Key reference:

Hamblin, P. S., Wong, R., Ekinci, E. I., Sztal-Mazer, S., Balachandran, S., Frydman, A., Hanrahan, T. P., Hu, R., Ket, S. N., Moss, A., Ng, M., Ragunathan, S., & Bach, L. A. (2021). Capillary Ketone Concentrations at the Time of Colonoscopy: A Cross-Sectional Study With Implications for SGLT2 Inhibitor–Treated Type 2 Diabetes. Diabetes Care, 44(6), e1–e3. https://doi.org/10.2337/DC21-0256

Quick Summary

• Recent case series highlighted an association between diabetes patients taking sodium-glucose cotransporter 2 inhibitors (SGLT2 inhibitors) undergoing colonoscopy and development of diabetic ketoacidosis (DKA).

• Previous guidelines recommend postponing colonoscopies if capillary ketone concentrations exceed 1.0 mmol/L without withholding SGLT2 inhibitors for 72 hours, but this was formulated without data on non-diabetic patients ketone levels during colonoscopy.

• To address this gap, the multicentre observational study by Hamblin et al. (2021) study investigated capillary ketone concentrations in patients undergoing colonoscopies and compared normoglycemic adults with those of diabetic patients, taking and not taking SGLT2 inhibitors.

• In normoglycemic individuals undergoing colonoscopy, the reference capillary ketone concentrations was determined to be 0.0–1.7 mmol/L

• However, the study found no statistically significant differences in ketone concentrations between diabetics treated with SGLT2 inhibitors and those who are not diabetic or not treated with SGLT2 inhibitors (p=0.051)

• Caution is warranted in interpreting the 1.7 mmol/L threshold as safe for those taking SGLT2 inhibitors (i.e not withheld for 72hrs)

• The study highlights the need for appropriate monitoring and management strategies to mitigate the risk of DKA in SGLT2 inhibitor-treated patients undergoing colonoscopy

CASE

James Smith is a 70 year-old gentleman with Type 2 diabetes who presents for a Cat 2 colonoscopy for investigation of iron deficiency anaemia. Despite instructions to withhold his sodium-glucose cotransporter 2 inhibitor (SGLT2 inhibitor) medication 2 full days before the procedure and on the day of procedure, he admits that he has taken his regular empagliflozin, having forgotten which pill not to take.

“I’m sorry, doc. It shouldn’t be a problem, right?”

The Basics

Diabetic Ketoacidosis

Diabetic ketoacidosis (DKA) is a serious complication of diabetes mellitus characterised by hyperglycaemia (high blood sugar levels), ketosis (elevated ketone bodies in the blood), and metabolic acidosis (increased acidity in the blood).

It typically occurs in individuals with type 1 diabetes (T1DM) but can also affect those with type 2 diabetes (T2DM), particularly in cases of severe insulin deficiency.

In DKA, the body’s cells are unable to access glucose for energy due to insulin deficiency, leading to increased fat breakdown and the production of ketone bodies as an alternative fuel source.

This results in elevated blood ketone levels, leading to metabolic acidosis, dehydration, electrolyte imbalances, and potentially life-threatening complications if left untreated.

Table 1: Risk Factors for DKA

Symptoms of DKA may include excessive thirst, frequent urination, nausea, vomiting, abdominal pain, rapid breathing, and confusion.

Prompt medical intervention, including intravenous fluids, insulin therapy and correction of electrolyte abnormalities is essential to manage DKA and prevent complications. The specific diagnostic criteria and management of DKA are beyond the scope of this article, and local protocols and relevant departments (Endocrine, Intensive Care) should be consulted immediately.

Sodium-Glucose Cotransporter 2 Inhibitors (SGLT2 inhibitors) and DKA:

Sodium-glucose cotransporter 2 inhibitors (SGLT2 inhibitors) are a class of medications used in the management of T2DM.

These medications work by inhibiting the action of the SGLT2 protein in the kidneys, which is responsible for reabsorbing glucose from the urine back into the bloodstream. SGLT2 inhibitors promote the excretion of glucose in the urine, leading to a decrease in blood sugar levels.

They are typically used as second or third-line therapy to diet and exercise in patients with T2DM who have not achieved adequate glycemic control with other antidiabetic medications, such as metformin or sulfonylureas.

SGLT2 inhibitors have also been incorporated into the management of heart failure with reduced ejection fraction (HFrEF) and chronic nephropathy, with robust evidence demonstrating reductions in hospitalisation and mortality rates independent of diabetes status.

There is also emerging evidence to show benefits for patients with heart failure with preserved ejection fraction (HFpEF). The EMPEROR-Preserved trial demonstrated that SGLT2 inhibitors, specifically empagliflozin, reduced the risk of decompensation-related hospitalisation irrespective of their diabetes status. This landmark trial highlighted the efficacy of SGLT2 inhibitors in improving outcomes for patients with HFpEF, a condition for which effective treatment options remain limited.

SGLT2 inhibitors are generally well-tolerated but may be associated with side effects such as urinary tract infections, genital yeast infections, and an increased risk of DKA, particularly in patients with additional risk factors such as dehydration or acute illness.

DKA can occur in patients treated with SGLT2 inhibitors with both high blood glucose levels and normal or only slightly elevated blood glucose levels (euDKA). Specifically, interventional gastroenterology procedures like colonoscopies present a significant risk for DKA when using SGLT2 inhibitors. This risk is heightened by factors such as bowel preparation, fluid-only dietary restrictions, and fasting.

The pathophysiology of SGLT2 inhibitor-related euDKA has not been fully elucidated. Hypothesised mechanisms suggest that, in response to lower baseline plasma glucose levels secondary to concurrent glycosuria (from SGLT2 inhibition) and carbohydrate deficit (from fasting), there is a homeostatic reduction in insulin release. This insulinopenia can be further exacerbated by acute illness or metabolic stress in part due to elevated catecholamine and cortisol. Subsequently, there is an upregulation of glucagon release, lipolysis and ketogenesis as alternative energy sources, leading to DKA.

Figure 1: Proposed pathophysiology of SGLT2-inhibitor induced euglycaemic ketoacidosis

As SGLT2 inhibitors become increasingly prevalent, It is essential for healthcare providers to be aware of this potential risk and to carefully monitor patients treated with SGLT2 inhibitors for signs and symptoms of DKA.

In patients with signs and symptoms of DKA, but normal glucose levels, a blood gas to assess bicarbonate and anion gap is critical to not miss the diagnosis.

Table 2: Symptoms and signs of DKA

How do we monitor for DKA? The Study Rationale

Ketone monitoring plays a crucial role in patients on SGLT2 inhibitors undergoing surgical procedures, particularly in the context of preventing DKA.

In response to emerging case series of SGLT2 inhibitor-related DKA in patients undergoing colonoscopy, a clinical alert update in 2020 recommended canceling colonoscopies if capillary ketone concentrations exceeded 1.0 mmol/L without discontinuation of SGLT2 inhibitors therapy for 72 hours prior.

However, this recommendation lacked empirical data regarding the normal range of ketone concentrations during colonoscopy procedures in non-diabetic patients.

Given the potential consequences of unnecessary procedure cancellation, such as delays in cancer detection and psychological impacts, the study by Hamblin et al. (2021) aimed to assess this normal range and to establish a more precise ketone concentration threshold to balance risks associated with procedure cancellation and the risk of DKA. This approach aims to mitigate the risk of adverse outcomes, such as DKA, while ensuring timely medical interventions when necessary.

Study Design

Inclusion Criteria:

• Normoglycemic adults undergoing colonoscopy

• Participants with T2DM (treated or not treated with SGLT2 inhibitors were also included for comparison

Exclusion Criteria:

• Global exclusion criteria:

  • pancreatitis, pancreatic cancer, pancreatic surgery, hemochromatosis, cystic fibrosis or pregnancy

• Non-diabetic group specific:

  • Fasting capillary glucose >5.5 mmol/L (100 mg/dL)

Participants:

• Normoglycemic reference interval population: 151 participants

• Participants with type 2 diabetes:

  • Non-SGLT2 inhibitor treated subgroup: 105 participants

  • SGLT2 inhibitor treated subgroup: 37 participants

Control:

• The control group comprised normoglycemic individuals undergoing colonoscopy

Data Points:

• Capillary ketone and glucose concentrations measured before colonoscopy (<90 minutes prior)

• Assessment of blood gases when ketone concentrations were >1.0 mmol/L

Outcome:

The reference interval for capillary ketone concentrations in non-diabetic individuals undergoing colonoscopy was determined to be 0.0–1.7 mmol/L.

However, the findings did not show statistically significant differences in ketone concentrations between diabetics treated with SGLT2 inhibitor and those that are not diabetic or not treated with SGLT2 inhibitor (p=0.051).

Therefore, those taking SGLT2 inhibitor can have ketones up to 1.7 mmol/L and still be at a theoretically elevated risk of DKA.

While higher ketone concentrations were observed in patients with T2DM treated with SGLT2 inhibitors compared to those not on SGLT2 inhibitor therapy, the lack of statistical significance means that the 1.7 mmol/L ketone level cannot be confidently applied to those treated with SGLT2 inhibitors.

Given the study’s limitations, such as its cross-sectional design, small sample size of patients treated with SGLT2 inhibitors, and statistically insignificant findings, caution is warranted when interpreting the 1.7 mmol/L threshold as safe for those taking SGLT2 inhibitors.

The study underscores the need for appropriate monitoring and management strategies to mitigate the risk of DKA in SGLT2 inhibitor treated patients undergoing colonoscopy.

Revised Ketone Monitoring Guideline in diabetic patients receiving SGLT2 inhibitors

Pre-operative plan:

• Withhold SGLT2 inhibitors for 2 full days prior to surgery AND on the day of surgery (i.e. withhold for 72 hrs) for:

  • Surgery requiring admission

  • Colonoscopy requiring bowel prep and carbohydrate restrictions

• Withhold SGLT2 inhibitors on the day of surgery for day procedures NOT requiring above

• Patients should monitor blood sugar levels (BSLs) and seek medical assistance if 2 readings are above 15 mmol/L in a a 24 hour period

• If a combination antihyperglycaemic medication is is prescribed to a patient, cease the SGLT2 inhibitors and prescribe the non SGLT2 inhibitors medication as a sole agent

• If possible, educating patient on signs and symptoms of DKA, discussing risk/benefit and providing written information prior to their operation

• A patient who is on SGLT2 inhibitor and NOT diabetic, they do not need to cease their SGLT2 inhibitor prior to surgery

Day of Surgery (DOS):

• Global recommendations:

  • Strongly consider postponing non-urgent procedures if the patient is unwell

  • Measure both blood glucose and blood ketone levels

• SGLT2 inhibitor appropriately withheld:

  • If the patient is clinically well and ketones are < 1.7 mmol/L, proceed with the procedure

  • Consider hourly blood glucose and blood ketone testing during the procedure and every 2 hours following the procedure until the patient is eating and drinking normally

• SGLT2 inhibitor not withheld:

  • Course of action depends on the urgency of the procedure combined with patient comorbidity, surgical factors, HbA1c, blood ketones, and base excess

  • All patients on SGLT2 inhibitors undergoing emergency surgery should be admitted post procedure to a ward capable of managing diabetic ketoacidosis in collaboration with endocrinology and critical care

  • Where blood gas analysis is not readily available, and the ketones are > 1.0 mmol/L, the procedure should not be performed

Table 3: Suggested management for clinically well patients who have not ceased SGLT2 inhibitors

Post Procedure:

• Resume SGLT2 inhibitor once patient is eating and drinking normally

• Provide patient with written advice to seek medical attention if unwell

Back to the case…

During the pre-operative assessment, his blood glucose levels are within the normal range, but his capillary ketone concentration is elevated to 1.5 mmol/L and base excess > -5. He denies any symptoms of DKA, such as polyuria, polydipsia or abdominal pain.

Concerned about the potential risk of DKA associated with SGLT2 inhibitor use, the gastroenterologist consults with the endocrinology team for guidance. They discuss the recent clinical alert update from 2022. On balance of the urgency of Mr. Smith’s colonoscopy, the team decides to proceed with the procedure with insulin and dextrose infusion.

The colonoscopy proceeded without complications. His intraop and post-op gas and ketones were unremarkable. Mr. Smith was discharged 2 hours later having had some light snacks with his wife.

References:

Australian Diabetes Society. (2020). Alert update: Periprocedural diabetic ketoacidosis (DKA) with SGLT2 inhibitor use. Retrieved 1st of May 2024 from https://diabetessociety.com.au/downloads/20201015%20ADS_DKA_SGLT2i_Alert_update_Sept_2020.pdf

Australian Diabetes Society. (2022). Alert update: Periprocedural diabetic ketoacidosis (DKA) with SGLT2 inhibitor use. Retrieved 1st of May 2024 from https://www.diabetessociety.com.au/downloads/20220726%20ADS%20ADEA%20ANZCA%20NZSSD_DKA_SGLT2i_Alert_Ver%20July%202022.pdf

Ceriotti, F., Kaczmarek, E., Guerra, E., et al. (2015). Comparative performance assessment of point-of-care testing devices for measuring glucose and ketones at the patient bedside. Journal of Diabetes Science and Technology, 9, 268–277.

Chirila, A., Nguyen, M. E., Tinmouth, J., & Halperin, I. J. (2023). Preparing for Colonoscopy in People with Diabetes: A Review with Suggestions for Clinical Practice. Journal of the Canadian Association of Gastroenterology, 6(1), 26–36. https://doi.org/10.1093/jcag/gwac035

Meyer, E. J., Mignone, E., Hade, A., Thiruvenkatarajan, V., Bryant, R. V., & Jesudason, D. (2020). Periprocedural euglycemic diabetic ketoacidosis associated with sodium-glucose cotransporter 2 inhibitor therapy during colonoscopy. Diabetes Care, 43, e181–e184.

Thiruvenkatarajan, V., Meyer, E. J., Nanjappa, N., Van Wijk, R. M., & Jesudason, D. (2019). Perioperative diabetic ketoacidosis associated with sodium-glucose co-transporter-2 inhibitors: A systematic review. British Journal of Anaesthesia, 123, 27–36.

Zannad, F., Ferreira, J. P., Pocock, S. J., Anker, S. D., Butler, J., Filippatos, G., et al. (2020). SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: A meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. The Lancet, https://doi.org/10.1016/S0140-6736(20)31824-9

Wagdy, K., & Nagy, S. (2021). EMPEROR-Preserved: SGLT2 inhibitors breakthrough in the management of heart failure with preserved ejection fraction. Global Cardiology Science & Practice, https://doi.org/10.21542/gcsp.2021.17

]]> https://www.anaesthesiacollective.com/a-single-case-of-a-successful-sphenopalatine-block-in-a-patient-with-a-post-dural-puncture-headache/ Tue, 14 May 2024 06:31:36 +0000 https://www.anaesthesiacollective.com/?p=19562 Case Report

Corresponding Author: S. Muthu

S. Muthu,¹ L. Amaratunge,²

1. Intensive Care Registrar, Western Health, Melbourne, Australia

2. Anaesthetist, Western Health, Melbourne, Australia

MeSH terms: Post Dural Puncture Headache (D051299), Sphenopalatine Ganglion Block (D059387), Pain Management (D059408).

Acknowledgements

Published with the written consent of the patient with appropriate deidentification. No external funding or competing interests declared.

Summary

This article examines the case of a 35-year-old woman with a history of herpes simplex virus (HSV) meningitis, who experienced a post dural puncture headache (PDPH). Conventional simple analgesic treatments were ineffective in providing relief. The implementation of a sphenopalatine ganglion block (SPGB), via both topical and drip methods, resulted in significant pain reduction and was favourably received by the patient. The article underscores the efficacy and improved patient comfort associated with SPGB in the management of PDPH, advocating for its consideration as a potential standard for enhancing patient experiences in PDPH treatment. Furthermore, the discussion delineates the benefits of SPGB alongside the traditional approach involving an epidural blood patch and oral analgesics, as demonstrated by a local successful case.

Introduction

PDPH presents a notable challenge within anaesthesia, often disrupting the recovery trajectory for patients who have undergone such procedures. Traditional management, ranging from pharmacologic interventions to hydration, remains the first line of defence but does not consistently deliver adequate relief. Consequently, the epidural blood patch (EBP) has become a gold standard, despite its invasiveness, associated patient discomfort and often similarities with the culprit procedure itself. Within this context, less invasive yet effective treatments would be a necessary addition to clinical practice.

This case report examines the implementation of the SPGB, an alternative treatment modality, in a patient suffering from PDPH. The patient, a 35-year-old female with a medical history of recurrent HSV meningitis, presented with PDPH for which conventional analgesics proved insufficient. A SPGB was successfully administered through both topical and drip methods, offering a noteworthy case study on the efficacy of this approach.

The sphenopalatine ganglion (SPG) is an extracranial parasympathetic ganglion with sensory, sympathetic, and parasympathetic fibres, situated in the pterygopalatine fossa (Fig 1a). It is accessible trans-nasally, allowing for a minimally invasive approach to block its associated neural pathways. The SPGB aims to anesthetise the SPG through the application of local anaesthetics, thereby diminishing pain signals from various craniofacial regions. Its application in PDPH leverages the ganglion’s role in the cranial autonomic system, hypothesising that blocking the SPG can reduce the vasodilation thought to contribute to the headache’s pathophysiology¹⁰.

Previous randomized control trials have acknowledged the potential of SPGB in PDPH management, advocating for its therapeutic promise⁷. Likewise in the Middle East and USA, there also has been further investigation regarding the local anaesthetics used as well as the timing of the block, suggesting a more widespread use in these areas^5,8. This report seeks to build upon such research, exploring how SPGB might offer an optimal balance between efficacy and patient comfort. The details of the patient’s case contribute to an evolving conversation about improving pain management strategies and enhancing patient experiences following dural punctures.

Report

The patient, a thirty-five-year-old female, presented to the emergency department with meningitis symptoms persisting for five days. The patient’s medical history includes recurrent HSV meningitis (Mollaret’s Syndrome), diagnosed through lumbar punctures, the most recent being five years prior. She has not experienced post-puncture headaches in the past. Although she occasionally suffers from migraines, no current medication is prescribed following ineffectiveness of triptans. Apart from this, her medical and hospitalisation history is unremarkable.

The patient maintains full independence in daily activities while employed as an administrator. She reports infrequent alcohol use and denies ever having smoked or used other illicit substances. Significantly, she is not on regular analgesics and does not suffer from chronic pain.

Upon arrival, the patient reported progressive headaches, neck stiffness, and photophobia, associated with some nausea and diaphoresis. She however did not report any fevers, rigors, vomiting, or loss of consciousness. She was also menstruating at the time of presentation. Assessment revealed orientation to time and place, though her responses to questions were notably sluggish. Her vital signs remained within normal ranges, and she was normothermic. A comprehensive neurological examination, including assessments of cranial, upper, and lower limb functions, yielded no positive findings. Similarly, no signs were elicited on Kernig’s or Brudzinski’s tests, and a systemic review revealed no other significant findings. Initial bloodwork, including CRP, and a CT scan of the brain were unremarkable.

An attempted lumbar puncture in the Emergency Department was unsuccessful and subsequently abandoned. The documentation regarding the specifics of the equipment utilised such as the gauge and type of needle, was not available. There was however clear documentation of consent, outlining potential risks, including post-puncture headache. There was only a single puncture attempted in the emergency department prior to the procedure being abandoned.

Despite administration of broad-spectrum antibiotics, antiviral therapy, and a pain management regimen of regular paracetamol, ibuprofen, tapentadol, and oxycodone, her pain persisted. Following this, a CT-guided lumbar puncture on the second day of admission was successful; however, she continually had a fronto-occipital, positional headache. This was despite escalation of opioid analgesics post-review by the remote pain service team. With infectious aetiologies ruled out, antibiotics and antiviral therapy was ceased, and given the symptoms the working diagnosis was presumed to be a post-dural puncture headache.

On day five, a sphenopalatine ganglion block (SPGB) was proposed. The patient consented to the SPGB after a detailed explanation. The block was first performed with the topical method which involved 2.5ml of 1% lignocaine soaked swabs being inserted into the nasal passage and positioned appropriately abutting the ganglion (Fig 1b). This promptly yielded significant pain relief, substantiated by the patient’s decreased need for breakthrough opioids for the following eight hours.

Given the transient nature of the block, a repeat SPGB was performed the following day. However, this time the drip method was used in which a small catheter attached to a syringe was advanced just past the nasal passage. Once positioned appropriately (Fig 1.2b), a mixture of 3mls of 2.5% bupivacaine and 2.5mls of 2% lignocaine was slowly dropped directly onto the ganglion. Despite the positive outcome immediately post block, an EBP was also performed, with the aim of sustained analgesia despite the time interval since the initial puncture. Her symptoms resolved entirely by that evening and was discharged home the same day.

Follow-up was conducted four weeks later via a phone interview. At this time the patient reflected very positively on the SPGB, emphasising its immediate relief and non-invasive approach. She favoured this over the EPB citing that she felt that it was far more intrusive and uncomfortable a procedure that didn’t provide the same immediacy in pain relief. Furthermore, the patient advised that she found the drip method more comfortable than the topical method and that the relief she felt post both blocks were not discernible from each other. She expressed a preference for SPGB for future analgesic needs should she sustain any further dural puncture headaches, valuing its efficacy and minimal side effects over oral medication and more invasive procedures.

Discussion

Severe headaches are a widely recognised complication post dural puncture, with incidence rates reaching up to 9% following spinal anaesthesia, 11% after lumbar punctures, and approximately 6% in unintentional epidural placements¹⁰. A plethora of independent risk factors contribute to this phenomenon, including but not limited to the female sex, needle gauge, the volume of cerebrospinal fluid extracted, patient age, and lower body mass index (BMI).

Historically, the benchmark for therapeutic intervention has been the administration of an EBP, which has demonstrated a notable success rate ranging from 65-98%¹⁰, often providing swift and effective relief. Despite these figures, the invasiveness of EBPs, coupled with an extensive list of potential contraindications and adverse effects such as back pain, bleeding, haematoma, and neuropathies, prompt the consideration of alternative treatment modalities.

The SPGB presents a promising and less invasive technique that offers rapid analgesia by delivering local anaesthetic directly to the sphenopalatine ganglion via a trans-nasal route. Randomized controlled trials (RCTs) underscore the SPGB as a procedure with immediate impact, significantly reducing the requirement for adjunctive analgesics as well as EBPs¹. Presently, there are three recognised methods for administering the local anaesthetic in SPBs: the drip method, first mentioned in the Indian Journal of Anaesthesia in 2020, the more traditional topical method and finally the spray method, which is essentially a modification of the drip method². In the case presented, the drip method was better tolerated however there have been other studies showing that while overall the drip method may be more comfortable there may be increased efficacy with the applicator method. The drip method employs a syringe coupled with a small catheter, positioned to traverse beyond the nasal passage, thereby allowing the anaesthetic to be incrementally administered to the target site (Fig1c). Alternatively, the topical method entails the application of an anaesthetic-coated soft applicator, inserted nasally to reach the site of effect.

Furthermore, RCTs have been completed comparing choice of local anaesthetics bupivacaine vs lignocaine⁵, which so far have indicated to significant clinical difference between the choice of local anaesthetic. In the case presented the patient received lignocaine the first time and a combination of both the second time. During the follow up interview there was no indication that either had any noticeable difference. Finally, a RCT completed in 2023 comparing late vs early blocks showed quite demonstrably that an early block resulted in fewer days in hospital⁸.

Although utilisation of the SPGB is predominantly observed in the Middle East, with a substantial body of evidence originating from the region, its adoption in different locales is gradually increasing. Overall, patient preference trends towards the drip method, attributed to its enhanced tolerability and the absence of discernible disparity in efficacy between the two approaches. This case report details a successful local implementation of the drip method, reinforcing the viability and potential for broader application of SPBs in the management of post-dural puncture headaches.

References

1. Nazir N, Saxena A, Asthana U. Efficacy and Safety of Trans-nasal Sphenoid Ganglion Block in Obstetric Patients With Post-dural Puncture Headache: A Randomized Study. Cureus. 2021;13(12):e20387. doi:10.7759/cureus.20387
2. Levin D, Cohen S. Images in anesthesiology: three safe, simple, and inexpensive methods to administer the sphenopalatine ganglion block. Reg Anesth Pain Med. 2020;45(11):880-882. doi:10.1136/rapm-2020-101765
3. Bhargava T, Kumar A, Rastogi A, Srivastava D, Singh TK. A Simple Modification of Sphenopalatine Ganglion Block for Treatment of Postdural Puncture Headache: A Case Series. Anesth Essays Res. 2021;15(1):143-145. doi:10.4103/aer.aer_67_21
4. Marques A, Morais I, Costa V, Romao H. Sphenopalatine Ganglion Block for Headache Treatment After an Incidental Durotomy: A Case Report. Turk Anestezi Ve Reanim. 2023;51(1):72-74. doi:10.5152/TJAR.2023.21634
5. Kirkpatrick DL, Townsend T, Walter C, et al. Lidocaine Versus Bupivacaine in the Treatment of Headache with Intranasal Sphenopalatine Nerve Block. Pain Physician. 2020;23(4):423-428.
6. Cohen S, Levin D, Mellender S, Zhao R, Patel P, Grubb W, Kiss G. Topical Sphenopalatine Ganglion Block Compared With Epidural Blood Patch for Postdural Puncture Headache Management in Postpartum Patients: A Retrospective Review. Reg Anesth Pain Med. 2018;43(8):880-884. doi:10.1097/AAP.0000000000000840
7. Gayathri GA, Karthik K, Saravanan R, Meshach MD, Pushparani A. A randomized control study to assess the efficacy of the sphenopalatine ganglion block in patients with post dural puncture headache. Saudi J Anaesth. 2022;16(4):401-405. doi:10.4103/sja.sja_780_21
8. Santos NS, Nunes JM, Font ML, Carmona C, Castro MM. Early versus late sphenopalatine ganglion block with ropivacaine in postdural puncture headache: an observational study. Braz J Anesthesiol. 2023;73(1):42-45. doi:10.1016/j.bjane.2021.01.007
9. Takmaz SA, Karaoglan M, Baltaci B, Bektas M, Basar H. Transnasal Sphenopalatine Ganglion Block for Management of Postdural Puncture Headache in Non-Obstetric Patients. J Nippon Med Sch. 2021;88(4):291-295. doi:10.1272/jnms.JNMS.2021_88-406
10. Post-Dural Puncture Headache. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc., Wolters Kluwer; [14/02/2024]. Accessed [20/03/2024]. Available at: https://www.uptodate.com/contents/post-dural-puncture-headache?search=rates+of+post+dural+puncture+headaches&source=search_result&selectedTitle=1%7E150&usage_type=default&display_rank=1.

Key reference:

Devereaux et al. (2022). Tranexamic Acid in Patients Undergoing Noncardiac Surgery. The New England journal of medicine, 386(21), 1986–1997. https://doi.org/10.1056/NEJMoa2201171

Quick Summary

• Tranexamic acid (TXA) is an antifibrinolytic that reversibly antagonises plasminogen’s binding site for fibrin and tissue plasminogen activator, thus preventing plasminogen activation and fibrinolysis.

• TXA has been demonstrated to be safe and effective in reducing bleeding and improving patient outcomes in multiple critical resuscitative and operative settings, including post-partum haemorrhage, major trauma, cardiac surgery, major lower limb arthroplasties and other bleeding presentations commonly seen in the Emergency Department.

• The Perioperative Ischemic Evaluation 3 (POISE-3) trial was a large, international multicentre placebo-controlled trial aimed to determine if perioperative TXA was safe and effective in at-risk patients undergoing non-cardiac surgeries.

• POISE-3 found TXA considerably reduced bleeding events compared to placebo (9.1% vs 11.1%, HR 0.76, 95% CI 0.67 to 0.87; absolute difference, −2.6 percentage points; 95% CI, −3.8 to −1.4; two-sided P<0.001).

• POISE-3 also found that TXA was associated with a small increase in cardiovascular thrombotic complications (14.2% vs. 13.9%, HR 1.03; 95% CI, 0.92 to 1.14; upper boundary of the one-sided 97.5% CI, 1.14; absolute difference, 0.3 percentage points; 95% CI, −1.1 to 1.7; one-sided P=0.04 for noninferiority), which the trial was unable to establish non-inferiority compared to placebo.

• Nevertheless, TXA’s routine use in non-cardiac surgery with selective considerations in elevated-risk patients should be strongly encouraged given the significant improvement in bleeding-associated morbidity and mortality.

Preamble

You are an anaesthetic trainee allocated to the elective orthopaedic list. You review Mr. TX, a 56 yo M, BMI 35, arriving today for his right hip replacement for osteoarthritis. His PMHx includes:

• Ischaemic heart disease (IHD) with 2x stents and low-normal left ventricular ejection fraction (LVEF),

• Non-valvular atrial fibrillation (AF) and

• Iron-deficiency anaemia (IDA) with background peptic ulcer disease (PUD). His latest Hb was 110 three weeks ago.

His medications are apixaban 5mg BD, aspirin 100mg mane, metoprolol 50mg BD, perindopril 4mg mane, paracetamol 1g QID.

Having just read the outcomes of the PREVENTT trial, you have worked-up Mr. TX pre-operatively per the Blood Management Plan for Mr.TX’s IDA:

1. Treat underlying cause of anaemia

   1. Mr. TX has never had issues with iron intake

   2. Mr. TX denies recent haematemesis/haematochezia or melaena, with a recent routine gastroscopy and colonoscopy showing no bleeding lesions

   3. Mr. TX received an IV iron infusion per the “International Consensus Statement on the Peri-operative Management of Anaemia and Iron Deficiency”

2. Minimise blood loss

   1. Mr. TX’s apixaban was ceased 3 days prior to day of surgery

   2. Per discussion with Mr. TX’s cardiologist and your orthopaedic colleague, the team was happy for Mr. TX to continue his aspirin

3. Improve patient tolerance to anaemia

   1. Mr. TX is ASA grade III

   2. He has robust exercise tolerance with regular MET>4 activities, remained asymptomatic from his IHD or AF over last year with no hospitalisations, with an echocardiogram 3 months ago showing normal LVEF and valvular function.

   3. Mr. TX has made considerable gains in lifestyle modifications, having quit smoking 3yr ago, intentionally lost weight through exercise, and has cut down on EtOH. He is keen to get his hip replaced so that he can get back on his gym routine.

You ask your consultant if there are any other perioperative strategies to minimise blood loss for Mr. TX, which your boss answers:

“Let’s give some tranexamic acid (TXA) before the cut”

As you nod to this conceptually-sound suggestion, you question if there is evidence that TXA reduces perioperative major bleeding, and if the theoretical increase in thromboembolic risk is significant given Mr. TX’s cardiac history…

What is TXA and its effect?

Pharmacodynamics:

Fibrinolysis, the process of fibrin clot dissolution, requires the conversion of hepatic-synthesised pro-enzyme plasminogen to its active form, plasmin, to cleave fibrin into fibrin degradation products. This activation process only occurs through direct binding of plasminogen to fibrin and interaction with tissue plasminogen activator (tPA).

TXA is a synthetic competitive reversible antagonist at the plasminogen lysine binding site for fibrin, which prevents the binding of plasminogen to fibrin and formation of plasminogen-fibrin-tPA complex. This ultimately inhibits fibrinolysis, promotes clot stability, and achieves therapeutic haemostasis. (Fig 1)

Interestingly, TXA demonstrates pleomorphic immunomodulatory effects by virtue of inhibiting plasmin-mediated activation of complement and its downstream pro-inflammatory pathways.

Fig 1. Simple schematic of TXA mechanism of action, depicting plasminogen competitively antagonising the plasminogen lysine receptor site, preventing plasminogen-fibrin binding and fibrinolysis.

Pharmacokinetics

Absorption:

• Comes in IV vials 500mg in 5mls (1g/10mls), and 500mg PO tablets

• PO bioavailability ~34%

Distribution:

• 3% protein binding with no albumin binding at therapeutic levels

• Mostly bound to plasminogen/plasmin

Metabolism:

• Minimal hepatic metabolism

• Nil dosage adjustment in hepatic impairment

Elimination:

• 95% renally excreted

• Renal half-life 2hrs, >90% cleared within 24hrs

• Dosing consideration in renal impairment

Current indications and evidence for TXA

Post-partum haemorrhage (PPH):

PPH is the leading cause of maternal mortality worldwide, with disproportionately higher rates in low-resource countries where women have limited access to adequate obstetric care. TXA presents as an affordable intervention that can be readily administered to reduce bleeding and mortality rates.

The World Maternal Antifibrinolytic Trial (WOMAN) was an international, double-blinded placebo controlled randomised control trial (RCT) that demonstrated a significant reduction in bleeding-related mortality in women who received IV 1g TXA for PPH compared to placebo (1.5% vs 1.9%, risk ratio 0.81, 95%CI 0.65-1.00, p=0.045), with effect most pronounced when given within 3 hours from birth (RR 0·69, 95% CI 0·52-0·91; p=0·008). This benefit was not offset by increased thromboembolic events.

In light of this trial, the World Health Organisation has endorsed IV TXA given within 3 hours of birth as a key recommendation for management of PPH.

Trauma

Trauma resuscitation has evolved significantly over recent years, with increasing recognition of trauma-induced coagulopathy as a key pathology contributing to exsanguination and mortality.

It is characterised by hyperfibrinolysis and clotting factor/platelet dysfunction secondary to tissue injury, often accentuated by acidosis and hypothermia as part of traumatic haemorrhagic shock to form the “lethal triad”. As such, TXA lends itself naturally as a direct antifibrinolytic to improve haemostasis, in addition to haemorrhage control and shock reversal with blood product replacement as key priorities.

CRASH-2 was a large, international, multicentre, placebo-controlled double blinded trial investigating the effects of early administration of TXA 1g (within 3 hours of injury) on mortality, transfusion requirements and thrombotic complications. It noted:

• Reduction in all-cause mortality (14.5% vs 16.0%, RR 0.91; 95%CI 0.85 to 0.97; p = 0.0035) and

• Reduction in mortality associated with haemorrhage (4.9% vs 5.7%, RR 0.85; 95% CI 0.76 to 0.96; p = 0.0077), most notably in patients who received TXA within 1 hour of injury (5.3% vs 7.7%, RR 0.68; 95% CI 0.57 to 0.82; p < 0.0001)

• no reduction in blood product requirements (50.4% vs 51.3%, RR 0.98; 95%CI 0.96 to 1.01, p=0.21

• no increase in vascular occlusive events (1.7% vs 2.0%, 95%CI 0.68 to 1.02, p = 0.084)

• no increase in rates of surgical management (47.9% vs 48.0%, 95%CL 0.97 to 1.02, p=0.79)

The subsequent CRASH-3 trial also demonstrated a statistically non-significant trend towards mortality benefit of early TXA for traumatic brain injury patients.

As such, early TXA (given as 1g over 10min with subsequent 1g given over 8hrs, commenced within 3hrs of injury) is now widely adopted as part of major trauma resuscitation in Australia and New Zealand.

Cardiac surgery

Cardiac surgeries carry increased risks of intraoperative bleeding, transfusion requirements, morbidity and mortality associated with poorer cardiopulmonary reserve, and need for urgent re-operation from life-threatening postoperative bleeding.

The ATACAS trial lead by Prof. Myles and colleagues aimed to investigate whether intraoperative TXA in at-risk patients undergoing coronary-artery surgery improved outcomes. It found

• No increase in composite rates of death and thrombotic complications (nonfatal MI stroke, PE, renal failure, or bowel infarction) (16.7% vs 18.1%; RR 0.92; 95% confidence interval, 0.81 to 1.05; P=0.22)

• Significant reduction in transfusion requirements (4331u vs 7994u, P<0.001) and rates of major haemorrhage + cardiac tamponade (1.4% vs 2.8%, P=0.001)

• Increase in rates of seizures (0.7% vs. 0.1%, P=0.002)

Besides an increased rate of seizures, TXA is superior in preventing major bleeding complications without increase in thromboembolic events. TXA is now selectively used in our cardiac theatres for at-risk patients.

Orthopaedic surgery

In Mr. TX’s case, the use of TXA perioperatively to reduce intraoperative bleeding during elective lower limb arthroplasties is now common practice. A survey of active ANZCA fellows by Painter and colleagues in 2019 showed that 67% of our supervisors would routinely give TXA, with another 31% giving it on surgeon’s request or selectively on a case by case basis.

Not surprisingly, meta-analysis of existing small trials by Fillingham and colleagues (2018) has demonstrated that TXA, in oral, topical, or IV formulations, safely reduces risk of bleeding and need for transfusions.

It is a practice guideline in Western Health in Victoria for TXA to be administered for “all patients undergoing THR and TKR where the specialist anaesthetist providing perioperative care deems the benefits outweigh the risks, in consultation with a haematologist”.

Hereditary angioedema

Given its pleomorphic inhibition of plasmin-mediated complement activation, TXA has been used as prophylaxis as well as emergency management of hereditary angioedema with relative success in published small studies and case reports.

Emergency Department use: topical haemostatic & menorrhagia

One of the most common indications for TXA encountered in ED is menorrhagia. It reduces menstrual bleeding by 30-60%, improves women’s quality of life, and is the superior medical management compared to NSAIDS and oral contraceptives.

TXA is also used topically in ear, nose and throat & dental presentations to achieve haemostasis. Classically, TXA-soaked gauze has been used off-label for management of epistaxis. Impromptu use of 5% TXA solution (500mg tablet dissolved in 10ml) is also used for oromucosal bleeding, in particular in patients with coagulopathies.

The POISE-3 trial. Is TXA effective and safe in non-cardiac surgery?

While large trials such as ATACAS has underlined TXA’s safety and effectiveness in cardiac surgery, no large pragmatic trials exist for use of TXA in non-cardiac surgeries.

The Perioperative Ischemic Evaluation 3 (POISE-3) trial was a large, international multicentre placebo-controlled trial designed to answer whether*:

In patients at risk of bleeding and cardiovascular complications undergoing non-cardiac surgery, is perioperative TXA effective in reducing significant bleeding and safe in terms of major cardiovascular complications compared to placebo.

*The POISE-3 trial utilised a partial factorial design to also investigate the effects of hypertension avoidance vs hypotension avoidance on bleeding and cardiovascular outcomes. This was not reported in the current paper.

Study design

Patient population

• 114 hospitals across 22 countries

• ≥45yo, undergoing inpatient non-cardiac surgery (excluding intracranial neurosurgery)

• Risk factors for bleeding and cardiovascular complications

  • Age ≥70

  • Major surgery

  • History of atherosclerotic / coronary artery disease

  • History of malignancy

  • History of chronic kidney disease (creatinine > 175micromol/L)

Randomisation to Treatment and control

• 1:1 randomisation

• “TXA” group = 1g TXA bolus at start and end of case

• “Control” group = Placebo at start and end of case

Outcomes

• Primary Efficacy outcome: composite of life-threatening bleeding, major bleeding, bleeding into critical organ at 30 days

• Primary Safety outcome: composite of myocardial injury, ischaemic stroke, peripheral arterial thrombosis, proximal VTE at 30 days

• Secondary outcomes included:

  • Individual components of composite efficacy and safety outcomes

  • Bleeding independently associated with death

  • Patient requiring transfusions

  • LOS and days alive at home

  • Seizures

Statistical design

• To satisfy efficacy hypothesis, that TXA is superior to placebo = two side P<0.05

• To satisfy safety hypothesis, that TXA is non-inferior to placebo = upper end of one-sided 97.5% CI must <1.125, and one-sided P<0.025, corresponding to risk increase of <12.5%

• 9500 recruited to achieve 90% power to detect hazard ratio (HR) of 0.8 or less for efficacy hypothesis (assuming 9% bleeding event at baseline), and 98% power for non-inferiority margin for HR <1.125 (assuming 14% cardiovascular event at baseline)

• Efficacy outcome analysed in intention-to-treat (ITT) population

• Safety outcome analysed in per-protocol (PP) and ITT population per sensitivity analysis

• Cox proportional-hazards models were used to calculate HR

Results

Total 9537 patients were randomised to TXA n=4757 and placebo n=4778, with similar demographic baselines

Primary outcomes

• Efficacy outcome

  • TXA was superior compared to placebo in preventing major bleeding events by 24% (9.1% vs 11.1%, HR 0.76, 95% CI 0.67 to 0.87; absolute difference, −2.6 percentage points; 95% CI, −3.8 to −1.4; two-sided P<0.001)

• Safety outcome

  • TXA could not be deemed non-inferior compared to placebo in cardiovascular outcomes

    • PP population (14.2% vs. 13.9%, HR 1.03; 95% CI, 0.92 to 1.14; upper boundary of the one-sided 97.5% CI, 1.14; absolute difference, 0.3 percentage points; 95% CI, −1.1 to 1.7; one-sided P=0.04 for noninferiority)

    • ITT sensitivity analysis HR 1.03; 95% CI, 0.92 to 1.14

Secondary outcomes

• TXA superior in preventing

  • Bleeding independently associated with death by 24%

    • 8.7% vs. 11.3%, HR 0.76, 95%CI 0.67 to 0.87

  • Major bleeding by 28%

    • 7.6% vs. 10.4%, HR 0.72, 95%CI 0.63 to 0.83

  • Number of patients requiring transfusions

    • 9.4% vs. 12.0%, odds ratio 0.77, 95% CI, 0.68 to 0.88

• TXA was not associated with statistically significant increase in risk of individual cardiovascular events (assuming 95% CI and p<0.05, differing from non-inferiority requirements)

Risk-benefit implications

The POISE-3 trial has clearly demonstrated that TXA is effective in reducing major bleeding and its associated morbidity and mortality (by 2.6 absolute percentage points or relative 24% reduction) in non-cardiac surgery, and presents an attractive, cost-effective intervention to improve clinical outcomes and reduce costs in terms of blood transfusions. Nevertheless, clinicians must also balance the theoretical 3% increase in cardiovascular complications, particularly in those at increased risk (recent VTE events, strokes, or active coronary artery disease). Ultimately, taking into account the significant gains in bleeding outcomes compared to the small probability of complications, one may argue for its routine use in non-cardiac surgery with selective considerations in elevated-risk patients.

References

CRASH-2 trial collaborators, Shakur, H., Roberts, I., Bautista, R., Caballero, J., Coats, T., Dewan, Y., El-Sayed, H., Gogichaishvili, T., Gupta, S., Herrera, J., Hunt, B., Iribhogbe, P., Izurieta, M., Khamis, H., Komolafe, E., Marrero, M. A., Mejía-Mantilla, J., Miranda, J., Morales, C., … Yutthakasemsunt, S. (2010). Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet (London, England), 376(9734), 23–32. https://doi.org/10.1016/S0140-6736(10)60835-5

CRASH-3 trial collaborators (2019). Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial. Lancet (London, England), 394(10210), 1713–1723. https://doi.org/10.1016/S0140-6736(19)32233-0

Chauncey JM, Wieters JS. Tranexamic Acid. [Updated 2023 Jul 24]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK532909/

Fillingham, Y. A., Ramkumar, D. B., Jevsevar, D. S., Yates, A. J., Shores, P., Mullen, K., Bini, S. A., Clarke, H. D., Schemitsch, E., Johnson, R. L., Memtsoudis, S. G., Sayeed, S. A., Sah, A. P., & Della Valle, C. J. (2018). The Efficacy of Tranexamic Acid in Total Hip Arthroplasty: A Network Meta-analysis. The Journal of arthroplasty, 33(10), 3083–3089.e4.

Leminen, H., & Hurskainen, R. (2012). Tranexamic acid for the treatment of heavy menstrual bleeding: efficacy and safety. International journal of women’s health, 4, 413–421. https://doi.org/10.2147/IJWH.S13840

Maj Richard Reed, LtCol Tom Woolley, Uses of tranexamic acid, Continuing Education in Anaesthesia Critical Care & Pain, Volume 15, Issue 1, February 2015, Pages 32–37, https://doi.org/10.1093/bjaceaccp/mku009

Myles, P. S., Smith, J. A., Forbes, A., Silbert, B., Jayarajah, M., Painter, T., Cooper, D. J., Marasco, S., McNeil, J., Bussières, J. S., McGuinness, S., Byrne, K., Chan, M. T., Landoni, G., Wallace, S., & ATACAS Investigators of the ANZCA Clinical Trials Network (2017). Tranexamic Acid in Patients Undergoing Coronary-Artery Surgery. The New England journal of medicine, 376(2), 136–148. https://doi.org/10.1056/NEJMoa1606424

Pabinger, I., Fries, D., Schöchl, H., Streif, W., & Toller, W. (2017). Tranexamic acid for treatment and prophylaxis of bleeding and hyperfibrinolysis. Wiener klinische Wochenschrift, 129(9-10), 303–316. https://doi.org/10.1007/s00508-017-1194-y

Painter TW, McIlroy D, Myles PS, Leslie K. A survey of anaesthetists’ use of tranexamic acid in noncardiac surgery. Anaesthesia and Intensive Care. 2019;47(1):76-84. doi:10.1177/0310057X18811977

Nickson (2020). Tranexamic acid. Life In The Fast Lane. Accessed on 25/09/23. URL: https://litfl.com/tranexamic-acid/

Schutgens, Roger E. G.1; Lisman, Ton2. Tranexamic Acid Is Not a Universal Hemostatic Agent. HemaSphere 5(8):p e625, August 2021. | DOI: 10.1097/HS9.0000000000000625

WOMAN Trial Collaborators (2017). Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial. Lancet (London, England), 389(10084), 2105–2116. https://doi.org/10.1016/S0140-6736(17)30638-4

by Dr. Matthew Vella

@mjv.igee

#Anaesthesia #anaesthetics #anesthesiology #anaesthesia #anaesthetic #abcsofanaesthesia #medicine #anesthesiologist #anaesthetist #anesthetist #anaesthesiology #nurse #medical #meded #FOAMed #medicalstudent #dementia #delirium #cognitivedysfunction #generalanaesthesia #GA #regionalanaesthesia #RA #inhalational #spinal #epidural #TIVA #hipfracturesurgery #longtermanaestheticrisk #anaestheticconsent

Title:

Dementia risk amongst older adults with hip fracture receiving general anaesthesia or regional anaesthesia: a propensity-score-matched population-based cohort study

Sun, M., Chen, W. M., Wu, S. Y., & Zhang, J. (2023). Dementia risk amongst older adults with hip fracture receiving general anaesthesia or regional anaesthesia: a propensity-score-matched population-based cohort study. British journal of anaesthesia, 130(3), 305–313. https://doi.org/10.1016/j.bja.2022.11.014

Where is it published?

British Journal of Anaesthesia

Who is involved?

A research group in Taiwan with funding from the Lo-Hsu Medical Foundation

What did they set out to do?

Compare long-term risk of dementia following inhalational GA vs TIVA vs regional anaesthesia (RA), and to clarify associations (if any) between dementia and age, gender, comorbidities, ASA physical status.

What is significant about the study?

We have an ageing population with increasing accessibility of surgery, so it’s important to understand the effect anaesthesia may have on development of dementia – considering its high morbidity, mortality, and associated healthcare costs.

How was it done?

This was a retrospective population-based cohort study with propensity-score-matching using a huge national health database in Taiwan (National Health Insurance Research Database NHIRD) that is well validated with high data accuracy. 268, 014 patients were divided into 3 groups (inhalational GA or TIVA or Regional) and compared with regard to incidence of diagnosis of dementia.

This included patients aged over 65-years, who had elective hip fracture surgery, and were hospitalised for >1 day over 17 years (2002-2019).

Those who received a combination of inhalational and IV anaesthesia, had a history of dementia, received anaesthesia between surgery and follow-up, or passed-away, were excluded.

What did they find?

Undergoing general anaesthetic may expose people over 65-years of age to a higher risk of developing dementia in the long-term, and this risk may be mitigated by offering regional anaesthetic techniques (where appropriate).

The Details

Confounding variables were adjusted for with participants matched in a 1:1 ratio, a time-varying Cox proportional hazards model was used to quantify incidence. Statistical significance (p < 0.017 -> Bonferroni-adjusted 0.05/3). Endpoints were reported as incidence rates per 100,000 person-years and incidence ratios. Subgroup analyses were completed via multivariate time-varying Cox regression model.

Dementia incidence was significantly different between all 3 groups:

• Inhalational > TIVA > Regional anaesthesia (RA)
• Dementia risk increased over time for all groups
• For ASA 4 patients, risk of dementia was equal in all groups

Dementia incidence rates for the groups were:

Inhalational general anaesthesia (GA) 4821/100 000 person-years

Total intravenous anaesthesia (TIVA-GA) 3400/100 000 person-years

Regional anaesthesia (RA) 2692/100 000 person-years

The dementia incidence rate ratio (95% confidence intervals [CI]) were:

Inhalational GA to RA 1.19 (1.14;1.25) p = 0.011

Inhalational GA to RA 1.51 (1.15;1.66) p = <0.001

TIVA-GA to RA 1.28 (1.09;1.51) p = <0.001

Some interesting discussion points

The current study’s findings are congruent with animal studies, where propofol shows superior post-administration cognitive outcomes compared with inhalational anaesthetic (both are implicated with increased production of AB peptides, AB amyloidosis, tau hyperphosphorylation, and neurofibrillary tangles).

Methodology was directed at improving on limitations and design flaws from prior cohort studies (i.e., insufficient sample size / follow-up, inappropriate control groups, failed distinction between dementia comorbidities, surgery type, anaesthesia type). For example, Velkers et al. (2021) (a retrospective cohort study also using propensity score matching) found no association between dementia risk and GA or RA, however they were limited by: inclusion of different surgeries, smaller sample size (i.e., 7499 per group) and short follow-up (<5 years).

Any limitations?

Only patients from Taiwanese / Asian background were included, there is potential for errors in diagnosis (ICD coding in the database), specific anaesthetic agents were not specified, and there was no specified formal testing for pre-operative cognitive impairment; so undiagnosed pre-operative cognitive impairment may have added bias.

Perhaps most significantly, as this was a retrospective cohort study, so the researchers could not determine the reason for selection of type of anaesthesia.

However, with the “propensity-score matching, no significant differences between groups were observed in age, sex, comorbidities, smoking, alcohol-related diseases, or ASA physical status. The crude dementia incidence in the inhalational GA group differed significantly from that in the TIVA and RA groups.”

What’s the overall take-home?

People may be at increased risk of developing dementia depending on the type of anaesthesia they receive, and this warrants further investigation (prospective randomised control trials). Further, it may be appropriate to include explanation of this risk as a routine part of consent.

Further reading

The RAGA Randomized Trial (delirium):

Li, T., Li, J., Yuan, L., Wu, J., Jiang, C., Daniels, J., Mehta, R. L., Wang, M., Yeung, J., Jackson, T., Melody, T., Jin, S., Yao, Y., Wu, J., Chen, J., Smith, F. G., Lian, Q., & RAGA Study Investigators (2022). Effect of Regional vs General Anesthesia on Incidence of Postoperative Delirium in Older Patients Undergoing Hip Fracture Surgery: The RAGA Randomized Trial. JAMA, 327(1), 50–58. https://doi.org/10.1001/jama.2021.22647

Retrospective cohort study with contrary findings:

Velkers, C., Berger, M., Gill, S. S., Eckenhoff, R., Stuart, H., Whitehead, M., Austin, P. C., Rochon, P. A., & Seitz, D. (2021). Association Between Exposure to General Versus Regional Anesthesia and Risk of Dementia in Older Adults. Journal of the American Geriatrics Society, 69(1), 58–67. https://doi.org/10.1111/jgs.16834

Directions for future research methodology:

Vacas S. (2023). Advancing our understanding of postoperative cognitive trajectories in older adults. British journal of anaesthesia, 130(3), 250–252. https://doi.org/10.1016/j.bja.2022.12.021

Key reference:

Olesnicky, B. (2023). GLP-1 agonists and gastric emptying. Bulletin. Australian and New Zealand College of Anaesthetists (ANZCA) & Faculty of Pain Medicine (FPM). Winter 2023 edition, p20

Quick Summary

• Glucagon-like peptide 1 (GLP-1) is a short-acting, endogenous incretin hormone produced by the gastrointestinal tract to reduce glycaemia by:

  • stimulating beta cell insulin release,

  • delaying gastric emptying, and

  • promoting satiety.

• GLP-1 agonists (~tide, e.g semaglutide) are used as second/third line agents for management of non-insulin dependent type 2 diabetes mellitus (T2DM).

• Owing to their pleiotropic effects, GLP-1 agonists are also approved for management of weight loss, and are increasingly recognised for their cardiometabolic protective effects.

• However, the risk of aspiration due to delayed gastric emptying has raised concern regarding the safety of GLP-1 agonists in the perioperative setting:

• The ANZCA Safety and Quality Committee recently presented two case reports of gastric contents identified on elective gastroscopy in patients using GLP-1 agonists despite adequate fasting times.

• Further research is required to determine the risk-benefit profile of GLP-1 agonists and inform clinicians whether these agents can be safely continued perioperatively.

Preamble

You are an anaesthetic trainee allocated to the elective scope list. You review Ms. OZ, a 56 yo F, BMI 33, awaiting her gastroscopy for her iron-deficiency anaemia. Her PMHx includes type 2 diabetes mellitus (T2DM) for which she takes metformin XR 1g BD, gliclazide 60mg daily, and her recently commenced weekly semaglutide injection. She tells you she has diligently followed your fasting instructions, and didn’t take her morning diabetes med as instructed. Her BSL is 7.5 on arrival.

Gentle propofol sedation proceeds smoothly as your gastroenterology colleague inserts the gastroscope. Suddenly, your colleague exclaims in annoyance

“this patient isn’t fasted!”

You glance over the big screen, and to your disbelief, there are old chunks of the patient’s dinner. You immediately perform a rapid sequence induction to protect the patient’s airway and the gastroenterologist is able to take some biopsies and to a limited scope.

After the procedure Ms. OZ wakes up safely. You disclose to them that because of the food identified on the scope. Ms. OZ is puzzled as to why there was food in her system, given she last ate during dinner last night, to which her husband corroborates.

The above scenario was not dissimilar to recent case reports presented at the latest ANZCA Safety and Quality Committee published in the ANZCA Bulletin, Winter 2023. In the report, two patients on glucagon-like peptide 1 (GLP-1) agonists had significant gastric contents during elective gastroscopy despite adequate fasting.

This has significant implications on the risk profile of GLP-1 agonists in the perioperative setting. Whilst there is consensus appreciation of the reduction in perioperative cardiometabolic complications these agents provide in improving glycaemic control, it would be remiss to discount the unquantified risk of aspiration from GLP-1 agonists during airway management.

Presently, the Australian Diabetes Society (ADS) and ANZCA Perioperative Diabetes and Hyperglycaemia Guidelines (November 2022) provide the universal recommendation to withhold all non-insulin antihyperglycaemics on day of surgery, including GLP-1 agonists, with SGLT2 inhibitors to be withheld 2 days prior to surgery. This generalised rule certainly does not address the prolonged therapeutic effects of newer weekly GLP-1 formulations and unknown legacy effects on reduced gastric motility.

Here, we review the physiology and pharmacology of GLP-1 agonists, their current clinical indications, nuanced perioperative considerations, and areas of research needed to establish the safest use of these agents for our patients.

What is GLP-1 and its effect?

GLP-1 is an endogenous incretin peptide hormone produced from intestinal L-cells predominantly located in the terminal ileum. It is produced rapidly in response to nutrient ingestion, and has multiple endocrine and CNS effector sites through GLP-1 receptors which lead to reduced glycaemia. GLP-1 is subsequently rapidly inactivated by dipeptidyl peptidase-4 (DPP-4) with a half-life of 1-3 minutes.

In T2DM, there is reduced prandial release of GLP-1 with preserved pancreatic response, making GLP-1 an attractive pathway for antihyperglycaemic agents.

Table 1. Effects of GLP-1 agonism at various effector sites

Clinical indications of GLP-1 agonists

Like insulin, GLP-1 agonists are hormone mimics restricted to subcutaneous injectables as their only route of administration. The first generation of GLP-1 agonists (e.g. exenatide, lixisenatide) were designed to resist DPP-4 metabolism, and had half-lives of ~3hrs necessitating twice-daily or daily dosing. With second generation GLP-1 agonists (liraglutide, dulaglutide), emphasis turned to increasing protein binding, reducing renal clearance, thus further prolonging drug half-life to now permit weekly injectable formulations (e.g semaglutide).

GLP-1 agonists is currently approved as second/third-line therapy for T2DM patients with inadequate glycaemic control (HbA1c ≥7.0 or ≥53 mmol/mol) despite lifestyle modifications and first-line antihyperglycaemics (metformin/sulfonylurea/insulin).

Liraglutide, a long-acting GLP-1 agonist, is also approved as adjunct pharmacotherapy with lifestyle modification for weight management, particularly for patients with BMI ≥27 kg/m2, with or without T2DM.

In addition to established efficacy for glycaemic control and weight loss, there has been growing enthusiasm surrounding the cardioprotective effects of GLP-1 agonists, as demonstrated from their superiority to placebo in multiple large studies in preventing major cardiovascular adverse events, namely reduced rates of myocardial infarcts, stroke, and rates of revascularisation procedures (Table 2). Whilst exact mechanisms remain unclear, a combination of risk factor reduction in improved HbA1c, weight, metabolic profile, as well as direct effects of GLP-1 agonism on coronary endothelial function and improved microvascular perfusion is likely at play.

Table 2. Overview of currently available GLP-1 agonists, detailing dose half-life, HbA1c lower effects, and outcomes of major cardiovascular safety trials.

Perioperative considerations

With their superiority in glycaemic control, low incidence of fasting hypoglycaemia, roles in weight management, and established evidence for their cardiovascular benefits, GLP-1 agonists present as highly attractive agents in improving patient outcomes in the perioperative setting, with growing interest for these agents to be continued without perioperative interruption.

Indeed, several recent studies using perioperative GLP-1 agonists have demonstrated improved glycaemic control and reduced insulin requirements in cardiac and non-cardiac surgeries without increase in hypoglycaemia or other adverse events.

However, anaesthetists must take into account the theoretical increased risk of aspiration in patients taking GLP-1 agonists, as presented by the aforementioned case reports. The effects of delayed gastric emptying may further compound the risk factors harbored by the obese, diabetic patient:

• Gastroparesis secondary to diabetes-related autonomic dysfunction

• Bowel dysmotility from opioids (chronic pain) and prolonged bed-rest

• Altered oesophageal-gastric anatomy from bariatric surgery

• Gastric insufflation from overzealous bag-valve ventilation with high PEEP and difficult airway

• Reduced efficacy of routine antiemetic regime

Nausea and vomiting are reported by approximately 50% of patients using GLP-1 agonists, as direct results of reduced gastric motility and activation of central satiety centers. However, these effects are often mild, and appear to dissipate over time with continuous use, with patients treated with liraglutide returning to near-baseline gastric emptying by week 8 of therapy.

Moreover, in patients with established gastroparesis, such as those with long-standing diabetes or critical illness, GLP-1 agonists did not significantly worsen gastric motility. Existing literature has also failed to establish an association between GLP-1 agonist and increased postoperative nausea and vomiting.

Nevertheless, concerning case reports and retrospective studies have emerged in 2023 of undigested gastric contents in sedated/anaesthetised patients undergoing elective endoscopy with unprotected airways:

• Klein and Hobai (2023) published a case report of a patient taking semaglutide for weight loss who experienced pulmonary aspiration from undigested food content identified during routine gastroscopy, despite fasting 18hr prior to the procedure.

• Kobori and colleagues (2023) identified through their case-control study significantly higher gastric residues on gastroduodenoscopy in diabetic patients treated with GLP-1 agonists than paired controls.

• Silveira and colleagues (2023) highlighted in a retrospective chart review semaglutide-treated patients were 5 times more likely to have residual gastric content on elective esophagogastroduodenoscopies than non-semaglutide-treated patients.

Risk-benefit implications

With increasing prevalence of GLP-1 agonists in our perioperative population and emerging reports of retained gastric content despite recommended fasting guidelines, a review on the perioperative handling of GLP-1 agonists and assessment of these patients are warranted to balance their cardiometabolic benefits and unquantified risk of catastrophic pulmonary aspiration.

Considering the prolonged half-life of most GLP-1 agonists currently prescribed, it is unfeasible to withhold these agents for weeks prior to surgery to achieve normalisation of gastric function with unknown impact on aspiration rates, appreciating the detrimental effects of poorer glycaemic control on withholding these agents and associated higher risk of peri/postoperative complications (major cardiovascular events, poor wound healing, increased wound infection etc.).

With paucity of high-quality data informing practice, anaesthetists must employ higher vigilance towards patients using GLP-1 agonists, acknowledging the already elevated risks these patients have for complex airways. Use of gastric ultrasound may be prudent for high-risk patients presenting with symptoms of indigestion or nausea/vomiting, however its utility in high-turnover, low resource settings is limited. Further research into the optimal management of GLP-1 agonists in the perioperative period is therefore needed.

References

Australian Diabetes Society and Australian and New Zealand College of Anaesthetists. ADS-ANZCA Perioperative Diabetes and Hyperglycaemia Guidelines Adults (November 2022)

Beam, W. Guevara, L. (2023). Are Serious Anesthesia Risks of Semaglutide and Other GLP-1 Agonists Under-Recognized? Case Reports of Retained Solid Gastric Contents in Patients Undergoing Anesthesia. Anesthesia Patient Safety Foundation. June 8, 2023. Accessed on 31 Aug 2023. URL: https://www.apsf.org/article/are-serious-anesthesia-risks-of-semaglutide-and-other-glp-1-agonists-under-recognized/

Hulst, A. H., Polderman, J. A. W., Siegelaar, S. E., van Raalte, D. H., DeVries, J. H., Preckel, B., & Hermanides, J. (2021). Preoperative considerations of new long-acting glucagon-like peptide-1 receptor agonists in diabetes mellitus. British journal of anaesthesia, 126(3), 567–571. https://doi.org/10.1016/j.bja.2020.10.023

Klein, S. R., & Hobai, I. A. (2023). Semaglutide, delayed gastric emptying, and intraoperative pulmonary aspiration: a case report. Sémaglutide, vidange gastrique retardée et aspiration pulmonaire peropératoire : une présentation de cas. Canadian journal of anaesthesia = Journal canadien d’anesthesie, 10.1007/s12630-023-02440-3. Advance online publication. https://doi.org/10.1007/s12630-023-02440-3

Kobori, T., Onishi, Y., Yoshida, Y., Tahara, T., Kikuchi, T., Kubota, T., Iwamoto, M., Sawada, T., Kobayashi, R., Fujiwara, H., & Kasuga, M. (2023). Association of glucagon-like peptide-1 receptor agonist treatment with gastric residue in an esophagogastroduodenoscopy. Journal of diabetes investigation, 14(6), 767–773. https://doi.org/10.1111/jdi.14005

Olesnicky, B. (2023). GLP-1 agonists and gastric emptying. Bulletin. Australian and New Zealand College of Anaesthetists (ANZCA) & Faculty of Pain Medicine (FPM). Winter 2023 edition, p20

Silveira SQ, da Silva LM, de Campos Vieira Abib A, de Moura DTH, de Moura EGH, Santos LB, Ho AM, Nersessian RSF, Lima FLM, Silva MV, Mizubuti GB. Relationship between perioperative semaglutide use and residual gastric content: A retrospective analysis of patients undergoing elective upper endoscopy. J Clin Anesth. 2023 Aug;87:111091. doi: 10.1016/j.jclinane.2023.111091. Epub 2023 Mar 2. PMID: 36870274.

The Royal Australian College of General Practitioners. Management of type 2 diabetes: A handbook for general practice. East Melbourne, Vic: RACGP, 2020.

Quick Summary

Propofol (2,6-diisopropylphenol) is one of the most widely-used hypnotic agents in critical care departments worldwide, owing to its rapid and predictable onset/offset, favourable safety profile and low adverse effect rates.

However, emerging evidence suggests an association between propofol used in operative and ICU settings and increased mortality.

Most recent meta-analysis of current RCTs by Kotani et al. (2023) highlights a statistically significant 10% increase in mortality in patients undergoing sedation or anaesthesia with propofol versus other agents (RR 1.10, 95%CI 1.01-1.20, p=0.03, I2=0%).

Key subgroups where propofol conferred increased mortality included

• Patients undergoing cardiac surgery vs. any comparator agents (21% increase) 
• Volatile anaesthetic as comparator (25% increase)
• Analysis of large RCTs (n>500) (45% increase)
• Studies with low mortality in comparator arm (35% increase)

Four mechanism has been hypothesised explaining propofol’s negative effect on survival

1. Propofol infusion syndrome
2. Bacterial contamination and infection due to lipophilic medium supporting bacterial growth
3. Inferiority compared to, and possible disruption of, organ-protective mechanism of other interventions such as volatile anaesthetic preconditioning
4. Intraoperative hypotension secondary to propofol induced vasodilation

Preamble: revision of propofol pharmacology

What is it? 

• Chemical structure 2,6-diisopropylphenol
• Intravenous HYPNOTIC AGENT
  • Causes sedation, loss of consciousness and amnesia
  • DOES NOT HAVE ANALGESIC PROPERTIES
• Due to its low water solubility, it is prepared in mixture of oil emulsion medium, giving its characteristic “milky” appearance:
  • 10% soybean oil
  • 1.2% purified egg phospholipid
  • 2.25% glycerol (for tonicity)
  • Sodium hydroxide (for pH control between 6 – 8.5)
  • EDTA (antimicrobial additive)

Indications

Anaesthesia

• Induction and maintenance of anaesthesia (total intravenous anaesthesia)
• Sedation

Emergency

• Procedural sedation (usually bolus dosing)
• Rapid sequence induction (can occur in any critical care setting)

ICU

• Maintenance of sedation in mechanically ventilated patients (infusions)
• Neuroprotection (part of multimodal approach) in traumatic brain injury (reduces cerebral metabolism, ICP, cerebral blood flow)

Other

• Off-label use for refractory postoperative nausea and vomiting (antiemetic) and status epilepticus (anti-convulsant)

Pharmacodynamics 

• Agonist at beta subunit of CNS γ-aminobutyric acid (GABA)-mediated chloride channels
• Prolongs channel opening, chloride influx, and maintains membrane hyperpolarisation and inhibits postsynaptic neuronal action potential.

Pharmacokinetics

Absorption/administration

• Intravenous administration only
• Not suitable for PO administration due to bitter taste and low oral bioavailability from first pass metabolism (<1%)

Distribution

• Highly protein bound to albumin (predominant) and erythrocyte
  • Plasma free fraction 1.2-1.7%
• Highly lipophilic, minimally soluble in water
  • Weak acid with pKa 11 = mostly unionised in plasma (pH 7.4) (hence require oil emulsion medium)
  • Volume of distribution 2-10L/kg (3-4 times total body volume, despite highly protein bound)
  • Readily crosses blood-brain barrier (BBB), free fraction ~31% in CSF
• Rapid onset and offset
  • Onset ~30-60s
  • Bolus half life ~120s
    • Duration of action ~5-10min
    • Rapid offset of bolus doses mainly due to rapid redistribution
  • Context sensitive half life (time for 50% reduction of plasma drug concentration on STOPPING infusion)
    • 10min for 3hr infusion
    • 30min for 8hr infusion
    • 1-2 days for 10 day infusion (commonly encountered in ICU)
    • Half-life INCREASES with prolonged infusion, as more and more drug accumulates in fatty tissue
      • Usually not significant in anaesthesia setting
  • Half-life to reach steady state: 5-12hrs.

Metabolism

• Mainly hepatic (glucouronide conjugation and hydroxylation)
• Extrahepatic clearance: indicated by clearance rate ~2.2L/min -> higher than liver flow
• Renal and GIT metabolism contributing to extrahepatic clearance

Elimination/excretion

• Renal excretion of inactive metabolites
• Phenolic metabolites rarely (< 1% of patients) result in green discolouration of the urine

Foetal-specific

• Readily crosses the placenta, however rapidly cleared from neonatal circulation
• Non-teratogenic
• Theoretical risk of neonatal respiratory depression
• Induction agent of choice for stable general anaesthesia caesarean sections

Common ADRs 

Transient localised pain at injection site

• Offsetted by concurrent IV lidocaine administration

Hypotension

• Indirect effect of sympathetic depression

• Reduced venous vascular tone -> reduced venous return -> reduced preload
• Reduced systemic vascular tone -> reduced total peripheral resistance -> reduced afterload
• Depressed baroreceptor response -> reduced reflex vasoconstriction & tachycardia
• Inotropy is largely unaltered (negative inotropy only at supra-clinical ranges)
• MAP drop largely due to peripheral vasodilation with preserved cardiac output

Respiratory depression

• Dose-dependent dampening of sensitivity to hypoxaemia and hypercarbia, leading to bradypnoea and apnoea
• Attenuated airway reflexes
• Reduced tidal volume via intercostal relaxation
• Bronchodilation (attenuates vagal tone)

Propofol and increased mortality: rationale of meta-analysis by Kotani et al.

Propofol has become a staple in critical care departments in Australia and worldwide, with hundreds and millions of patients each year receiving propofol as their hypnotic agent in theatre, ED departments and ICU. As described it ia an ideal hypnotic with rapid onset, short duration, fast offset and recovery, favourable side effect profile, non-teratogenic and less environmentally harmful compared to volatile gases

With its ubiquitous use presently, any association with worsened survival would have far-reaching ramifications from the sheer number of deaths that may be implicated with the use of propofol.

Kotani and colleagues performed a meta-analysis in 2015 of 133 RCTs, demonstrating a trend towards higher mortality rates with use of propofol compared to other sedation/anaesthesia agents. They postulated 4 mechanisms by which propofol may confer increased harm:

1. Propofol infusion syndrome

First described in 1998 in predominantly paediatric ICU populations, it is becoming increasingly recognised in adult ICU patients with prolonged high dose infusion of propofol (greater than 4mg/kg/hr for more than 48 hours), characterised by profound cardiogenic dysfunction and metabolic acidosis.

Incidence

• 1.1%
• 3-4 cases per year for standard ICU

Mortality

• 10-18%

Clinical presentation

• Acute refractory bradycardia leading to asystole and cardiogenic shock
• Preceded by Brugada-like STE in V1-3 and RBBB
  • And one or more of:
    • HAGMA metabolic acidosis (lactic acidosis)
    • Rhabdomyolysis and AKI
    • Hypertriglyceridemia
    • Hepatomegaly or fatty liver
• Mechanism postulated to be inhibition of mitochondrial electron chain reaction, therefore halting muscle aerobic respiration and lipid metabolism

-> anaerobic metabolism predominant -> lactic acidosis

-> cardiac/skeletal muscle lysis, lipidaemia

• Check ABG, UEC, CK, lipid levels and cease propofol infusion immediately with high index of suspicion

1. Iatrogenic Infection

Due to the lipid emulsion preparation, propofol provides an optimal microbial growth environment at room temperature, and hence carries an increased risk of contamination and iatrogenic infection, despite efforts to reduce such risk with the additive EDTA.

In their literature review, Zorilla-Vaza and colleagues identified 20 propofol-related infection outbreaks described between 1989 and 2014 (latest being in Australia, see link: https://www.tga.gov.au/alert/propofol-provive-and-sandoz-propofol-1-emulsion-injection-all-sizes-and-all-batches-update-3), affecting 144 patients and resulting in 10 deaths.

Damningly, poor handling by healthcare professionals accounts for most cases of contamination, some of these described continues to be perpetrated:

• Missed moments of hand hygiene
• Failure to use sterile gloves
• Multiple pre-prepared syringes with prolonged environment exposure

1. Inferiority of protective mechanisms compared to other interventions

This relates to propofol’s weaker effect when compared to volatile anaesthetic in preventing ischaemia-reperfusion injury (IRI) in cardiopulmonary bypass and transplant surgery.

In brief, IRI is characterised by mitochondrial respiratory chain dysfunction and uncontrolled production of reactive oxygen species (ROS) after reperfusion of stressed ischaemic tissue, leading to oxidative cell injury, cell apoptosis, pro-inflammatory cell signalling and leukocyte migration.

This translates clinically, in cardiopulmonary bypass, with worsened myocardial infarct and post-operative function; in transplant’s case, this entails delayed graft function and higher rates of primary graft failure.

Preconditioning aims to prime tissue to better tolerate prolonged ischaemic insult during surgery. In this domain, volatile anaesthetics’s pleiotropic effects have been demonstrated to exert cellular protection superior to propofol. Meta-analysis by Bonnani and colleagues (2020) highlighted patients undergoing cardiopulmonary bypass with volatile anaesthetic had reduced myocardial infarct, less inotropic support, better cardiac index and reduced 1-year mortality than those receiving propofol TIVA. Mechanistically, volatiles have been shown to prevent mitochondrial dysfunction by activating protein kinase C, reduce endothelial injury, and upregulation of endogenous hypoxia-protective factors.

In fact, propofol may disrupt these protective mechanisms, by neutralising superoxides and peroxides produced from volatiles implicated in mitochondrial protection.

1. Haemodynamic instability

Perhaps one of the better known adverse effects, propofol causes intraoperative hypotension and via sympathetic depression and vasodilation. Combined with critically ill patient populations in ICU (septic, hypovolaemic shock states) and multimorbid surgical candidates with fragile cardiopulmonary reserves, small losses in preload and perfusion pressures often translates to poor survival outcomes.

With further evidence published, Kotani and colleagues have updated their meta-analysis in 2022 to include new RCTs, in hope, with added statistical power, that a clear increase in mortality with propofol compared to other comparactors can be elucidated.

Study design

PICO question

• Population: patients receiving general anaesthesia or sedation
• Intervention: propofol
• Comparison: any comparator drug
• Outcome: mortality at the longest follow-up available

Search method

• 4 investigators
• Database:
  • Pubmed, Google Scholar, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov
  • Abstracts of major congresses within last 3 years

Inclusion

• All RCTs comparing propofol vs. any comparator in any clinical setting
• All age, all language

Exclusion

• Cross-over trials
• Non-human studies
• Comparators were loco-regional anaesthesia
• Indication for palliative / end-of-life care
• Propofol used as single bolus in intervention arm, or simple procedures

Study selection / data collection / risk of bias

• 2 investigators selected eligible studies, disagreement discussed with 2 senior investigators
• 2 investigators extracted data: publication details, n (propofol), n (comparator), comparator type, no. deaths, settings (ICU / surgery (non-cardiac vs cardiac) / adult vs. paediatric)
• Risk of bias was assessed with Cochrane risk-of-bias tool ver. 2 (RoB 2 )

Data analysis

• Relative risk (RR) calculated from:
  • Fixed-effect Mantel-Haenszel model for low heterogeneity (I2<25%)
  • Random-effect Mantel Haenszel model for high heterogeneity (I2≥25%)
• Standard two tailed 0.05 significance level for unadjusted p values
• Prespecified subgroup analysis
  • Settings: Cardiac / non-cardiac / ICU
  • Bolus propofol in comparator arm: yes / no
• Sensitivity analysis subgroups
  • Age: adult / paediatric
  • Comparator type: volatile, total IV, miscellaneous
  • Study size: large (n≥500) / small (n<500)
  • Comparator mortality: high (>4.5%), low (≤4.5%)
  • Exclusion of high bias risk studies
• RR and 95% confidence interval (95% CI) plotted on probability density function (100,000 simulated trials on log scale using kernel density estimation)
• Post-hoc sensitivity analysis with Bayesian meta-analysis and trial sequential analysis (TSA)

Outcome

252 RCTs were selected for analysis, with 30,757 total patients.

• Most common setting was non-cardiac surgery (153 RCTs) > ICU (52 RCTs) > cardiac surgery (47 RCTs).
• Most common comparator was volatile anaesthetics (172 RCTs), followed by total IV agents other than propofol (71 RCTs) and miscellaneous (9 RCTs)
• 75 RCTs included propofol bolus in their comparator arm (for anaesthesia induction)

Bias assessments:

RoB2 identified 41 high risk studies (16%), 114 moderate risk (45%) and 97 low risk (38%).

Funnel plot showed no obvious asymmetry to suggest publication bias.

Bubble plot did not show influence of year of publication on mortality ratio.

Primary outcome: Morality

Analysis demonstrated a statistically significant 10% increase with use of propofol

• 5.2% propofol vs. 4.3% comparator, RR 1.10, 95% CI 1.01–1.20, p = 0.03, I2=0%
• Probability density function with Bayesian meta-analysis confirms a 98.4% probability of increase in mortality
• TSA fell in “inconclusive” range, Z-line favouring “comparator” but not crossing into significance range

Subgroup analysis

Significant mortality increase with propofol were noted in:

• Patients undergoing cardiac surgery vs. any comparator (21% increase) 
  • RR 1.21, 95%CI 1.04-1.41, p=0.01, I2=0%
• Volatile anaesthetic as comparator (25% increase)
  • RR 1.25, 95%CI 1.06-1.47, p=0.009, I2=11%
• Analysis of large RCTs (n>500) (45% increase)
  • RR 1.45, 95%CI 1.10-1.92, p=0.009, I2=0%
• Studies with low mortality in comparator arm (35% increase)
  • RR 1.35, 95%CI 1.03-1.76, p=0.03, I2=0%

Overall significance was retained after removing high risk RCTs based on RoB2

• RR 1.12, 95% CI 1.02-1.23, p=0.02, I2=0%

Of note, propofol’s use in non-cardiac surgery and ICU setting were not associated with significant increase in mortality compared to comparators.

This was also the case irrespective of whether propofol was used for bolusing in the comparator arm.

Implications of current meta-analysis

Kotani and colleagues have shown that propofol, one of the most commonly used medications in any anaesthetist’s trolley, is associated with a 10% increase in mortality compared to other hypnotics.

Not unexpectedly, this meta-analysis has shown that propofol is worse than volatile anaesthetics, particularly in cardiac surgery. This brings more credibility to the hypothesis that propofol offsets the organ-conditioning effects of volatile anaesthetics and leads to greater IRI in cardiac surgeries, where cardiopulmonary and renal circulations are often subjected to prolonged ischaemia and sudden reperfusion. It would also be remiss to discount the detrimental haemodynamic effects of propofol in such high-risk surgery types.

We may infer that propofol infusion syndrome is unlikely to play a major role in mediating increased mortality. As a syndrome most commonly observed in paediatric populations subjected to prolonged propofol infusion, neither the ICU nor paediatric subgroups saw significant risk increases.

Infection risk of propofol leading to worsen mortality rates is difficult to extrapolate. Data continues to observe significant increases in mortality when investigating RCTs published post-2005 (RR 1.11, 95% CI 1.00-1.22, p=0.04, I2=0%), a timeframe after the widespread adoption of EDTA as an antimicrobial additive in propofol preparation. As described, poor handling and preparation techniques remain preventable sources of microbial contamination and harm to patients. Whether this risk is independently observed is up for further debate, amidst an increasingly complex and at-risk surgical population under an environment with ever-evolving antibiotic resistance patterns.

In the ICU setting, propofol’s negative effect, if any, appears to be less overt. The authors highlighted the heterogeneity of the ICU population requiring sedation in terms of their presenting pathologies and background co-morbidities, making propofol effects difficult to discern from confounding noise. High baseline mortality rates of ICU patients also makes detecting any treatment effects of propofol challenging, as demonstrated in the statistical non-significance of the “high-mortality comparator arm” subgroup.

Nevertheless, it is important to note that all subgroups, irrespective of statistical significance,  had effect sizes in favour of propofol reducing survival. Kotani and colleagues affirmed the robustness of the outcomes with a consistent Bayesian post-hoc meta-analysis.

However, the data at hand does highlight some limitations to our interpretations.

• Substantial proportion of studies included propofol in the comparator arm (as part of induction protocol), which may undermine the legitimacy of the supposed “control” group
• The TSA finding was “inconclusive”, implying that additional data from future studies has the potential to unmask and correct any Type I error within the current RCT pool.

What does our finding imply? Assuming millions of patients worldwide receive propofol annually, this implies an unacceptably high mortality burden that the critical care specialties are subjecting our patients to.

Will this meta-analysis inform clinical change at present? Very unlikely, given the lack of large megatrials informing this meta-analysis, contamination of propofol in the comparator arm, as well as our clinical inertia ingrained in our practice guidelines and the financial implications. However, it is likely to provoke a consideration of a large trial, which will be a resource-intensive undertaking.

References

Kotani, Y., Pruna, A., Turi, S. et al. Propofol and survival: an updated meta-analysis of randomized clinical trials. Crit Care 27, 139 (2023). https://doi.org/10.1186/s13054-023-04431-8

De Cassai, A., Tassone, M., Geraldini, F., Sergi, M., Sella, N., Boscolo, A., & Munari, M. (2021). Explanation of trial sequential analysis: using a post-hoc analysis of meta-analyses published in Korean Journal of Anesthesiology. Korean journal of anesthesiology, 74(5), 383–393. https://doi.org/10.4097/kja.21218

Folino TB, Muco E, Safadi AO, et al. Propofol. [Updated 2022 Jul 25]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK430884/

Nieuwenhuijs-Moeke, G. J., Bosch, D. J., & Leuvenink, H. G. D. (2021). Molecular Aspects of Volatile Anesthetic-Induced Organ Protection and Its Potential in Kidney Transplantation. International journal of molecular sciences, 22(5), 2727. https://doi.org/10.3390/ijms22052727

Sahinovic, M. M., Struys, M. M. R. F., & Absalom, A. R. (2018). Clinical Pharmacokinetics and Pharmacodynamics of Propofol. Clinical pharmacokinetics, 57(12), 1539–1558. https://doi.org/10.1007/s40262-018-0672-3

Yartsef, A (2015), Propofol. CICM Primary Exam. Deranged Physiology. Last accessed 24/04/2023. Available from: https://derangedphysiology.com/main/cicm-primary-exam/required-reading/nervous-system/Chapter%20211/propofol

Zorrilla-Vaca, A., Arevalo, J. J., Escandón-Vargas, K., Soltanifar, D., & Mirski, M. A. (2016). Infectious Disease Risk Associated with Contaminated Propofol Anesthesia, 1989-2014(1). Emerging infectious diseases, 22(6), 981–992. https://doi.org/10.3201/eid2206.150376

by Dr. Matthew Vella @mjv.igee

PADDI (The Perioperative ADministration of Dexamethasone and Infection Trial)

Corcoran, T. B., Myles, P. S., Forbes, A. B., Cheng, A. C., Bach, L. A., O’Loughlin, E., Leslie, K., Chan, M. T. V., Story, D., Short, T. G., Martin, C., Coutts, P., Ho, K. M., PADDI Investigators, Australian and New Zealand College of Anaesthetists Clinical Trials Network, & Australasian Society for Infectious Diseases Clinical Research Network (2021). Dexamethasone and Surgical-Site Infection. The New England journal of medicine, 384(18), 1731–1741. https://doi.org/10.1056/NEJMoa2028982

Where is it published?

New England Journal of Medicine (NEJM)

What kind of study is it?

International, multi-centre, randomised, placebo controlled, triple blind, non-inferiority trial

Who is involved?

ANZCA (Australian and New Zealand College of Anaesthetists) Clinical Trials network
Australasian Society for Infectious Diseases Clinical Research Network
Centres across Australia, Hong Kong, China, New Zealand and South Africa

What did they set out to do?

To see if intraoperative dexamethasone is associated with increased rates of surgical site infection

What is significant about the study?

It explores whether we have been exposing patients to greater risk of surgical site infection by providing PONV prophylaxis

This time we’re looking at a higher, single intraoperative dose (8mg) compared with previous studies [e.g., 4mg single dose in Kurz et al (2015); 14mg tapered over 3 days in Abdelmalak et al (2013)]

How was it done?

Many adults, from centres across the globe, with ASA scores 1-4 (American Society of Anaestheiology), were randomly allocated to receive dexamethasone (8mg intravenous) or placebo during GA (general anaesthesia) for elective non-cardiac surgery

Patients with diabetes were included (Hba1c <9), however those receiving surgery for a primary infection were excluded. All other anaesthetic care was provided according to local practice / guidelines (including antibiotic provision and BGL management)

See full list of inclusions / exclusions:
https://bmjopen.bmj.com/content/9/9/e030402.long

Patients were followed-up in PACU (post acute care unit), with post-op wound reviews on day 1, 3, discharge, 30-days, and 6-months

The primary outcome was the occurrence of surgical site infection within 30-days

Why do we care about dexamethasone use?

PONV remains a major challenge in perioperative care. Around 1 in 4 people will experience PONV after general anaesthesia, and this rate jumps to around 3 in 4 in high-risk populations (i.e., younger, female, previous PONV, history of motion sickness, non-smoker, post-op opioid usage)

While dexamethasone is a potent, prophylactic anti-emetic, we know that long-term glucocorticoid therapy is associated with increased risk of surgical site infection and wound dihescence

In short, we want to ensure our effort to minimise PONV – with the aim to improve patient experience / care, length-of-stay, mortality and morbidity, and associated healthcare costs – is not subjecting patients to greater risk of surgical site infection

What did they find?

We’re doing the right thing by the patient!
There was no difference between dexamethasome and placebo in incidence of surgical site infection within 30 days of non-urgent, non-cardiac surgery

Dexa, diabetics and other at-risk patients
There was not an increased incidence of surgical site infection in diabetics or at-risk patients – in fact, dexamethasone was equal to placebo across all subroups and is considered safe for patients with implanted prosthetic material

Any limitations?

1. No pre-trial data collected on baseline patient risk-factors (e.g., subtype of GI surgery, pre-op bowel or skin preparation, antibiotic prophylaxis duration / schedule)

2. Potential for mild infections to be missed due to failed follow-up (i.e., patient not returning)

3. Issues with non-adherence to protocol (i.e., non-trial provision of post-op glucose)

What’s the overall take-home?

Dexamethasone can be used safely and effectively for PONV prophylaxis without fear of exposing patients to increased risk of surgical site infection.

Importantly, the PADDI trial suggests our total knee replacement case with diabetes and a history of severe PONV can have dexamethasone providing they have a reasonable pre-operative BGL control (i.e., Hba1c <9).

Further reading:

PADDI trial: rationale and design

https://bmjopen.bmj.com/content/9/9/e030402.long

PADDI trial results webinar

https://www.youtube.com/watch?v=-XdkpDmD1rM

CDC – centers for disease control and prevention: surgical site infection guideline

https://www.cdc.gov/infectioncontrol/guidelines/ssi/index.html

Previous studies with lower / tapered dose of dexamethasone:

Abdelmalak, B. B., Bonilla, A., Mascha, E. J., Maheshwari, A., Tang, W. H., You, J., Ramachandran, M., Kirkova, Y., Clair, D., Walsh, R. M., Kurz, A., & Sessler, D. I. (2013). Dexamethasone, light anaesthesia, and tight glucose control (DeLiT) randomized controlled trial. British journal of anaesthesia, 111(2), 209–221.

A. Kurz, E. Fleischmann, D. I. Sessler, D. J. Buggy, C. Apfel, O. Akça, the Factorial Trial Investigators, Edith Fleischmann, Erol Erdik, Klaus Eredics, Barbara Kabon, Friedrich Herbst, Sara Kazerounian, Andre Kugener, Corinna Marschalek, Pia Mikocki, Monika Niedermayer, Eva Obewegeser, Ina Ratzenboeck, Romana Rozum, Sonja Sindhuber, Katja Schlemitz, Karl Schebesta, Anton Stift, Andrea Kurz, Daniel I. Sessler, Endrit Bala, Samuel T. Chen, Jagan Devarajan, Ankit Maheshwari, Ramatia Mahboobi, Edward Mascha, Hassan Nagem, Suman Rajogopalan, Luke Reynolds, Adrian Alvarez, Luca Stocchi, Anthony G. Doufas, Raghavendra Govinda, Yusuke Kasuya, Ryu Komatsu, Rainer Lenhardt, Mukadder Orhan-Sungur, Papiya Sengupta, Anupama Wadhwa, Susan Galandiuk, Donal Buggy, Mujeeb Arain, Siun Burke, Barry McGuire, Jackie Ragheb, Akikio Taguchi, the Factorial Trial Investigators, Effects of supplemental oxygen and dexamethasone on surgical site infection: a factorial randomized trial, BJA: British Journal of Anaesthesia, Volume 115, Issue 3, September 2015, Pages 434–443

Key reference:

Richards, T., Baikady, R. R., Clevenger, B., Butcher, A., Abeysiri, S., Chau, M., Macdougall, I. C., Murphy, G., Swinson, R., Collier, T., Van Dyck, L., Browne, J., Bradbury, A., Dodd, M., Evans, R., Brealey, D., Anker, S. D., & Klein, A. (2020). Preoperative intravenous iron to treat anaemia before major abdominal surgery (PREVENTT): a randomised, double-blind, controlled trial. Lancet (London, England), 396(10259), 1353–1361. https://doi.org/10.1016/S0140-6736(20)31539-7

Quick Summary

• Anaemia (haemoglobin <130g/L male, <120g/L female) is associated with post-operative complications and is an independent risk factor for peri-/post-operative mortality
• Pre-operative intravenous iron infusion is routinely used to correct anaemia and iron deficiency, however its efficacy in improving post-operative outcomes remains unclear
• PREVENTT is a multicentre, randomised, double blinded, controlled trial investigating if intravenous iron infusion before major elective abdominal surgery reduces blood transfusion and mortality
• PREVENTT found pre-operative iron infusion was NON-SUPERIOR to placebo in reducing blood transfusions, mortality rate, length of ICU/hospital stay, and quality of life
• The outcome of PREVENTT means the correction of anaemia / iron deficiency with intravenous iron infusion alone cannot be recommended, and that a multidisciplinary approach to pre-operative anaemia management may be required to reduce post-operative morbidity/mortality

Preamble

In your pre-admission clinic, you meet Darren, a 67yo gentleman with PMHx of peptic ulcer disease, stage III chronic kidney disease and ischaemic heart disease on aspirin, awaiting his Cat 1 left hemicolectomy 2 weeks from now for colon cancer. He is feeling washed out and breathless, but is keen to get his operation done and dusted for good this time.

You note on his bloods that his haemoglobin (Hb) is 98g/L, and an iron study showing ferritin of 25ng/L. You tell Darren that he has iron deficiency anaemia, which needs to be optimised prior to his surgery. Darren is highly anxious, as he does not want his operation to be delayed. He tells you he has had multiple iron infusions before, which usually corrects his haemoglobin count.

Do you allow Darren to proceed with his operation with an iron infusion beforehand?

What is Iron deficiency and anaemia? What are the peri-operative implications?

Anaemia:

• Hb <130g/L in male,
• <120g/L in non-pregnant females, and
• <110g/L in pregnant females
• Iron deficiency is the most common cause

Iron deficiency (with or without anaemia):

• Serum ferritin <30ng/L, or
• Serum ferritin 30-100ng/L with CRP >5mg/L and transferrin saturation <20% in context of inflammatory process

Iron deficiency anaemia (IDA):

• Decreased erythropoiesis due to inadequate iron stores
• Biochemical Hb and iron studies reflecting anaemia and iron deficiency
• Most common cause include
  • Nutritional deficiency (reduced intake or malabsorption)
  • Chronic blood loss (gastrointestinal, gynaecological, iatrogenic (pharmacologically-impaired haemostasis, phlebotomy, haemodialysis) etc.

Anaemia of chronic disease with iron deficiency

• Inflammatory cytokines elicit production of hepcidin, which produces a net functional low iron state by:
  • Reducing mobilisation of intracellular iron stores,
  • Reducing gastrointestinal absorption of dietary iron, and
  • promoting sequestration of iron into macrophages
• Inflammatory cytokines further inhibit erythropoiesis by suppressing renal production of erythropoietin and direct inhibition of marrow erythroid cell proliferation

Darren’s case is not unique. Anaemia is present in approximately 30-60% of pre-operative population, with IDA and anaemia of chronic disease being two most common causes. Darren’s PMHx certainly puts him at higher risk for chronic GI bleeding and impaired erythropoiesis.

Anaemia is a serious pre-operative condition:

• Independent risk factor for peri- and post-operative morbidity and mortality
• Increase length of hospital stay, requirement for ICU/HDU, as well as rates of readmission
• Need for peri-operative blood transfusions with associated risk of dose-dependent transfusion-related complications

Surgical population are particularly at risk of iatrogenic blood loss and anaemia, with outcomes worsened by:

• Emergency surgery,
  • where pre-operative optimisation of anaemia is unlikely to be adequately achieved
• High risk surgeries with likelihood of significant blood loss
  • (intra-abdominal, cardiothoracics, obstetrics)
• Co-morbid cardiovascular and neurovascular conditions
  • Reduced tolerance to anaemia and anaemia-related complications
• Patient and/or medication related impairment in haemostasis

Current consensus on pre-operative management of Iron deficiency & IDA

As per the International Consensus Statement on the Peri-operative Management of Anaemia and Iron Deficiency:

1. Treatment of low iron store (Ferritin <100ng/L with expected operative Hb drop of 30g/L) or iron deficiency anaemia should be initiated as soon as possible, ideally within 6-8 weeks;
2. IV iron transfusion should be first line for patients unresponsive or not tolerating oral iron replacement, or if surgery is planned in less than 6 weeks, given at least 2 weeks prior

Gaps in our knowledge

• There is established association between IDA and increased transfusion requirement, duration of stay and mortality,
• However, preoperative treatment of IDA and iron deficiency with IV iron infusion is only weakly supported by low-quality evidence and the theoretical hypothesis that correction of iron deficiencies & IDA will reduce the rates of aforementioned complications
• Hence, there remains uncertainty regarding the actual benefits of routine use of pre-operative IV infusions in these patients

The PREVENTT trial

The PREVENTT trial is an UK-based, multicentre, double-blinded, placebo-controlled trial looking to determine whether pre-operative iron infusion for patients with anaemia undergoing major elective abdominal surgery would:

1. Correct anaemia prior to surgery
2. Reduce requirement and number of blood transfusions
3. Reduce number of deaths

Study design

• Patient selection :
  • >18yo adults, identified with anaemia as defined as Hb <130g/L for males, <120g/L for females
  • Undergoing elective major abdominal surgery within 10-42 days
  • Across 46 UK tertiary centers
  • Exclusion criteria:
    • Laparoscopic surgery
    • Concurrent infection
    • Weight <50kg
    • Chronic liver disease or known alternate cause for anaemia, acquired iron overload, FHx of haemachromatosis / thalassaemia, transferrin saturation >50%
  • Iron studies were used to identify iron deficiency & IDA in pre-defined subgroup analysis

• 487 patients were recruited and randomised to
  • Intervention group (n=244): IV 1000mg iron carboxymaltose (Ferrinject) in 100ml saline
  • Placebo group (n=243): 100ml saline
• Groups were well matched in terms of baseline characteristics, including age, sex, Hb levels, comorbidities, and surgical factors including American Society of Anesthesiology (ASA) grade, type/duration/timing of surgery
• Of note, known iron deficiency (28% intervention vs 29% placebo group) and predisposing factors for iron deficiency (reflux/gastric ulcer, bleeding disorder, coeliac disease, inflammatory bowel disease, renal/hepatic disease, diabetes, antiplatelet/anticoagulant use) were similar in the two groups
• Patients were blinded through vision shielding, and research participants were blinded to treatment allocation
  • Administration of infusions were complete by unblinded personnel with nil further role in the study

• Primary endpoints were:
  • Requirement of blood product transfusion AND rate of death
  • Number of blood product transfusions <30 days post-op
• Secondary endpoints were:
  • Number of blood product transfusions 30 days to 6 months post-op
  • Hb change at 1) immediately pre-op, 2) 8 weeks and 3) 6 months post-op
  • Total length of stay +/- ICU length of stay
  • Readmission rate at 8 weeks and 6 months post-op
  • Health related quality of life

Findings of PREVENTT

Endpoint 1: Requirement of blood product transfusion AND rate of death <30 days post-op

• There was NO DIFFERENCE in combined transfusion rate and mortality rate
  • 69 intervention vs 67 placebo, risk ratio 1.03, 95% CI 0.78-1.37, p=0.84

Endpoint 2: Number of blood product transfusions <30 days post-op

• There was NO DIFFERENCE in number of blood product transfused
  • 105 intervention, 111 placebo, rate ratio 0.98, 95 % CI 0.68-1.43, p=0.93

Subgroup analysis:

Subgroup analysis for age (70, <70yo), gender, BMI (30, <30) and type/complexity of surgery did NOT SHOW a difference in primary endpoints

Surprisingly, subgroup analysis for level of anaemia (100g/L, <100g/L) and iron deficiency in ferritin <100ng/ml and TSAT <20% again DID NOT SHOW a difference in primary endpoints

Secondary endpoints:

Hb change:

• Hb levels were similar at randomisation (111.0g/L intervention vs 111.2 placebo)
• IV iron infusion was significantly effective in correcting anaemia pre-operatively
  • 21% intervention vs 10% placebo, risk ratio 2.07 95% CI 1.27-3.35
• Hb levels was also significantly higher in the delayed post-operative period for IV transfusion group:
  • 8 weeks post-op (mean difference 10.7g/L, 95% CI 7.8-13.7)
  • 16 weeks post-op (mean difference 7.3g/L, 95% CI 3.6-11.1)

Readmission rate at 8 weeks and 6 months post-op

• IV transfusion group had significantly reduced rates of readmission at 8 weeks compared to placebo

Total length of stay +/- ICU length of stay, health related quality of life, number of blood product transfusions 30 days to 6 months post-op

• No significant difference was observed for these secondary endpoints

Implications of PREVENTT on future practice

• Pre-operative IV iron infusion improves haemoglobin levels in patients with anaemia (not isolated to IDA) prior to elective major abdominal surgeries,
• However, this does not translate to improved clinical outcomes in blood transfusion requirement, post-op mortality, length of stay and quality of life.
• Detection and treatment of pre-operative anaemia / iron deficiency with IV iron infusion alone appear insufficient in addressing known association between anaemia and operative complications, and therefore cannot be recommended based on this evidence.
• A multidisciplinary approach based on Patient Blood Management guidelines may be required:
  1. Treat underlying cause of anaemia
  2. Minimise blood loss
  3. Improve patient tolerance to anaemia

Based on the PREVENTT trial, you tell Darren that, on top of his iron transfusions, you would ideally get an opinion from his cardiologist regarding his latest stress testing, review his renal function, and consider suspending his aspirin to medically optimise his overall fitness for surgery.

References

Abbott, T. E. F., & Gillies, M. A. (2021). The PREVENNT randomised, double-blind, controlled trial of preoperative intravenous iron to treat anaemia before major abdominal surgery: an independent discussion. British journal of anaesthesia, 126(1), 157–162. https://doi.org/10.1016/j.bja.2020.08.053

Muñoz, M., Acheson, A. G., Auerbach, M., Besser, M., Habler, O., Kehlet, H., Liumbruno, G. M., Lasocki, S., Meybohm, P., Rao Baikady, R., Richards, T., Shander, A., So-Osman, C., Spahn, D. R., & Klein, A. A. (2017). International consensus statement on the peri-operative management of anaemia and iron deficiency. Anaesthesia, 72(2), 233–247. https://doi.org/10.1111/anae.13773

Richards, T., Baikady, R. R., Clevenger, B., Butcher, A., Abeysiri, S., Chau, M., Macdougall, I. C., Murphy, G., Swinson, R., Collier, T., Van Dyck, L., Browne, J., Bradbury, A., Dodd, M., Evans, R., Brealey, D., Anker, S. D., & Klein, A. (2020). Preoperative intravenous iron to treat anaemia before major abdominal surgery (PREVENTT): a randomised, double-blind, controlled trial. Lancet (London, England), 396(10259), 1353–1361. https://doi.org/10.1016/S0140-6736(20)31539-7

https://www.clinicalkey.com.au/#!/content/playContent/1-s2.0-S2058534922000506

Epidemiology

• • Most common causes of CKD are diabetes and hypertension

What is the definition of CKD?

• • CKD definition: abnormality of kidney structure or function > 3 months (Renal Association)
    • Electrolyte abnormalities, proteinuria (ACR > 3), haematuria of renal origin, histological/radiological abnormalities in structure, raised creatinine and/or cystatin C (over 2 occasions 90 days apart)
  • Additional abnormalities include uraemia and anaemia

How is CKD classified?

• • Classification is based on eGFR
    • Stage 1: eGFR 90 or higher
    • Stage 2: eGFR 60-89
    • Stage 3a: eGFR 45-59
    • Stage 3b: eGFR 30-44
    • Stage 4: eGFR 14-29
    • Stage 5: eGFR less than 15
  • GFR not routinely measured because complex procedure requiring measurement of plasma or urinary clearance of exogenous marker (e.g., inulin) -> eGFR commonly used
  • 2021 CKD-EPI equation recommended for calculation of eGFR over MDRD and Cockcroft-Gault
    • Uses cystatin C clearance which is independent of muscle mass

What are manifestations of renal impairment in each body system?

• • Metabolic changes
    • Impaired ability to excrete water and sodium -> fluid overload -> general and pulmonary oedema
    • Hyperkalaemia, metabolic acidosis (2 most common and clinically concerning), hyperphosphatemia, hypocalcaemia, hypermagnesemia, hyperuricaemia, hypalbuminaemia
    • Bicarb supplements prescribed to treat metabolic acidosis
    • Low potassium diet and avoiding drugs known to cause hyperkalaemia
  • CVS
    • Hypertension is both a cause and effect of CKD
    • Increased risk of IHD
    • Most patients do not progress to ESRD but die of CVS complications
    • Increased circulating inflammatory mediators, hypercoagulability, arterial calcification, endothelial dysfunction
    • Chronic volume (water and sodium retention, presence of AV fistula or chronic anaemia)/pressure overload (from hypertension and atherosclerosis)-> LVH -> diastolic dysfunction + arrythmias
    • Atherosclerosis accelerated in CKD: postulated mechanism of impaired endothelial function, low-grade inflammation, and dyslipidaemia
    • Patients undergoing RRT may exhibit calciphylaxis (accumulation of calcium in small blood vessels)
    • Predisposed to pulmonary oedema
    • Severe uraemia -> pericarditis
  • Resp
    • Fluid overload -> pulmonary oedema + pleural effusions -> decreased compliancy -> reduced functional residual capacity and increased V/Q mismatch
    • Restrictive pulmonary dysfunction also common with CKD but unknown pathophysiology
  • Haematology
    • Decreased erythropoietin synthesis -> anaemia
    • Iron supplementation and IV erythropoiesis-stimulating agents (erythropoietin or darbepoetin alfa)
    • Uraemic platelet dysfunction, thrombasthenia -> hypo-coagulable
    • Prothrombotic state: decreased fibrinolysis, increased initial fibrin formation, increased fibrin-platelet interaction and increased qualitative platelet function. Increased risk of VTE with decreasing eGFR
  • Gastrointestinal
    • Anorexia, N/V, diarrhoea from CKD -> dehydration & impaired wound healing postoperatively
    • Delayed gastric emptying from autonomic neuropathy

• • CNS
    • Myoclonus, asterixis, chorea, uraemic encephalopathy, seizures
    • Incidence of seizures in CKD = 10%
    • Creatinine metabolites inhibit GABA and stimulate NMDA. Electrolyte imbalance also plays a role
    • Dialysis disequilibrium syndrome: rare transient encephalopathy usually due to rapid or omitted dialysis sessions
    • Penicillins, cephalosporins, carbapenems and quinolones -> cortical irritability -> seizures
    • Uraemia, T2DM, hyperparathyroidism -> decreased baroreceptor sensitivity, SNS overactivity and PSNS dysfunction -> autonomic neuropathy -> difficulties controlling BP and predisposition to perioperative arrythmias
  • Endocrine
    • Reduced synthesis of calcitriol (active vitamin D) -> impaired calcium absorption from GIT and kidneys
    • Increased serum phosphate also contributes to hypocalcaemia -> hyperparathyroidism -> parathyroid hyperplasia -> bone demineralisation and increased fracture risk
    • Vitamin D analogues and calcimimetics suppress PTH

Management of CKD

• • Principles
    • Treating reversible causes
    • Preventing progression
    • Manage complications
    • Identify patients requiring RRT
  • Prevention of AKI and subsequent progression to CKD
    • Anaesthetist has role in preventing AKI in perioperative period
    • Renal hypoperfusion may occur due to hypovolaemia, hypotension or infection
    • Consider ceasing nephrotoxic drugs: aminoglycosides, NSAIDs, radiographic contrast
    • Relief of urinary tract obstruction
  • Slowing progression
    • Optimal bp control and control of proteinuria through ACE inhibitors/ARBs
    • Diet: recommended daily energy intake is 30-40kcal/kg ideal body weight per day with adjustments needed to consider age and physical activity
    • Minimum protein intake for CKD 4-5 not on dialysis is 0.8g/kg IBW/day
    • Sodium restriction to <2.4g/day
    • Patients with hyperkalaemia, hyperphosphatemia may need dietary K+ and PO4- restriction
    • Dietitian involvement

Renal replacement therapy

• • Options for ESRF include conservative mx focused on symptom control, RRT and renal transplantation
  • RRT: HD, PD or kidney transplantation
  • PD
    • Dialysate infused in peritoneal cavity
    • Contains sodium chloride, lactate or bicarbonate and high concentration of glucose ensuring hyperosmolarity
    • Proteins and electrolytes exchanged over membrane driven by osmosis
    • Allows pts to be treated at home and obviates need for invasive vascular access
    • Complications: peritonitis, hyperglycaemia, weight gain, hernias, back pain
    • Rare complication: Encapsulating peritoneal sclerosis -> bowel obstruction
  • Haemodialysis
    • Dialysate pumped in counter-current direction to blood flow
    • Solutes equilibrate after diffusion
    • Complications: vascular access complications, hypotension, arrhythmias, disequilibrium syndrome
  • Kidney transplantation
    • Cadaveric or living donor
    • Best outcomes
    • During induction of renal transplantation, patients require Abs directed against T cells
    • Transplant recipients require long-term maintenance immunosuppression
  • Vascular access
    • Temporary: short-term lines, tunnelled and cuffed lines and subcutaneous port catheter systems. 1 week only due to risk of infection. Most common is right internal jugular vein (ease of access, lower risk of stenosis than left and subclavian routes and lower risk of infection than femoral)
    • Permanent: native AV fistula (best choice), arteriovenous grafts or long-term catheters
    • Infection, stenosis, thrombosis and aneurysm are complications related to HD vascular access

Pharmacology

• • Pharmacokinetics
    • Absorption
      • Gastroparesis -> delayed gastric emptying
      • Fluid overload -> small bowel oedema
      • Both contribute to delayed absorption
      • Gastric urease converts urea to ammonia -> increased gastric pH -> drug ionisation and subsequently drug bioavailability altered
    • Distribution
      • V_D is influenced by total body water, protein binding and tissue binding
      • Decreased protein binding of acidic drugs due to:
        • Hypoalbuminemia
        • Conformational changes in protein binding sites
        • Competition for binding sites with organic acids
      • Increased protein binding of basic drugs due to:
        • Increased plasma concentration of alpha1-acid glycoprotein
      • Increased V_D for hydrophilic drugs due to fluid retention
    • Metabolism
      • In CKD, CYP3A4 and CYP2C9 are inhibited whereas CYP2E1 is induced
    • Excretion
      • Renally excreted drugs may accumulate
      • Interestingly, non-renal clearance of many drugs is also reduced
      • Creatinine clearance often used to aid dosage modifications

CKD and anaesthesia

• • Preoperative considerations
    • When conducting a history and exam, what is pertinent for CKD patients?
      • Aetiology of CKD
      • Severity of renal impairment (clinical and biochemical)
      • Fluid status, dry weight, ability to produce urine
      • Renal replacement therapy: modality, last session, amount of fluid removed
      • Drug history, including immunosuppressant and long-term steroid therapy (may require perioperative steroid replacement)
      • Presence of AV fistula
      • Volume status: capillary refill time, skin turgor and auscultatory findings

• • • What clinical investigations would you consider?
      • FBC (anaemia), UEC (severity of CKD), coagulation studies (do not preclude coagulopathy)
      • ECG (screen for LVH, ischaemia and arrhythmias), echocardiogram (if suspicion of cardiac impairment of pericardial effusion)
      • CXR (if clinical evidence of overload)
    • What preoperative management would you consider?
      • Continuing disease-specific treatment throughout perioperative period if safe and practicable
      • No current consensus regarding whether preoperative ACE inhibitor therapy is beneficial or harmful
      • If patient requires dialysis before surgery, liaise with patient’s specialist team
  • Conduct of anaesthesia
    • What else should I consider in addition to the minimum monitoring standards by the Association of Anaesthetists?
      • Invasive arterial pressure monitoring (arterial line) for patients with poor BP control or undergoing prolonged major surgery
      • Central venous access if peripheral venous access is poor to facilitate use of potent vasoactive drugs and aid in assessment of fluid status
      • Preserve current arteriovenous fistulae and protect potential fistula sites (avoid forearm veins)
      • AV fistulae should be carefully wrapped in cotton wool and non-invasive BP cuff placed on opposite arm
      • Urine output monitoring
    • What may be necessary if your patient has gastroparesis?
      • RSI may be necessary
        • Modified approach: rocuronium and sugammadex reversal if required
    • Drugs with shorter half-lives and drugs not reliant on renal elimination should be used
    • Inhalational agents
      • Production of inorganic fluoride from metabolism of volatile anaesthetics, particularly methoxyflurane by hepatic cytochrome P450 system -> vasopressin-resistant high-output renal insufficiency
      • Neither peak value of fluoride nor duration of exposure correlate with anaesthetic nephrotoxicity
      • Sevoflurane encounters soda lime absorbers -> dehydrofluorination -> haloalkenes formed (compound A)
      • Compound A is severely nephrotoxic in rats
      • Insufficient concentration in clinical practice to induce nephrotoxicity -> sevoflurane safe in CKD
      • Desflurane and isoflurane are metabolised to a minimal extent -> no concerns in CKD

• • • Neuromuscular blocking agents
      • Atracurium is NMBA of choice in CKD
        • Undergoes ester hydrolysis and Hofmann degradation – both independent of renal function
      • Cisatracurium also permitted in CKD
        • Predominantly Hofmann degradation
        • Clearance reduced by 13% in CKD -> elimination half-life increased by 4.2min
      • Up to 30% of vecuronium is excreted renally
      • Up to a third of rocuronium is excreted renally in 24h period
      • Pancuronium should be avoided in CKD
      • Suxamethonium should be avoided due to risk of exacerbating pre-existing hyperkalaemia
      • Sugammadex can successfully reverse blockage from aminosteroid NMBAs in patients with severe renal impairment
        • Rocuronium-sugammadex complex:
          • Can persist in vivo for up to 7 days
          • Very stable
          • Can be cleared by high-flow dialysis

• • • Opioid analgesics
      • Antidiuretic effect -> urinary retention
      • Morphine-6-glucuronide is metabolite responsible for potent analgesic, sedative and resp depressant effects of morphine
        • Elimination dependent on renal function (half-life prolonged from 2 to 27h in CKD)
      • Fentanyl: approximately 7% is excreted unchanged in urine
      • Alfentanil: in CKD, less protein binding -> more free drug to exert effect
      • Remifentanil: not dependent on renal function
      • Oxycodone and metabolites: accumulate in CKD with prolongation in elimination half-life of 2.3-3.9h
      • Tramadol: 30% excreted unchanged in urine, may be epileptogenic in uraemia (lowered seizure threshold)
    • NSAIDs
      • Should be avoided in CKD
      • Reduced renal blood flow and GFR
      • Can also cause interstitial nephritis
      • Increases risk of major vascular events and bleeding in CKD patients with coagulopathy (uraemia and platelet dysfunction)
      • Can contribute to hyperkalaemia
    • Regional anaesthesia
      • Can be used as primary anaesthetic technique, depending on type of surgery
      • Central neuraxial blockage -> promptly address hypotension to prevent worsening of renal perfusion
      • Maintain BP with vasoconstrictions
      • Prevent fluid overloading by judiciously carrying out fluid preloading
      • Bear in mind coagulation abnormalities
    • Other important points of consideration
      • Essential to maintain normovolaemia irrespective of technique and drugs used
      • Careful fluid balance extends postoperatively – patients may require dialysis
      • CKD patients may take longer to emerge from anaesthesia with prolonged residual drowsiness -> require extended supplemental oxygen and continuous O2 sats monitoring

By Dr Luke Chan

Title:

Neurodevelopmental outcome at 5 years of age after general anaesthesia or awake-regional anaesthesia in infancy (GAS): an international, multicentre, randomised, controlled equivalence trial

McCann, M. E., de Graaff, J. C., Dorris, L., Disma, N., Withington, D., Bell, G., Grobler, A., Stargatt, R., Hunt, R. W., Sheppard, S. J., Marmor, J., Giribaldi, G., Bellinger, D. C., Hartmann, P. L., Hardy, P., Frawley, G., Izzo, F., von Ungern Sternberg, B. S., Lynn, A., Wilton, N., … GAS Consortium (2019). Neurodevelopmental outcome at 5 years of age after general anaesthesia or awake-regional anaesthesia in infancy (GAS): an international, multicentre, randomised, controlled equivalence trial. Lancet (London, England), 393(10172), 664–677. https://doi.org/10.1016/S0140-6736(18)32485-1

Journal:

The Lancet

Author(s):
A consortium of researchers across 7 countries including Australia, New Zealand, UK, USA, Canada, Italy and Netherlands

Type of study:
An international, multi-centre, randomised controlled equivalence trial

Study question and hypothesis:

Does a single exposure to general anaesthesia in early infancy adversely affect neurodevelopmental outcomes?

There would be no difference in neurodevelopmental outcomes between 5-year-old children who had undergone general anaesthesia and those who had undergone awake regional anaesthesia as infants.

Significance:
It seeks to provide evidence to inform decision-making around exposure to general anaesthesia in infancy with regard to the risk of adverse neurodevelopmental outcomes.

Early childhood exposure to general anaesthesia is common (i.e., in the order of millions per year in developed countries), and animal studies suggest exposure can be associated with neurotoxicity – exhibited as neuronal cell death, abnormal behaviour and cognition.

Without clear consensus among prior cohort studies on humans, there is the potential for adverse neurodevelopmental outcomes, and for medical providers and parents to unnecessarily delay or avoid important interventions requiring general anaesthesia.

Participants:

5-year-old children whom – as infants – received general anaesthesia or awake regional anaesthesia for a hernia operation.

Various exclusion criteria were used at randomisation and later follow-up testing, including:
– any acquired / congenital or chromosomal disorder that may affect neurodevelopment

– previous exposure to general anaesthesia or benzodiazepines
– any neurological insult (e.g., history of intracerebral bleed)

How it was done:

Across 28 hospitals, spanning 7 countries, 5-year-old children who had been randomised to receive either general anaesthesia or awake regional anaesthesia to facilitate inguinal herniorrhaphy as infants, had their neurodevelopmental progress examined using formal IQ testing, and additional subtests for attention and executive function.

Findings:
Strong evidence for equivalence in neurodevelopmental outcomes between 5-year-olds who received general anaesthesia or awake regional anaesthesia in infancy. This was consistent across a range of neuropsychological domains. This was consistent with prior findings from PANDA and MASK cohort studies.

Strength:
At time of publishing, this was the only known randomised controlled trial on humans in this area.
Cohort studies completed prior were more prone to errors through confounding, bias, heterogenous populations and heterogenous outcome measures.

Weakness / areas for consideration:
Too early to tell?
IQ at 5-years of age has strong correlation with adult IQ, however other executive functions and social/emotional development occurs later, and would require testing later in life

Longer duration of general anaesthesia?

Infants received less than 120 minutes of general anaesthesia. Prior animal studies show longer duration of anaesthesia is associated with neurotoxicity, so the findings aren’t strictly generalisable to longer procedures (i.e., those requiring >120min of general anaesthesia)

Frequency of general anaesthesia?

As children were exposed to general anaesthesia once, the findings can’t be extrapolated to the safety of repeated / multiple exposures

Using multiple agents?

Infants received Sevoflurane only for general anaesthesia, however in practice other agents are routinely used – both alone and in combination with others (e.g., Isoflurane, Desflurane, Propofol)

Some other sources of bias?
– The study did not mask parents, so their awareness of group allocation may have biased parent-reported outcomes
– Anaesthetists were able to choose their own airway management, ventilation technique, concentration of Sevoflurane, and neuromuscular blocking agent

– The participant population is predominantly male (81-85%)

Take home:
Overall, this trial explores an important clinical question and – from a neurodevelopmental point-of-view – allows us to provide reassurance to parents about the safety of general anaesthesia.

Further reading:

A more recent systematic review and meta-analysis released in 2022 (i.e., Reighard et al. 2022) suggests associations between anaesthetic exposure during childhood and subsequent neurodevelopmental deficits may differ based on neurodevelopmental domain.

Reighard, C., Junaid, S., Jackson, W. M., Arif, A., Waddington, H., Whitehouse, A. J. O., & Ing, C. (2022). Anesthetic Exposure During Childhood and Neurodevelopmental Outcomes: A Systematic Review and Meta-analysis. JAMA network open, 5(6), e2217427. https://doi.org/10.1001/jamanetworkopen.2022.17427