusion, substance use disorder has enormous impacts, including health  issues,  patient  risk,  mandatory  notification  requirements, future career implications and ultimately escalation to more dangerous substances. It is a chronic medical condition and management requires a multidisciplinary team, long-term support, sensitivity and experience. It is important to recognise that, while medical students are often high functioning and high achieving and generally appear to have similar rates of substance use to the general university population, they are not immune to substance abuse issues. In a profession with high levels of psychological distress, burnout and minor psychiatric morbidity, it is necessary to have a higher index of suspicion. [12] The biggest barrier to treatment is denial, not only by the impaired student, but also by friends, family and colleagues. It would therefore seem imperative that student substance abuse is detected early and treatment provided immediately to prevent the serious consequences of ignoring the situation.

If this article raises concerns for you or anyone you know, information on your local state service can be accessed at the Australasian Doctors’ Health Network website http://www.adhn.org.au/. Crisis support is available 24hrs/day from Lifeline Australia on 13 11 14.

For useful general wellbeing information focused on medical students, Keeping Your Grass Greener is a fantastic guide available from the Australian Medical Student Association at: https://www.amsa.org.au/ initiatives/community-and-wellbeing/keeping-your-grass-greener/

Acknowledgements

The author wishes to acknowledge Dr Kym Jenkins, Clinical Director of the Victorian Doctor’s Health Program for information on the management of substance abuse in Australia.

Conflict of interest

None declared.

Correspondence

L Fry: lefry3@student.monash.edu

References

[1] Wile C, Jenkins K. The value of a support group for medical professionals with substance use disorders. Australas Psychiatry [Internet]. 2013;21(5):481–5. Available from: http://apy.sagepub.com/lookup/doi/10.1177/1039856213498289

[2] Baldwin DC, Hughes PH, Conard SE, Storr CL, Sheehan DV. Substance Use Among Senior Medical Students: A Survey of 23 Medical Schools. JAMA. American Medical Association; 1991;265(16):2074–8.

[3]  American  Society  of  Anesthesiologists  Chemical  Dependency  Task  Force.  Model Curriculum  on  Drug  Abuse  and  Addiction  for  Residents  in  Anesthesiology  [Internet]. 2002 [cited 2015 Jan 11]. pp. 1–23. Available from: http://uthscsa.edu/gme/documents/ModelCurriculumonDrugAbuseandAdditionforResidentsinAnesthesiology.pdf

[4]   American   Psychiatric   Association.   Substance-Related   and   Addictive   Disorders. Diagnostic and Statistical Manual of Mental Disorders. Fifth Edition. American Psychiatric Association; 2014.

[5] Dumitrascu CI, Mannes PZ, Gamble LJ, Selzer JA. Substance Use Among Physicians and Medical Students. Medical Student Research Journal [Internet]. 2014;3:26–35. Available from: http://msrj.chm.msu.edu/wp-content/uploads/2014/04/MSRJ-Winter-2014-Substance-Use-Among-Physicians-and-Medical-Students.pdf

[6]  Australian  Health  Practitioner  Regulation  Agency  (AHPRA).  Legal  Practice  Note  – Students with an Impairment – LPN 5 [Internet]. AHPRA. 2013 [cited 2015 Jan 16]. pp. 1–4. Available from: http://www.ahpra.gov.au/Publications/legal-practice-notes.aspx

[7] Victorian Drug and Alcohol Prevention Council. 2009 Victorian Youth Alcohol and Drug Survey [Internet]. Department of Health (VIC); 2010. pp. 1–92. Available from: http://www.health.vic.gov.au/vdapc/downloads/vyads-report-01092010.pdf

[8] Pickard M, Bates L, Dorian M, Greig H, Saint D. Alcohol and drug use in second-year medical students at the University of Leeds. Med Educ. 2000;34(2):148–50.

[9] Conard S, Hughes P, Baldwin DC, Achenbach KE, Sheehan DV. Substance use by fourth- year students at 13 U.S. medical schools. J Med Educ. 1988;63(10):747–58.

[10] Akvardar Y, Demiral Y, Ergor G, Ergor A. Substance use among medical students and physicians in a medical school in Turkey. Soc Psychiatry Psychiatr Epidemiol. Steinkopff-Verlag; 2004;39(6):502–6.

[11] Boland M, Fitzpatrick P, Scallan E, Daly L, Herity B, Horgan J, et al. Trends in medical student use of tobacco, alcohol and drugs in an Irish university, 1973–2002. Drug Alcohol Depend. 2006;85(2):123–8.

[12] BeyondBlue. National Mental Health Survey of Doctors and Medical Students. 2014 Aug 22:1–156.

[13] Said D, Kypri K, Bowman J. Risk factors for mental disorder among university students in Australia: findings from a web-based cross-sectional survey. Soc Psychiatry Psychiatr Epidemiol. 2012;48(6):935–44.

[14] Newbury-Birch D, Walshaw D, Kamali F. Drink and drugs: from medical students to doctors. Drug Alcohol Depend. 2001;64(3):265–70.

[15] Mayfield D, McLeod G, Hall P. The CAGE questionnaire: validation of a new alcoholism screening instrument. Am J Psychiatry. 1974;131(10):1121–3.

[16] Ewing JA. Detecting alcoholism. The CAGE questionnaire. JAMA. 1984;252(14):1905–7.

[17] Dyrbye LN, Thomas MR, Shanafelt TD. Medical student distress: causes, consequences, and proposed solutions. Mayo Clin Proc. 2005;80(12):1613–22.

[18] Hughes PH, Storr CL, Brandenburg NA, Baldwin DC Jr., Anthony JC, Sheehan DV. Physician Substance Use by Medical Specialty. J Addict Dis. 2008;18(2):23–37.

[19] Fry RA, Fry LE, Castanelli DJ. A retrospective survey of substance abuse in anaesthetists in Australia and New Zealand from 2004 to 2013. Anaesth Intensive Care. 2015;43(1):111–7.

[20]  Bryson  EO,  Silverstein  JH.  Addiction  and  Substance  Abuse  in  Anesthesiology. Anesthesiology. 2008;109(5):905–17.

[21]  The  Association of  Anaesthetists of  Great  Britain  and  Ireland.  Drug  and  Alcohol Abuse  amongst  Anaesthetists Guidance on Identification and Management [Internet]. The Association of Anaesthetists of Great Britain and Ireland. 2011 [cited 2015 Jan 5]. 1–40. Available  from:  http://www.aagbi.org/sites/default/files/drug_and_alcohol_abuse_2011_0.pdf

[22] Berge KH, Seppala MD, Schipper AM. Chemical dependency and the physician. Mayo Clin Proc. 2009;84(7):625–31.

[23]  Australian  Health  Practitioner Regulation  Agency  (AHPRA).  Legal  Practice  Note  – Practitioners and Students with an Impairment – LPN 12 [Internet]. AHPRA. 2012 [cited 2015 Apr 14]. Available from: http://www.ahpra.gov.au/documents/default.aspx?record=WD13%2f9983&dbid=AP&chksum=cNb7VU68ZOvtXoQiaFacKA%3d%3d

[24] Doctors Health Advisory Service. Australasian Doctor’s Health Network [Internet].Australasian Doctors Health Network. 2015 [cited 2015 Apr 14]. Available from: http://www.adhn.org.au/

[25]  Wile  C,  Frei  M,  Jenkins  K.  Doctors  and  medical  students  case  managed  by  an Australian Doctors Health Program: characteristics and outcomes. Australas Psychiatry. 2011;19(3):202–5.

[26] DuPont RL, McLellan AT, Carr G, Gendel M, Skipper GE. How are addicted physicians treated? A national survey of Physician Health Programs. J Subst Abuse Treat. 2009;37(1):1–7.

[27] McLellan AT, Skipper GS, Campbell M, DuPont RL. Five year outcomes in a cohort study of physicians treated for substance use disorders in the United States. BMJ. 2008;337:a2038.

[28]  Skipper  GE,  Campbell  MD,  DuPont  RL.  Anesthesiologists  with  Substance  Use Disorders: A 5-Year Outcome Study from 16 State Physician Health Programs. Anesth Analg. 2009;109(3):891–6.

[29] DuPont RL, Skipper GE. Six Lessons from State Physician Health Programs to Promote Long-Term Recovery. J Psychoactive Drugs. 2012;44(1):72–8.

[30] Oreskovich MR, Caldeiro RM. Anesthesiologists recovering from chemical dependency: can they safely return to the operating room? Mayo Clin Proc. 2009;84(7):576–80.

[31]  Ackerman  TF,  Wall  HP.  A  programme  for  treating chemically  dependent  medical students. Med Educ. 1994;28(1):40–6–discussion55–7.

[32] Boisaubin EV, Levine RE. Identifying and assisting the impaired physician. Am J Med Sci. 2001;322(1):31–6.

[33]  Garcia-Guasch  R,  Roigé  J,  Padrós  J.  Substance  abuse  in  anaesthetists. Curr  Opin Anaesthesiol. 2012 Apr;25(2):204–9.

[34] Petrie A. Abortion doctor knew he had hepatitis C, court told [Internet]. The Age. 2011 [cited 2015 Mar 10]. Available from: http://www.theage.com.au/victoria/abortion-doctor-knew-he-had-hepatitis-c-court-told-20111206-1oh80.html

Apoptosis is considered the main form of cell death in cancer cells undergoing cytotoxic treatments such as chemotherapy and radiotherapy. However, disappointing treatment response rates in some cancers have prompted a rethink regarding oncological control methods. Cellular senescence has emerged as a possible tumour suppression strategy that may effectively control cancer cells when apoptosis fails. Understanding the mechanistic workings of senescence in the context of cancer cells may shed light on its feasibility as a clinical strategy.

Introduction

Conventional cancer therapeutics such as chemotherapy rely heavily on cytotoxicity to achieve maximal cell death. The rationale behind this approach is that elimination of cancer cells, and consequently tumour burden, will help achieve the best clinical outcome. Induction of cell death as an immediate clinical endpoint might be seen as an obvious choice, but it is worth contemplating whether this short-term benefit is incurred at the expense of long-lasting remissions. Many of the anti-cancer agents used in chemotherapy activate DNA damage signaling pathways which lead to apoptosis. However, apoptotic pathways tend to be defective in cancer cells. This could explain why response rates are sub-optimal despite aggressive regimens. The continued use of cytotoxic agents also promotes the development of resistant clones which can repopulate the primary tumour or metastasise to distal sites. If cell death is not always the best way to achieve sustainable cancer control, is there an alternative strategy or endpoint that overcomes the subversion of apoptotic cell death by tumour cells and is just as effective in blunting their proliferative nature?

One possible answer seems to be the induction of cellular senescence. Cellular senescence is classically defined as an irreversible state of growth arrest that occurs when cells encounter stress stimuli. Senescent cells are characterised by the following major features (Table 1).

 

Different forms of cellular senescence such as replicative (i.e. due to telomere shortening) or oncogene-induced senescence exist. Senescence-like phenotypes can be rapidly induced by genotoxic stress imposed by chemotherapy or radiotherapy, also known as accelerated cellular senescence (ACS). [1] Both apoptosis-competent and apoptosis-defective cancer cells may still be controlled by senescence, therefore implicating it as an important tumour-suppressive mechanism. [2] However, chemotherapy may not always provide durable responses as subsets of cancer cells are capable of escaping senescence and resuming cell division. The utility of senescence has, thus, remained inconclusive. This article will attempt to briefly explore the mechanistic insights of cellular senescence in cancer cells and assess its feasibility as a clinical strategy or endpoint in oncological control.

Mechanistic insights into the role of cellular senescence in cancer cells

It was originally observed that cells that undergo senescence often do not divide even in the presence of mitogenic stimuli. Genomic stress from the environment can induce DNA damage pathways which inhibit cell cycle progression. In cancer cells, two important pathways are the p53 and p16INK4a/pRB pathways. [2] p53, p16INK4a, and pRB are important tumour suppressor proteins. While the mechanisms are still unclear and the contributions of p53 and p16INK4a may differ in different cancer cell types, it is suggested that p53 may be important for the establishment of senescence while p16INK4a maintains it (Figure 1). [3,4]

 

Activation of p53 by stresses such as oxidation and telomere dysfunction lead to upregulation of the cyclin-dependent kinase (CDK) inhibitor p21^Waf1 which, in addition to apoptosis, causes cell cycle arrest and senescence. The activity of p53 is sustained by stress-induced DNA damage response signals which come from DNA damage foci, also known as DNA segments with chromatin alterations reinforcing senescence (DNA-SCARS). On the other hand, p16INK4a is essential for maintenance of senescence via the activation of the retinoblastoma (pRB) tumour suppressor protein. The pRB protein helps form senescence-associated heterochromatin foci (SAHF) which can silence tumour-promoting genes. [4]

Cancer cells can be cleared by apoptotic cell death, however, those which are resistant to initial apoptosis may be diverted to alternate pathways such as senescence, where they face a number of possible outcomes. [5] Firstly, cancer cells that undergo senescence are still capable of being eliminated by apoptosis at a later time. Secondly, senescent cancer cells may go into a terminal proliferative arrest state. It has been suggested that there is significant cross-talk between terminally arrested cancer cells and the immune system. Prolonged terminal arrest can trigger the clearance of cancer cells via phagocytosis and immunogenic cell death by autophagy. [6] Alternatively, immune mediators such as cytokines may be required for the maintenance of terminal arrest. [7] Dysregulation of this cross-talk can potentially result in bypass of cellular senescence and escape of cancer cells. The second outcome is interesting in a therapeutic sense as the involvement of immunogenic cell death is likely to bring about more sustained control than apoptosis. Apoptosis generally does not trigger an inflammatory response and the fact that cancer cells may harbor apoptotic defects suggests that this method of tumour suppression is not efficient. In fact, there is recent evidence that apoptosis may not even be the predominant mode of cell death in most cells, implying that other modes of cell death should be considered in cancer therapy. [8]

Senescence-associated secretory phenotype

While senescent cells exist in a state of growth arrest, they are still metabolically active and secrete a number of cytokines, chemokines, growth factors, and proteases which have important tumour-suppressive and tumour-promoting consequences. This unique phenotype is known as senescence-associated secretory phenotype (SASP) and can be found in senescent cells with DNA-SCARS. [9] As mentioned above, terminal arrest may be maintained by certain immune mediators. [4] These immune mediators may be secreted in an autocrine manner and help reinforce growth arrest. Examples of these tumour-suppressive mediators include plasminogen activator inhibitor-1 (PAI-1), and insulin-like growth factor binding protein-7 (IGFBP-7). On the other hand, tumour-promoting mediators can be secreted in a paracrine manner and induce aggressive phenotypes in neighbouring cells. These include factors such as matrix metalloproteinases (MMPs), amphiregulin, vascular endothelial growth factor (VEGF), as well as growth-related oncogene-alpha and beta (GRO-α & GRO-β). [4]

Certain pro-inflammatory cytokines such as interleukin-6 and interleukin-8 (IL-6 and IL-8) have paradoxical effects on tumour progression and their exact role may depend on the immune contexture. Chronic low-level inflammation can promote tumour progression whereas an acute high-grade inflammatory response can result in tumour regression. [10] It is worth postulating that the stimulation of immunogenic cell death via the second outcome may actually assist in augmenting pro-inflammatory cytokine levels in the acute phase, leading to elimination of cancer cells. On the other hand, apoptosis does not promote adequate IL-6 and IL-8 levels to result in clearance of these cells. Instead, epithelial-to-mesenchymal transition and the cell migration/invasion effects of these cytokines may become dominant, resulting in metastatic phenotypes. Besides secreting chemokines to attract immune cells, senescent cells also express ligands for cytotoxic immune cells such as natural killer (NK) cells, allowing for immune-mediated clearance of cancer cells. [11] It would seem counterintuitive that cellular senescence can have tumour-suppressive and tumour-promoting effects at the same time. How then, can we reconcile these paradoxical effects?

A temporal model of senescence

Cellular senescence is not a phenomenon restricted to cancer cells. In fact, it is a highly conserved process also found in normal cell types such as fibroblasts, and is involved in tissue repair as well as age-related degeneration. [12] Many of the tumour-promoting secreted factors found in the SASP are actually required for tissue regeneration. For example, VEGF is involved in angiogenesis while MMPs are required for degrading of fibrotic tissues found in damaged tissues. [13] Similarly, ageing tissues are characterised by low levels of chronic inflammation which can be mediated by factors such as IL-6 and IL-8. [14] The SASP is therefore a changing entity which differs in its secretory repertoire depending on the context it is expressed in. Rodier and Campisi proposed a model in which the senescent phenotype can be organised temporally. [15] In this model, the senescent phenotype increases in complexity with time. The initiating event is an oncogenic stress which either results in immediate repair and recovery of cells or induction of senescence.  Once senescence occurs, cells are terminally arrested, resulting in tumour suppression. The SASP is then activated and IL-1α is secreted. This cytokine binds to the IL-1 receptor and induces a signalling cascade which leads to the activation of transcription factors such as NF-kB and C/EBPβ. This in turn simulates SASP factors such as IL-6, IL-8, and matrix metalloproteinases (MMPs) which are involved in both tissue repair and tumour progression. At the same time, pro-inflammatory cytokines such as IL-6 and IL-8 may increase to such high levels that they feed back and reinforce tumour suppression.

In addition, senescent cells may express a number of cell surface ligands and adhesion molecules which attract immune cells and result in clearance. During the later stages of senescence, the SASP phenotype is tuned down through the expression of microRNAs such as mir146a and mir146b so as to prevent the persistence of an acute inflammatory response. [16] However, the consequence is a chronic inflammatory state which can be perpetuated by imperfect immune clearance. A small number of senescent cells persist and contribute to chronic inflammation via their pro-inflammatory cytokines, which can eventually lead to the formation of an ageing phenotype. This phenotype is characterised by impaired functionality and increased vulnerability to cell death. It is apparent from this model that there is a delicate balance between different SASP phenotypes and imperfect immune processes can easily tilt the balance towards detrimental outcomes such as tumour progression and ageing phenotypes.

Susceptibility to tumour progression is not unexpected considering that important tumour suppressive proteins such as p53 and p16INK4a are often deficient or defective in cancer cells. [17] Although the defects in p53 and/or p16INK4a can be hurdles, these ‘weaknesses’ also provide unique opportunities for therapeutic interventions. In fact, cellular senescence might have originated foremost as a beneficial biological response. From an evolutionary perspective, it is suggested that senescence could have evolved to promote tumour suppression and tissue repair in young organisms. [4] These activities were selected as they are necessary for organismal survival in early harsh environments. However, unselected activities such as tumour progression and aging still occur as survival to old age is rare in harsh environments, and therefore selection against these detrimental activities is weak and tends to decline with age. It is therefore quite likely that senescence was meant to be a major tumour-suppressive mechanism and not simply a ‘backup’ plan to the more widely recognised apoptotic cell death.

Cellular senescence as a clinical strategy

While cellular senescence was initially thought to be irreversible in normal cells, a few studies have suggested that this process is reversible in cancer cells under the right conditions. For example, studies focusing on the tumour suppressors p53, pRB, and p16 found that suppression of these proteins in fibroblasts led to the reversal of the senescent phenotype. [18] Similarly, lung cancer cells were able to escape senescence through the up-regulation of Cdc2/Cdk1 and subsequently increased production of survivin, a protein involved in cell resistance to chemotherapy drugs such as paclitaxel. [19] This potentially implicates senescent cells as a repository for re-emergence of carcinogenesis. However, it should be noted that that there is a lack of evidence which suggests that cell-cycle re-entry is a sign of recovery of full proliferative capacity. Cells which re-enter the cell cycle may still be subjected to cell death by apoptosis or mitotic catastrophe at a later stage. [20]

In solid tumours, the use of chemotherapy alone yields a disease response rate of 20-40% and complete tumour eradication is often difficult to achieve. Considering that most anti-cancer agents kill by apoptotic cell death, this seems to suggest that apoptosis may be limited in its clinical efficacy. [21] Furthermore, regardless of whether cellular senescence is reversible or not, in vivo analysis of treatment responses in primary lymphomas have shown that senescence improves the outcome of cancer therapy despite the lack of intact apoptotic machinery. [17] One of many possible reasons for the improved outcome could be the prevention of cancer stem cells (i.e. precursor cancer cells) via the inhibition of mechanisms similar to induced pluripotent stem (iPS) cell (i.e. stem cells generated from adult tissue) reprogramming. [21] This is because potent inducers of senescence such as p53 and p16INK4a are also potent inhibitors of iPS reprogramming. There is also potential for senescence-based therapies to yield synergistic and additive treatment effects as conventional modalities such as chemotherapy and radiotherapy can induce ACS. [22] Therefore, attempts should be made to further consider senescence as a potential treatment strategy.

There are a number of possible directions that can be pursued in a senescence-based strategy. Firstly, the activity of tumour suppressor proteins and senescence-inducers such as p53 can be enhanced. This can be attained through p53 stabilisation or mutant p53 reactivation. p53 stabilisation was found to be mediated by small molecules known as nutlins. These molecules inhibit the E3 ubiquitin-protein ligase MDM2, which is a potent inhibitor of p53. Similarly, restoration of p53 was achieved by compounds such as the pro-apoptotic factor PRIMA-1^MET  and DNA intercalator ellipticine, which  induce structural changes in the mutant protein and promote transcription of p53 targets . [23,24] Another possible target could be the inhibition of cell cycle progression via CDK inhibitors. One of the first CDK inhibitors to be tested in clinical trials is flavopiridol, which has been shown to exert tumour-suppressive effects in a number of malignancies such as colon and prostate cancer. [25] Flavopiridol, in certain doses, also appears to enhance treatment response when used in conjunction with standard chemotherapy agents, illustrating the proof of concept that senescence can augment existing treatment modalities.  More recently, studies have investigated the use of statins in patients after neoadjuvant chemotherapy. Statins were shown to down-regulate key cell cycle mediators such as Cdk1, cyclin B1, and survivin, and up-regulate the CDK inhibitor p27. [21] However, antagonistic effects were also observed when statins were administered alongside chemotherapy due to escape from senescence. These observations suggest that the effects of statins need to be examined further, particularly in relation to their use before, during, or after chemotherapy. Besides modulation of p53 function and the use of CDK inhibitors, senescence can also be induced by inhibition of important oncogenes such as MYC. [26] MYC over-expression in tumours is associated with a poor prognosis when chemotherapy is used. By inhibiting MYC through small molecule inhibitors such as 10058-F5 and its derivatives, the expression of a number of genes involved in cell proliferation can be suppressed, contributing to cellular senescence. [27]

Conclusion

In summary, cellular senescence may be a viable strategy for oncological control. Although its therapeutic potential was first recognised through its ability to bring about permanent growth arrest of cancer cells, this viewpoint is too simplistic. Cellular senescence is in fact a dynamic process characterised by a SASP which evolves in complexity with time. The reversibility or irreversibility of cellular senescence depends on the immune context and delicate processes that regulate senescence (e.g. immune clearance and deficiency of tumour suppressive proteins). Although senescence is dependent on multiple factors, we should consider it as a major tumour-suppressive mechanism alongside apoptosis. During carcinogenesis, subversion of anti-tumour responses is commonplace and should not be perceived simply as weaknesses in a clinical strategy. This is illustrated by the observation that cancer cells that do not apoptose can still subsequently undergo apoptosis at a later stage or are subjected to more immunogenic forms of cell death like autophagy. Senescence can therefore function as a potent failsafe tumour-suppressive mechanism.  On the contrary, therapeutic interventions should anticipate and augment existing barriers to tumour progression. In senescence, a number of possible solutions such as p53 enhancement, CDK inhibitors and oncogene inhibition provide reason for optimism and should be investigated further.

Acknowledgements

None.

Conflict of interest

None declared.

Correspondence

K Ho: koho2292@uni.sydney.edu.au

References

[1] Te Poele RH, Okorokov AL, Jardine L, Cummings L, Joel SP. DNA damage is able to induce senescence in tumour cells in vitro and in vivo. Cancer Res 2002; 62(6):1876-83.

[2] Miladi-Abdennadher I, Abdelmaksoud-Damak R, Ayadi L, Khabir A, Amouri A, Frikha F, et al. Expression of p16INK4a, alone or combined with p53, is predictive of better prognosis in colorectal adenocarcinoma in Tunisian patients. Appl Immunohistochem Mol Morphol 2011; 19(6):562-8.

[3] Yan Q, Wajapeyee N. Exploiting cellular senescence to treat cancer and circumvent drug resistance. Cancer Biol Ther 2010; 9(3):166-75.

[4] Campisi J. Cellular senescence: putting the paradoxes in perspective. Curr Opin Genet Dev 2011; 21(1):107-12.

[5] Chitikova ZV, Gordeev SA, Bykova TV, Zubova SG, Pospelov VA, Pospelova TV. Sustained activation of DNA damage response in irradiated apoptosis-resistant cells induces reversible senescence associated with mTOR downregulation and expression of stem cell markers. Cell Cycle 2014; 13(9):1424-39.

[6] Petrovski G, Ayna G, Majai G, Hodrea J, Benko S, Madi A, et al. Phagocytosis of cells dying through autophagy induces inflammasome activation and IL-1β release in human macrophages. Autophagy 2011; 7(3):321-30.

[7] Acquavella N, Clever D, Yu Z, Roelke-Parker M, Palmer DC, Xi L, et al. Type 1 cytokines synergize with oncogene inhibition to induce tumour growth arrest. Cancer Immunol Res 2015; 3(1):37-47.

[8] Tait SW, Ichim G, Green DR. Die another way—non apoptotic mechanisms of cell death. J Cell Sci 2014; 127(10):2135-44.

[9] Rodier F, Munoz DP, Teachenor R, Chu V, Le O, Bhaumik D, et al. DNA-SCARS: distinct nuclear structures that sustain damage-induced senescence growth arrest and inflammatory cytokine secretion. J Cell Sci 2011; 124(1):68-81.

[10] Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell 2010; 140(6):883-99

[11] Iannello A, Raulet DH. Immunosurveillance of senescent cancer cells by natural killer cells. Oncoimmunology 2014; 3:e27616. doi:10.4161/onci.27616.

[12] Kortlever RM, Bernards R. Senescence, wound healing and cancer: the PAI-1 connection. Cell Cycle 2006; 5(23):2697-703

[13] Kornek M, Raskopf E, Tolba R, Becker U, Klockner M, Sauerbruch T, et al. Accelerated orthotopic hepatocellular carcinomas growth is linked to increased expression of pro-angiogenic and prometastatic factors in murine liver fibrosis. Liver Int 2008; 28(4):509-18.

[14] Orjalo AV, Bhaumik D, Gengler BK, Scott GK, Campisi J. Cell surface-bound IL-1α is an upstream regulator of the senescence-associated IL-6/IL-8 cytokine network. Proc Natl Acad Sci USA 2009; 106(40):17031-36.

[15] Rodier F, Campisi J. Four faces of cellular senescence. J Cell Biol 2011; 192(4):547-56.

[16] Bhaumik D, Scott GK, Schokrpur S, Patil CK, Orjalo AV, Rodier F, et al. MicroRNAs miR-146a/b negatively modulate the senescence-associated inflammatory mediators IL-6 and IL-8. Aging (Albany NY) 2009; 1(4): 402-11.

[17] Schmitt CA, Fridman JS, Yang M, Lee S, Baranov E, Hoffman RM, et al. A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy. Cell 2002; 109(3):335-46.

[18] Coppe JP, Desprez PY, Krtolica A, Campisi J. The senescence-associated secretory phenotype: the dark side of tumour suppression. Annu Rev Pathol 2010; 5:99-108.

[19] Wang Q, Wu PC, Roberson RS, Luk BV, Ivanova I, Chu E, et al. Survivin and escaping in therapy-induced cellular senescence. Int J Cancer 2011; 128(7):1546-58.

[20] Khalem P, Dorken B, Schmitt CA. Cellular senescence in cancer treatment: friend or foe. J Clin Invest 2004; 113(2):169-74.

[21] Wu PC, Wang Q, Grobman L, Chu E, Wu DY. Accelerated cellular senescence in solid tumor therapy. Exp Oncol 2012; 34(3):298-305

[22] Gewirtz DA, Holt SE, Elmore LW. Accelerated senescence: an emerging role in tumour cell response to chemotherapy and radiation. Biochem Pharmacol 2008; 76(8):947-57.

[23] Zandi R, Selivanova G, Christensen CL, Gerds TA, Willumsen BM, Poulsen HS. PRIMA-1Met/APR-246 induces apoptosis and tumour growth delay in small cell lung cancer expressing p53. Clin Cancer Res 2011; 17(9):2830-41.

[24] Deane FM, O’Sullivan EC, Maguire AR, Gilbert J, Sakoff JA, McCluskey A, et al. Synthesis and evaluation of novel ellipticines as potential anti-cancer agents. Org Biomol Chem 2013; 11(8):1334-44.

[25] Motwani M, Li X, Schwartz GK. Flavopiridol, a cyclin-dependent kinase inhibitor, prevents spindle inhibitor-induced endoreduplication in human cancer cells. Clin Cancer Res 2000; 6(3):924-32.

[26] Reimann M, Lee S, Loddenkemper C, Dorr JR, Tabor V, Aichele P, et al. Tumour stroma-derived TGF-beta limits myc-driven lymphomagenesis via Suv39h1-dependent senescence. Cancer Cell 2010; 17(3):262-72.

[27] Wanner J, Romashko D, Werner D, May EW, Peng Y, Schulz R, et al. Reversible linkage of two distinct small molecule inhibitors of myc generates a dimeric inhibitor with improved potency that is active in myc over-expressing cancer cell lines. Plos One 2015; 10(4):e0121793.

Central sensitisation is the process whereby nociceptive inputs trigger increased excitability and synaptic efficiency of central nociceptive pathways, and is a key process in the development of chronic postoperative pain. Pre-emptive analgesia, whereby analgesia is given prior to surgical incision, has previously been advocated as a method of decreasing the process of central sensitisation and its clinical consequences – namely hyperalgesia, allodynia and chronic post-surgical pain (CPSP). A systematic review of pre-emptive analgesia has demonstrated positive studies existing only for the modalities of epidural analgesia, NSAIDs and local anaesthetic wound infiltration. [1]

A shift towards preventive analgesia has been advocated, a strategy in which analgesia is given for as long as the sensitising stimulus remains present. [2-6][Vadivelu, 2014 #8] This may include the preoperative, intraoperative and post-operative periods. Systematic reviews evaluating preventive analgesia have returned a greater proportion of favourable trials. In particular, NMDA antagonists have been shown to be promising in the preventive setting, and have been observed to decrease perioperative pain and post-operative analgesic consumption. [7]

The concept of pre-emptive analgesia, where the main focus is on the timing of the intervention with respect to incision, should be replaced with the broader approach of preventive analgesia. Appropriate analgesia should be provided for as long as a sensitising stimulus remains present. Further research should focus on determining the analgesic regimens that most effectively decrease the clinical consequences of central sensitisation, including hyperalgesia, allodynia and CPSP.

 Background

The relationship between intra-operative tissue damage and the amplification of post-operative pain was first described by Crile almost a century ago, in a process now referred to as central sensitization. [2] The concept of pre-emptive analgesia was proposed as a means of decreasing changes occurring in nociceptive pathways, resulting in minimisation of post-operative pain and analgesic consumption, as well as a decreased incidence of CPSP. [8] This approach involves the administration of analgesia prior to surgical incision. While this has been shown to effectively decrease dorsal horn changes associated with central sensitisation, clinical evidence has been equivocal. [9]

More recently, preventive analgesia has been proposed as a more effective method of modulating central sensitisation. Preventive analgesia focuses on blocking any nociceptive signals arriving at the dorsal horn by providing analgesia for as long as sensitising stimuli persist. [4] Interventions may extend from the pre-operative period until final wound healing, and are not confined to the pre-incisional period as for the pre-emptive approach. Preventive analgesia is defined in Acute Pain Management: Scientific Evidence as the “persistence of analgesic treatment efficacy beyond its expected duration”. [9, p.13] This approach has been found to be a more effective strategy for decreasing post-operative pain and analgesic consumption than a strictly pre-emptive approach. [2,6,9] Perioperative pain management should emphasise continuous analgesia for as long as a noxious stimulus is present, rather than focus on the timing of an intervention.

Central sensitisation

The surgical process produces nociceptive signals via several mechanisms, including skin incision, tissue damage and post-operative inflammation. Repeated afferent noxious signals at the level of the dorsal horn can induce neuronal hypersensitivity, mainly from alterations to glutamate receptors and ion channels. [4] Alterations at the dorsal horn include increased membrane excitability, greater synaptic efficiency and decreased activity of inhibitory interneurons. [10] This produces the clinical consequences of central sensitisation, namely hyperalgesia and allodynia. It may also lead to the development of chronic post-surgical pain (CPSP), which affects 10-50% of patients post-surgically, and is severe in 2-10% of these cases. [4]

While general anaesthesia attenuates the transmission of noxious afferent signals to the spinal cord, it does not completely block it. [3] Systemic opioids may similarly fail to provide sufficient blockade at the dorsal horn to prevent central sensitisation. Hence, while the patient is unconscious during the procedure, the stimuli necessary for central sensitisation persist, leading to increased post-surgical pain with greater analgesic consumption, and possibly increasing the chance of developing CPSP.

N-methyl-d-aspartate (NMDA) has been implicated as a key substance in the development of central sensitisation. [10] There has been increasing interest in the role of NMDA antagonists such as ketamine, dextromethorphan and magnesium as agents in providing preventive analgesia. Possible mechanisms include direct effects at the dorsal horn, and by reduction of the development of acute opioid tolerance. [7]

Search strategy

MEDLINE was searched through to June 2014 using the following search criteria: preventive OR pre-emptive OR preemptive AND analgesia. 1166 results were returned. Studies qualifying as level one evidence by NHMRC evidence hierarchy were included in the review (systematic reviews and meta-analyses). 1155 results were excluded from the review as they did not qualify as level one evidence. Eleven studies were identified for inclusion.

 Clinical evidence – pre-emptive analgesia

Clinical studies evaluating pre-emptive analgesia have shared several methodological flaws. Most often, this is due to a misunderstanding in what constitutes pre-emptive analgesia, with many studies instituting direct analgesia instead. There is also difficulty in establishing a valid control group, as all study participants must receive post-operative analgesia for ethical reasons. The administration of post-operative analgesia may attenuate the central sensitisation that occurs secondary to post-surgical inflammation, thus biasing the control group towards favourable outcomes.

Moiniche, Kehlet and Dahl reviewed double-blind, randomised, controlled trials (RCTs) which evaluated pre-incisional versus post-incisional analgesia, and the effect on postoperative pain control. [11] No clinical benefit was observed across the 80 included studies, across a spectrum of analgesic modalities. One included trial, however, found a significant reduction in pain at 6-months post radical prostatectomy with pre-emptive epidural analgesia. [12] An update on this systematic review revealed 30 further randomised trials published in the period 2001-2004. [13] Six out of eight trials published in this period reported reduced analgesic consumption and post-operative pain with pre-emptive NSAIDs .The results from studies evaluating other modalities remained uniformly negative.

A meta-analysis by Ong et al. [1] however supports the use of epidural analgesia, local anaesthetic wound infiltration and NSAID administration in the pre-emptive context. This analysis included RCTs comparing preoperative and intraoperative interventions. Outcomes measured were pain intensity scores, supplemental analgesic consumption and time to first analgesic consumption.

The meta-analysis by Ong et al. included 66 studies, with data from 3261 patients. The most marked effect size when combining outcome measures was observed with pre-emptive epidural analgesia (effect size 0.38; 95% CI, 0.28-0.47; p<0.01). Epidural analgesia produced a positive effect when the three outcome measures were considered individually.

For each of these outcome measures, an effect size was calculated in order to control for the variety of pain scales used across studies. The calculated effect size for each outcome was then combined to measure a single theoretical construct – termed ‘pain experience’. Where the effect size and confidence interval (CI) exceeded 0, the effect was deemed to be statistically significant. This differed to the approach by Moiniche et al., where the scores from the differing pain scales were converted into a single visual analogue scale (VAS) score and combined, and may have contributed to the conflicting results between the studies.

Anaesthetic wound infiltration and NSAID administration also produced statistically significant differences in ‘pain experience’. When outcomes were considered individually, time to first analgesic request was increased and analgesic consumption was decreased, but no effect on post-operative pain scores was observed. A 2012 systematic review of pre-emptive ketorolac administration observed decreased post-operative opioid requirements, and noted one small study which demonstrated benefits in post-operative pain scores. [14]

This meta-analysis includes trials that have since been withdrawn from publication. These trials related to pre-emptive local anaesthetic wound infiltration and NSAID administration. A re-analysis of the data by Marret et al. concluded that the retraction of these trials did not significantly alter the results of the study. [15] The study has further been criticised for a lack of detail regarding the review process, and the exclusion of non-English trials leading to publication bias. [1]

Katz and McCartney performed a systematic review of RCTs evaluating both pre-emptive and preventive approaches to analgesia, published from April 2001 to April 2002. [6] Of the twelve pre-emptive studies identified, five demonstrated a positive effect. The scope of the review is limited by the short time period analysed, but is the first to evaluate both pre-emptive and preventive study designs.

 Clinical evidence – preventive analgesia

15 studies evaluating the efficacy of preventive analgesia were identified by Katz and McCartney, nine of which were positive trials. [6] One of these positive trials, demonstrating pain reduction with bone marrow injection of opioids, has since been withdrawn from publication due to academic fraud. [16] Four of six studies examining the use of NMDA antagonists revealed lower post-operative pain and decreased analgesic consumption in the intervention group. Preventive effects were also observed with the use of clonidine and local anaesthetics.

The authors suggest that the percentage of positive trials observed in the study underestimates the true efficacy of preventive analgesia. This is because two of the pre-emptive trials may have in fact demonstrated preventive analgesia, but there was insufficient data presented regarding duration of analgesic effect to determine whether or not this had occurred. Three of the negative preventive studies were criticised due to inadequate provision of analgesia, thus precluding any preventive analgesic effect from occurring.

The limited amount of studies included means that the conclusions regarding the efficacy of preventive analgesia drawn from the review are weakened significantly by the retraction of the positive study by Reuben et al. [17] However, the study was influential in producing a shift from a pre-emptive approach to a preventive approach, by directly comparing these approaches in a single review. The efficacy observed in trials evaluating the role of NMDA antagonists also renewed interest in the role of these agents.

McCartney, Sinha and Katz performed a systemic review of RCTs evaluating NMDA antagonists (ketamine, dextromethorphan or magnesium) in preventive analgesia. [7] The primary outcome was reduction in pain, analgesic consumption or both in a time period beyond five half-lives of the drug utilised. Ketamine was found to have a positive effect in 58% (14 of 24) of included studies, and dexomethorphan was positive in 67% (8 of 12). No preventive effects were observed in four studies of magnesium.

The effect of NMDA antagonists on the incidence of CPSP is unclear. Low-dose intravenous ketamine administered with thoracic epidural analgesia has been observed to confer reduced post-thoracotomy pain in the immediate post-operative period and at one and three months after surgery. [18] A more recent RCT, however, noted no difference between ketamine and normal saline at four months post-thoracotomy, although it did confer post-operative pain relief. [19] The conflicting results may have been influenced by the difference in post-operative pain management, with the positive study providing a continuous ketamine infusion 3 days post-operatively. In the setting of colonic resection, a study of multimodal intraoperative epidural analgesia (local anaesthetic, opioids, ketamine and clonidine) revealed a reduction in pain 1-year post operatively. [20]

Practice guidelines

The aforementioned areas of uncertainty and controversy regarding pre-emptive and preventive analgesia have hindered the development of any formal guidelines to guide clinical practice. The Australian and New Zealand College of Anaesthetists (ANZCA) position statement ‘Guidelines on Acute Pain Management’ states that “preventive treatment of postoperative pain may reduce the incidence of chronic pain”. [21, p1] The ANCZA publication ‘Acute Pain Management: Scientific Evidence’ presents several key messages, and outlines the efficacy of pre-emptive epidural analgesia, preventive NMDA antagonist administration and ketamine (in colonic surgery only), but does not provide specific clinical recommendations. [9]

Regardless of the controversies that surround the issue, effective post-operative and long-term pain management is fundamental to quality patient care. Post-operative pain control should be individualised and a management plan should be developed prior to surgery, in partnership with the patient, taking into account psychosocial factors that may influence the pain experience. This should be based upon a thorough history, taking into account prior pain experiences, past analgesic use, current medications and immediate patient concerns. [2] ANZCA recommends a multimodal approach, as to improve efficacy of each drug, provide lower doses of individual drugs and reduce the risk of significant side effects. [21] Non-pharmacologic therapies should be instituted as a part of a multimodal approach where appropriate.

 

Conclusion

The process of central sensitisation has been the target of multiple methods of intervention in a wide array of treatment modalities, with the aim of decreasing post-operative pain, decreasing analgesic consumption and reducing the incidence of CPSP. The development of a meaningful evidence base has been encumbered by definitional confusion, difficulties with study design and academic misconduct leading to the retraction of articles. It is, however, apparent that the concept of pre-emptive analgesia should be replaced with the broader approach of preventive analgesia, and appropriate analgesia should be provided as long as a sensitising stimulus is present. Further research should focus on determining the analgesic regimens that most effectively decrease the clinical consequences of central sensitisation, including hyperalgesia, allodynia and CPSP.

Acknowledgements

The author would like to thank Dr. Andrew Powell, Staff Specialist Anaesthetist at John Hunter Hospital for providing feedback during the drafting of this article.

Conflict of interest

None declared.

Correspondence

L Anderson: luke.anderson2@hnehealth.nsw.gov.au

References

[1] Ong CK, Lirk P, Seymour RA, Jenkins BJ. The efficacy of preemptive analgesia for acute postoperative pain management: a meta-analysis. Anesth Analg 2005;100(3):757-73.

[2] Vadivelu N, Mitra S, Schermer E, Kodumudi V, Kaye AD, Urman RD. Preventive analgesia for postoperative pain control: a broader concept. Local Reg Anesth 2014;7:17-22.

[3] Katz J, Clarke H, Seltzer Z. Review article: Preventive analgesia: quo vadimus? Anesth Analg 2011;113(5):1242-53.

[4] Dahl JB, Kehlet H. Preventive analgesia. Curr Opin Anaesthesiol 2011;24(3):331-8.

[5] Pogatzki-Zahn EM, Zahn PK. From preemptive to preventive analgesia. Curr Opin Anaesthesiol 2006;19(5):551-5.

[6] Katz J, McCartney CJ. Current status of preemptive analgesia. Curr Opin Anaesthesiol 2002;15(4):435-41.

[7] McCartney CJ, Sinha A, Katz J. A qualitative systematic review of the role of N-methyl-D-aspartate receptor antagonists in preventive analgesia. Anesth Analg 2004;98(5):1385-400.

[8] Wall PD. The prevention of postoperative pain. Pain. 1988;33(3):289-90.

[9] Macintyre PE, Scott DA, Schug SA, Visser EJ, Walker SM, editors. Acute Pain Management: Scientific Evidence. 3rd ed: Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine; 2010.

[10] Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain. 2011;152(3 Suppl):S2-15.

[11] Moiniche S, Kehlet H, Dahl JB. A qualitative and quantitative systematic review of preemptive analgesia for postoperative pain relief: the role of timing of analgesia. Anesthesiology. 2002;96(3):725-41.

[12] Gottschalk A, Smith DS, Jobes DR, Kennedy SK, Lally SE, Noble VE, et al. Preemptive epidural analgesia and recovery from radical prostatectomy: a randomized controlled trial. JAMA. 1998;279(14):1076-82.

[13] Dahl JB, Moiniche S. Pre-emptive analgesia. Br Med Bull 2004;71:13-27.

[14] De Oliveira GS, Jr., Agarwal D, Benzon HT. Perioperative single dose ketorolac to prevent postoperative pain: a meta-analysis of randomized trials. Anesth Analg 2012;114(2):424-33.

[15] Marret E, Elia N, Dahl JB, McQuay HJ, Moiniche S, Moore RA, et al. Susceptibility to fraud in systematic reviews: lessons from the Reuben case. Anesthesiology. 2009;111(6):1279-89.

[16] Ni-Chonghaile M, Higgins BD, Costello J, Laffey JG. Hypercapnic acidosis attenuates lung injury induced by established bacterial pneumonia (Correction). Anesthesiology. 2009;110(3):689.

[17] Reuben SS, Vieira P, Faruqi S, Verghis A, Kilaru PA, Maciolek H. Local administration of morphine for analgesia after iliac bone graft harvest. Anesthesiology. 2001;95(2):390-4.

[18] Suzuki M, Haraguti S, Sugimoto K, Kikutani T, Shimada Y, Sakamoto A. Low-dose intravenous ketamine potentiates epidural analgesia after thoracotomy. Anesthesiology. 2006;105(1):111-9.

[19] Duale C, Sibaud F, Guastella V, Vallet L, Gimbert YA, Taheri H, et al. Perioperative ketamine does not prevent chronic pain after thoracotomy. Eur J Pain. 2009;13(5):497-505.

[20] Lavand’homme P, De Kock M, Waterloos H. Intraoperative epidural analgesia combined with ketamine provides effective preventive analgesia in patients undergoing major digestive surgery. Anesthesiology. 2005;103(4):813-20.

[21] Australian and New Zealand College of Anaesthetists Faculty of Pain Medicine. Guidelines on Acute Pain Management. ANZCA; 2013. [cited 2014 13/10]; Available from: http://www.anzca.edu.au/resources/professional-documents/pdfs/ps41-2013-guidelines-on-acute-pain-management.pdf.

Glycaemic control around the time of surgery is a critical part of surgical care in diabetic patients. There is a high prevalence of diabetes mellitus worldwide, and the disease is becoming more common in both medical and surgical patients. Even in patients without diabetes, surgery disrupts usual diabetic management and glucose homeostasis, often resulting in perioperative hyperglycaemia. Hyperglycaemia has been associated with increased postoperative mortality and morbidity, as well as worse surgical outcomes in both cardiac and non-cardiac surgery. Published evidence suggests that outcomes can be improved in perioperative patients by closer management and control of glucose.

Despite early studies in the intensive care unit (ICU) setting, subsequent trials were not able to demonstrate improved outcomes with the use of intensive insulin therapy, which aimed for stricter glycaemic control (4.5–6.0 mmol/L) that was closer to physiological ranges. Whilst the optimal blood glucose concentrations are still unknown, current literature supports the use of moderately strict glycaemic control (5.0–10.0 mmol/L) via a basal-bolus insulin regimen, so as to balance the risks of inducing hypoglycaemia with the benefits of avoiding hyperglycaemia.

Introduction

Diabetes mellitus is a highly prevalent group of metabolic diseases worldwide, and a significant proportion of surgical patients are diabetic. [1] An important component of diabetic perioperative management is glucose control, as glucose homeostasis is easily disrupted during periods of physical stress and illness. Recent studies have shown that hyperglycaemia during surgery is not a benign condition like it was once considered to be, and that treatment results in reduced mortality and morbidity. This literature review will focus on the current understandings of the effects of diabetes, how hyperglycaemia can affect clinical outcomes in the surgical setting, and the present consensus on the management of blood glucose in diabetic patients perioperatively.

Methods

This literature review is constructed as an unsystematic narrative review. The search for current literature was performed through the Ovid Medline database, the PubMed database, and the Cochrane Library. The following search terms and their related terms were used: perioperative glycaemic control, perioperative hyperglycaemic, perioperative diabetic management, intensive insulin therapy, sliding-scale insulin, basal bolus. The articles evaluated were limited to publication between January 1^st, 2000 and March 1^st, 2015. Articles published were restricted to the English language and to the adult surgical population. Given the breadth of literature on the topic, only major influential studies were selected for review. Studies performed on highly specific populations were excluded. Relevant retrospective observational studies, RCTs, and meta-analyses were included for analysis. Published review articles and editorials were examined for major influential studies. Any relevant in-text citations were also considered for inclusion. In total, forty-seven (n = 47) articles were selected for full text retrieval after abstract screening.

Background

Epidemiology

According to the Australian Institute of Health and Welfare, approximately 900 000 Australians have diabetes. [2] However, it has been estimated that up to half of all cases remain undiagnosed. [3] Similarly, the International Diabetes Federation estimates that diabetes prevalence in the adult Australian community is 9.99%. [4] Type 2 diabetes is the most common variant, accounting for 85-90% of all diabetics. [5] An audit across eleven hospitals in metropolitan Melbourne indicated that 24.7% of all inpatients had diabetes, with prevalence ranging from 15.7% to 35.1% in different hospitals. [6] Given the predicted exponential rise in obesity over the next decade and the current trend of an ageing population, projections suggest that 3.3 million Australians will have type 2 diabetes by 2031. [7]

Pathophysiology of diabetes

Although pathogenesis differs for the various forms of diabetes mellitus, hyperglycaemia is an underlying mechanism by which the disease can cause long-term complications. Diabetes is characterised by a lack of, or reduced effectiveness of, endogenous insulin, which then results in elevated fasting blood glucose concentrations and an inadequate response to glucose loads. Glucose homeostasis is tightly regulated, with normal blood glucose values being maintained within a narrow range between 4.4–7.8 mmol/L. [8] Chronic concentrations above 7.0 mmol/L are capable of producing end organ damage. [9]

Left untreated, diabetes mellitus is a disease associated with acute and chronic organ dysfunction and failure. Persistent hyperglycaemia leads to morbidity mainly through damaging medium and large-sized arteries (macrovascular disease) and causing capillary dysfunction in end organs (microvascular disease). Macrovascular disease increases the risk of developing ischaemic heart disease, cerebrovascular disease, and peripheral vascular disease, while microvascular disease results in diabetic retinopathy, nephropathy, and neuropathy. [10]

 Diabetes and surgery

Given the high prevalence of diabetes seen in the community and hospitals, we can expect a significant proportion of those who present for surgery to have the diagnosis. Diabetic complications such as ischaemic heart disease and diabetic eye disease also increase the likelihood of requiring surgical interventions, and it has been estimated that 50% of all diabetic patients will undergo surgery at some stage. [11] The prevalence of cardiovascular diseases, including hypertension, coronary artery disease and stroke, are two to four times higher in diabetic patients, compared to non-diabetics. [12] Diabetes is also the leading cause of end-stage renal failure, adult-onset blindness, and non-traumatic lower extremity amputations.

In addition, diabetes puts patients at a higher perioperative risk for adverse outcomes when compared to non-diabetics. Mortality has been reported to be up to 50% higher than that of the non-diabetic population. [13] Diabetic patients are also more likely to develop postoperative infections, arrhythmias, acute renal failure, ileus, stroke, and myocardial ischaemia. [14-16] Due to the wide range of complications that can occur, diabetic patients have a 45% longer length of stay postoperatively, with higher health care resource utilisation, compared with non-diabetic patients. [17]

Diabetic patients are prone to dysregulation of glucose homeostasis, especially during surgical stress or critical illness. Since most surgical patients will need to fast prior to surgery, there is often considerable disruption to their usual diabetes management routine. About 20% of elective surgical patients demonstrate impaired fasting blood glucose concentrations. [1] Other factors such as postoperative infections and emesis can all lead to labile blood glucose concentrations. Meanwhile, both surgery and anaesthesia produce a hypermetabolic stress response by elevating the levels of stress hormones and inflammatory cytokines such as catecholamines, cortisol, growth hormone, and TNF-α. [18] These hormones increase blood glucose concentrations by upregulating hepatic gluconeogenesis and glycogenolysis, as well as exacerbate insulin resistance and decrease insulin secretion. [18]

Discussion

Effects of perioperative hyperglycaemia and benefits of glycaemic control

Hyperglycaemia is a prevalent phenomenon in surgical patients. One study found that 40% of non-cardiac surgery patients had a blood glucose concentration >7.8 mmol/L, with 25% of those patients having a blood glucose concentration >10.0 mmol/L. [19] Perioperative hyperglycaemia was once considered to be a beneficial physiological adaptive response to surgery and critical illness, intended to supply energy to vital organs. This is now largely known to be untrue, with observational studies and randomised controlled trials indicating that improvement in glycaemic control results in lower morbidity and mortality, shorter length of stay, and fewer complications such as nosocomial infections, postoperatively. Outside of surgery, hyperglycaemia has also been associated with worse outcomes in critically ill, hospitalised patients. [20] Patients who are hyperglycaemic following a stroke demonstrate worse functional recovery and higher mortality compared to patients with normal glycaemic control. [21]

Retrospective observational studies

An observational study on patients undergoing non-cardiac surgery by Frisch et al. demonstrated that perioperative hyperglycaemia is associated with significantly increased risk of pneumonia, sepsis, urinary tract infection, skin infection, acute renal failure and death during the postoperative period. [19] Ramos et al. found a correlation between blood glucose concentrations and the rate of postoperative infection and length of hospital stay in general and vascular surgical patients. The study observed that every 2.2 mmol/L rise in postoperative blood glucose concentration above 6.1 mmol/L resulted in an increase in the infection rate by 30%. [22] In cardiac surgery, Gandhi et al. observed that intraoperative hyperglycaemia is an independent risk factor for post-operative complications, including death. [23] Schmeltz et al. demonstrated that the use of a combination of IV and subcutaneous insulin to improve glucose control in cardiac surgery reduced the mortality and infection rates among diabetic patients to those of non-diabetic patients. [24]

Hyperglycaemia has been shown to be the significant risk factor for perioperative morbidity and mortality, rather than diabetes itself. A retrospective cohort study based on 11,633 patients by Kwon et al. found that perioperative hyperglycaemia was associated with a near doubling in the risk of infection, mortality, and operative complications in both diabetic and non-diabetic general surgical patients. [25] A retrospective study by Doenst et al. concluded that a high peak blood glucose concentration during cardiopulmonary bypass was an independent risk factor for death and morbidity in diabetic patients. [26]

Prospective randomised controlled trials

A prospective randomised controlled study of surgical ICU patients by Van den Berghe et al. in 2001 (first Leuven study) demonstrated significantly reduced morbidity and mortality in critically ill patients when the blood glucose concentrations were maintained between 4.4–6.1 mmol/L via an intravenous insulin infusion. [27] In another randomised prospective study by Lazar et al., 141 diabetic cardiac surgery patients were assigned to either moderately tight glycaemic control (6.9–11.1 mmol/L) with a glucose-insulin-potassium (GIK) regimen, or to standard therapy (<13.9 mmol/L) using intermittent subcutaneous insulin. [28] The GIK patients had a lower incidence of atrial fibrillation and a shorter postoperative length of stay, compared to patients receiving standard therapy. The intervention was commenced prior to anaesthesia, and only continued for 12 hours postoperatively. Interestingly, the GIK patients were able to demonstrate a survival advantage two years postoperatively, with decreased episodes of recurrent myocardial ischaemia and fewer recurrent wound infections. This suggests that moderately tight control even for a brief period can make substantial differences to long-term outcomes.

The Diabetes Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study by Malmberg et al., which looked at 620 diabetic patients post-acute myocardial infarction, reported a 29% reduction in the 1-year mortality rate in patients who were randomised to receive intensive glucose management (mean blood glucose concentration of 9.6 mmol/L at 24 hours) when compared to patients assigned to receive conventional treatment (mean blood glucose concentration of 11.7 mmol/L at 24 hours). [29]

The question of whether the insulin therapy itself or the treatment of hyperglycaemia resulted in benefit has not been fully answered, as the metabolic and cellular actions of insulin may contribute to the beneficial outcomes. Insulin therapy has been shown to improve dyslipidaemias and prevent endothelial dysfunction and hypercoagulability in critically ill patients. [30] Treating a patient with insulin causes arterial vasodilation and capillary recruitment, via activation of the nitric oxide pathway and improves myocardial perfusion. [31] However, the first Leuven study found that the positive effects of intensive insulin therapy were related to the lower blood glucose concentrations, rather than insulin doses. [27]

Intensive versus conventional glycaemic control

Beyond avoidance of marked hyperglycaemia and hypoglycaemia, the optimal perioperative glucose targets are unclear. Conventional glycaemic control targets blood glucose concentrations <10.0 mmol/L, and there has been considerable controversy over the safety and efficacy of intensive insulin therapy (IIT), which aimed at a much lower and narrower concentration between 4.5–6.0 mmol/L. Despite early results, which suggested decreased mortality and other advantages of intensive glucose control, [27] later investigations found no benefits or increased mortality when hyperglycaemia was aggressively treated with insulin. [32-33] The current consensus is that intensive control does not actually confer any benefits with regards to mortality, but increases the risk for hypoglycaemia, which is a potentially life-threatening complication. [34] The brain is an obligate glucose metaboliser, hence neurons are particularly vulnerable to low blood glucose concentrations. Even brief periods of hypoglycaemia (i.e. blood glucose concentration <2.2 mmol/L) can induce arrhythmias, cardiac events, and brain injury. [35]

The first Leuven study published in 2001 by Van den Berghe et al. demonstrated significant reductions in morbidity and mortality (by 34%) in over 1500 surgical ICU patients with tight glycaemic control (4.4–6.1 mmol/L) when compared to conventional control (<10–11.1 mmol/L). [27] Intensive insulin therapy (IIT) was also shown to decrease the duration of mechanical ventilation and ICU length of stay. However, there were many study limitations that could have affected the validity of the results. Many subsequent randomised controlled trials and meta-analyses that were published contrasted with the initial Leuven study, finding no benefit when IIT was used for glycaemic control, as well as a significantly higher risk of hypoglycaemia. [32-34]

A second Leuven study published in 2006 by Van den Berghe et al. was a randomised controlled trial comparing IIT and conventional therapy in 1200 medical ICU patients, and it did not demonstrate any mortality benefit with intensive insulin therapy, while observing more prevalent hypoglycaemic events in the treatment group. [32] Kujik et al. observed that intensive glucose control in the perioperative period has no clear benefit on short-term mortality in patients undergoing major vascular surgery, and recommended that moderate tight glucose control be regarded as the safest and most efficient approach to patients undergoing surgery. [36] Duncan et al. found that in cardiac surgery, although severe intraoperative hyperglycaemia (>11.1 mmol/L) was associated with higher risk of mortality and morbidity, blood glucose concentrations closest to normoglycaemia (average of 7.78 mmol/L or less) were also associated with increased mortality and morbidity. [37] In fact, the lowest risk of adverse outcomes was observed in the range between 7.8–9.4 mmol/L, suggesting that mild hyperglycaemia was better tolerated than strict control. The association of tight blood glucose control with worse outcomes was observable despite rare episodes of hypoglycaemia, which suggests that there are factors other than hypoglycaemia that could contribute to the poor outcomes of intensive glucose control.

The largest and most definitive study to date is the Normoglycaemia in Intensive Care Evaluation – Survival Using Glucose Algorithm Regulation (NICE-SUGAR) study, which was a multicentre, international, randomised controlled trial aimed at comparing intensive insulin therapy (4.5–6 mmol/L) with conventional treatment (8–10 mmol/L). [33] The study reported a higher 28-day and 90-day mortality rate in surgical ICU patients who received IIT, with significantly more severe hypoglycaemia in those patients. The authors were not able to demonstrate a difference in hospital or ICU length of stay, length of mechanical ventilation, or the need for renal replacement. In contrast to the initial Leuven study, mortality rates were higher in the IIT group (27.5% vs 24.9%). The NICE-SUGAR trial also reaffirmed a higher incidence of hypoglycaemia in the IIT group.

A Cochrane meta-analysis of 12 randomised trials (1403 patients with diabetes) comparing intensive (blood glucose concentration of <6.7 or <8.3 mmol/L) versus conventional (variable) glycaemic control by Buchleitner et al. also found that intensive glycaemic control has no significant effect on infectious complications, cardiovascular events, or mortality, except for increasing the number of hypoglycaemic episodes. [34] Given the current data available from randomised controlled clinical trials, the authors concluded that intensive glycaemic control protocols with near-normal blood glucose targets cannot be generally recommended for patients with diabetes undergoing surgery.

Basal-bolus versus sliding scale insulin

Insulin is generally the preferred method of treatment for inpatients as it is an effective medication for immediate control of hyperglycaemia in the hospital setting. The dose can be titrated more rapidly than that of oral hypoglycaemic agents, and it does not have a dose ceiling. Insulin can be delivered either subcutaneously or intravenously as a continuous infusion, and the use of sliding-scale insulin (SSI) has traditionally been the mainstay of hyperglycaemia therapy. However, recent studies have shown that the use of SSI alone is insufficient in providing adequate glycaemic control, and that a combination of basal and supplemental insulin is a more effective approach.

The combined use of basal insulin (i.e., intermediate- to long-acting insulin) together with short- or rapid-acting insulin before meals is able to better mimic physiological patterns of glucose control. The RABBIT 2–Medical trial by Umpierrez et al. demonstrated an improvement in glycaemic control with basal-bolus insulin in 130 diabetic insulin-naïve medical patients, with no increase in the number of hypoglycaemic events. [38] The subsequent RABBIT 2–Surgical trial, which is a multi-institutional randomised trial that looked at 211 type 2 diabetic general surgical patients, also found improved glycaemic control and reduced hospital complications with the basal-bolus regimen when compared to the sliding-scale insulin regimen. [39] The most recent evidence suggests that both medical and surgical type 2 diabetic patients with poor glycaemic control (blood glucose concentration >10 mmol/L or HbA1c >7.5%) should be treated with the basal-bolus insulin regimen. [40]

Current Recommendations

Figure 1. Recommended perioperative BSL targets.

Given that studies have failed to show a benefit and some even show increased mortality with intensive insulin therapy, the management of glucose concentrations has undergone drastic changes in the past decade. Current recommendations from the UK, US, and Australia all recommend a similar range of blood glucose concentrations (Figure 1). Most guidelines tolerate mild hyperglycaemia as it reduces the potential for developing hypoglycaemia. Insulin therapy in both general medical and surgical settings should consist of a mixture of basal, prandial, and supplemental insulin (basal-bolus), instead of the sliding-scale regimen. However, differences in these recommendations indicate that the most optimal blood glucose concentrations are still unknown.

Preoperative insulin therapy should focus on obtaining good glycaemic control, while avoiding episodes of hypoglycaemia. The Endocrine Society’s Clinical Guidelines recommend a fasting blood glucose concentration of <7.8 mmol/l and a random blood glucose concentration of <10.0 mmol/l for the majority of hospitalised patients with non-critical illness. [41] For avoidance of hypoglycaemia, therapy should be reassessed when blood glucose concentration falls below 5.6 mmol/L. Similarly, the National Health Service Diabetes Guideline published in 2012 by Dhatariya et al. recommends blood glucose concentrations between 6.0–10.0 mmol/L, while accepting 4.0–12.0 mmol/L. [42] The Australian Diabetes Society currently recommends a blood glucose target of 5.0–10.0 mmol/L in both the ICU and non-ICU settings. [43] The American Diabetes Association and the American Association of Clinical Endocrinologists currently recommend commencing insulin therapy for critically ill patients with persistent hyperglycaemia (>10.0 mmol/L), and to aim for a blood glucose target range between 7.8–10.0 mmol/L, [44] while the American College of Physicians recommends 7.8–11.1 mmol/L  for critically ill patients. [45]

The mainstay of type 2 diabetes therapy is oral hypoglycaemic agents, such as metformin and sulfonylureas. Most guidelines suggest withholding oral anti-diabetic agents and non-insulin injectable medications on the day of surgery but not before. For major surgeries, metformin should be withheld for at least 24 hours. This is because oral diabetic medications can potentially produce hypoglycaemia during the fasting period prior to surgery, as well as systemic effects that may affect postoperative outcomes. For example, sulfonylureas can interfere with the opening of cardiac K_ATP channels, which increases the risk for myocardial ischaemic injury. [46] Metformin can potentially induce lactic acidosis if renal function is impaired. [47] However, ceasing anti-diabetic therapy too early may compromise glucose control, hence short- or medium-duration insulin should be used to treat acute hyperglycaemia during the operative period. Oral hypoglycaemic agents should not be restarted until adequate and regular oral intake is resumed.

The majority of patients receiving insulin therapy should use a basal-bolus insulin schedule. The long-acting agents are aimed at providing a steady, basal level of insulin while the shorter-acting bolus insulin is used to counter acute increases in blood glucose. It is important to note that not only type 1 diabetics, but all insulin dependent patients, will require insulin perioperatively, despite their fasting status. This is because these patients are insulin deficient and require consistent basal insulin replacement to prevent unchecked gluconeogenesis and ketosis.

Conclusion

Hyperglycaemia has been shown to produce deleterious effects in multiple body systems, both acutely and chronically. Studies indicate that adequate glycaemic control during the perioperative period is beneficial for both short-term and long-term surgical outcomes. While the optimal target blood glucose range is still unclear, the literature supports the use of moderately strict glycaemic control for the management of hyperglycaemia in surgical patients. The use of basal-bolus insulin is preferred over the more traditional sliding-scale insulin for its efficacy and safety. With the current trend of rising diabetes incidence in Australia, maintaining good glycaemic control during the perioperative period will become an increasingly important challenge faced by health professionals.

Acknowledgements

Professor Kate Leslie, Head of Research, Department of Anaesthesia and Pain Management, Royal Melbourne Hospital, Melbourne, Australia for her critical review and helpful comments and suggestions.

Conflict of interest

None declared.

Correspondence

A Zhang: zazhang@student.unimelb.edu.au

References

[1] Hatzakorzian R, Bui H, Carvalho G, Shan WL, Sidhu S, Schricker T. Fasting blood glucose levels in patients presenting for elective surgery. Nutrition. 2011;27(3):298-301.

[2] Australian Institute of Health and Welfare (AIHW). Diabetes prevalence in Australia: detailed estimates for 2007-2008. Diabetes series no. 17. Cat. no. CVD 56. Canberra: AIHW; 2011. [Cited 12 Aug 2014] Available from: http://www.aihw.gov.au/publication-detail/?id=10737419311

[3] Valentine NA, Alhawassi TM, Roberts GW, Vora PP, Stranks SN, Doogue MP. Detecting undiagnosed diabetes using glycated haemoglobin: an automated screening test in hospitalised patients. Med J Aust. 2011;194(4):160-4.

[4] International Diabetes Federation. IDF Diabetes Atlas. 6th ed. Brussels, Belgium: IDF; 2013. [Cited Feb 2015]. Available from: http://www.idf.org/diabetesatlas

[5] World Health Organization. Definition, diagnosis and classification of diabetes mellitus and its complications; Part 1: Diagnosis and classification of diabetes mellitus. Department of Noncommunicable Disease Surveillance, Geneva, 1999. (WHO/NCD/NCS/99.2).

[6] Bach LA, Ekinci EI, Engler D, Gilfillan C, Hamblin PS, MacIsaac RJ, et al. The high burden of inpatient diabetes mellitus: the Melbourne Public Hospitals Diabetes Inpatient Audit. Med J Aust. 2014;201(6):334-8.

[7] Vos T, Goss J, Begg S, Mann N. Australian Burden of Disease and Injury Study, Projected Health Care Costs Report. University of Queensland and AIHW, Canberra, 2007.

[8] Engelgau MM, Narayan KM, Herman WH. Screening for type 2 diabetes. Diabetes Care. 2000;23(10):1563-80.

[9] Bash LD, Selvin E, Steffes M, Coresh J, Astor BC. Poor glycemic control in diabetes and the risk of incident chronic kidney disease even in the absence of albuminuria and retinopathy: Atherosclerosis Risk in Communities (ARIC) Study. Arc Intern Med. 2008;168(22):2440-7.

[10] Fowler MJ. Microvascular and macrovascular complications of diabetes. Clin Diabetes. 2008;26(2):77-82.

[11] Clement S, Braithwaite SS, Magee MF, Ahmann A, Smith EP, Schafer RG, et al. Management of diabetes and hyperglycemia in hospitals. Diabetes Care. 2004;27(2):553-91.

[12] Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the multiple risk factor intervention trial. Diabetes Care. 1993;16:434-44.

[13] Stentz FB, Umpierrez GE, Cuervo R, Kitabchi AE. Proinflammatory cytokines, markers of cardiovascular risks, oxidative stress, and lipid peroxidation in patients with hyperglycemic crises. Diabetes. 2004;53(8):2079-86.

[14] Godoy DA, Di Napoli M, Biestro A, Lenhardt R. Perioperative glucose control in neurosurgical patients. Anesthesiol Res Pract 2012; 2012: 690362

[15] Milaskiewicz RM, Hall GM. Diabetes and anaesthesia: the past decade. Br J Anaesth. 1992;68(2):198-206.

[16] Thourani VH, Weintraub WS, Stein B, Gebhart SS, Craver JM, Jones EL, et al. Influence of diabetes mellitus on early and late outcome after coronary artery bypass grafting. Ann Thorac Surg. 1999;67:1045-52.

[17] Hall GM, Page SR. Diabetes and surgery. In: Page SR, Hall GM, editors. Emergency and hospital management. London: BMJ Publishing; 1999.

[18] Meneghini LF. Perioperative management of diabetes: Translating evidence into practice. Cleve Clin J Med. 2009;76(Suppl 4):S53-9.

[19] Frisch A, Chandra P, Smiley D, Peng L, Rizzo M, Gatcliffe C, et al. Prevalence and clinical outcome of hyperglycemia in the perioperative period in noncardiac surgery. Diabetes Care. 2010;33(8):1783-8.

[20] Krinsley JS. Effect of an intensive glucose management protocol on the mortality of critically ill adult patients. Mayo Clin Proc. 2004;79:992-1000.

[21] Capes SE, Hunt D, Malmberg K, Pathak P, Gerstein HC. Stress hyperglycemia and prognosis of stroke in nondiabetic and diabetic patients: a systematic overview. Stroke. 2001;32(10):2426-32.

[22] Ramos M, Khalpey Z, Lipsitz S, Steinberg J, Panizales MT, Zinner M, et al. Relationship of perioperative hyperglycemia and postoperative infections in patients who undergo general and vascular surgery. Ann Surg. 2008;248(4):585-91.

[23] Gandhi GY, Nuttall GA, Abel MD, Mullany CJ, Schaff HV, Williams BA, et al. Intraoperative hyperglycemia and perioperative outcomes in cardiac surgery patients. Mayo Clin Proc. 2005;80(7):862-6.

[24] Schmeltz LR, DeSantis AJ, Thiyagarajan V, Schmidt K, O’Shea-Mahler E, Johnson D, et al. Reduction of surgical mortality and morbidity in diabetic patients undergoing cardiac surgery with a combined intravenous and subcutaneous insulin glucose management strategy. Diabetes Care. 2007;30:823-828.

[25] Kwon S, Thompson R, Dellinger P, Yanez D, Farrohki E, Flum D. Importance of perioperative glycemic control in general surgery: a report from the Surgical Care and Outcomes Assessment Program. Ann Surg. 2013;257(1):8-14.

[26] Doenst T, Wijeysundera D, Karkouti K, Zechner C, Maganti M, Rao V, et al. Hyperglycemia during cardiopulmonary bypass is an independent risk factor for mortality in patients undergoing cardiac surgery. J Thorac Cardiovasc Surg. 2005;130(4):1144.

[27] Van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, et al. Intensive insulin therapy in critically ill patients. N Engl J Med. 2001;345(19):1359-67.

[28] Lazar HL, Chipkin SR, Fitzgerald CA, Bao Y, Cabral H, Apstein CS. Tight glycemic control in diabetic coronary artery bypass graft patients improves perioperative outcomes and decreases recurrent ischemic events. Circulation. 2004;109(12):1497-502.

[29] Malmberg K. Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. DIGAMI (Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction) Study Group. BMJ. 1997;314(7093):1512-5.

[30] Van den Berghe G. How does blood glucose control with insulin save lives in intensive care? J Clin Invest. 2004;114(9):1187-95.

[31] Duncan AE. Hyperglycemia and perioperative glucose management. Curr Pharm Des. 2012;18(38):6195-203.

[32] Van den Berghe G, Wilmer A, Hermans G, Meersseman W, Wouters PJ, Milants I, et al. Intensive insulin therapy in the medical ICU. N Engl J Med. 2006;354(5):449-61.

[33] Investigators N-SS, Finfer S, Chittock DR, Su SY, Blair D, Foster D, et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360(13):1283-97.

[34] Buchleitner AM, Martinez-Alonso M, Hernandez M, Sola I, Mauricio D. Perioperative glycaemic control for diabetic patients undergoing surgery. Cochrane Database Syst Rev. 2012;9:CD007315.

[35] Desouza CV, Bolli GB, Fonseca V. Hypoglycemia, diabetes, and cardiovascular events. Diabetes Care. 2010;33(6):1389-94.

[36] van Kuijk JP, Schouten O, Flu WJ, den Uil CA, Bax JJ, Poldermans D. Perioperative blood glucose monitoring and control in major vascular surgery patients. Eur J Vasc Endovasc Surg. 2009;38(5):627-34.

[37] Duncan AE, Abd-Elsayed A, Maheshwari A, Xu M, Soltesz E, Koch CG. Role of intraoperative and postoperative blood glucose concentrations in predicting outcomes after cardiac surgery. Anesthesiology. 2010;112(4):860-71.

[38] Umpierrez GE, Smiley D, Zisman A, Prieto LM, Palacio A, Ceron M, et al. Randomized study of basal-bolus insulin therapy in the inpatient management of patients with type 2 diabetes (RABBIT 2 trial). Diabetes Care. 2007;30(9):2181-6.

[39] Umpierrez GE, Smiley D, Jacobs S, Peng L, Temponi A, Mulligan P, et al. Randomized study of basal-bolus insulin therapy in the inpatient management of patients with type 2 diabetes undergoing general surgery (RABBIT 2 surgery). Diabetes Care. 2011;34(2):256-61.

[40] Umpierrez GE, Smiley D, Hermayer K, Khan A, Olson DE, Newton C, et al. Randomized study comparing a Basal-bolus with a basal plus correction insulin regimen for the hospital management of medical and surgical patients with type 2 diabetes: basal plus trial. Diabetes Care. 2013;36(8):2169-74.

[41] Umpierrez GE, Hellman R, Korytkowski MT, Kosiborod M, Maynard GA, Montori VM, et al. 
Management of hyperglycemia in hospitalized patients in non-critical care setting: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2012;97(1):16-38.

[42] Dhatariya K, Levy N, Kilvert A, Watson B, Cousins D, Flanagan D, et al. NHS Diabetes guideline for the perioperative management of the adult patient with diabetes. Diabet Med. 2012;29(4):420-33.

[43] Australian Diabetes Society. Peri-operative Diabetes Management Guidelines. 2012. [Cited 10 September 2014]. Available from: https://diabetessociety.com.au/documents/PerioperativeDiabetesManagementGuidelinesFINALCleanJuly2012.pdf

[44] Moghissi ES, Korytkowski MT, DiNardo M, Einhorn D, Hellman R, Hirsch IB, et al. American Association of Clinical Endocrinologists and American Diabetes Association Consensus statement on inpatient glycemic control. Diabetes Care. 2009;32(6):1119-31.

[45] Qaseem A, Humphrey LL, Chou R, Snow V, Shekelle P. Use of intensive insulin therapy for the management of glycemic control in hospitalized patients: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2011;154(4):260-7.

[46] Garratt KN, Brady PA, Hassinger NL, Grill DE, Terzic A, Holmes DR, Jr. Sulfonylurea drugs increase early mortality in patients with diabetes mellitus after direct angioplasty for acute myocardial infarction. J Am Coll Cardiol. 1999;33(1):119-24.

[47] Mercker SK, Maier C, Neumann G, Wulf H. Lactic acidosis as a serious perioperative complication of antidiabetic biguanide medication with metformin. Anesthesiology. 1997;87(4):1003-5.