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Intraoperative use of Ketamine for the reduction of acute postoperative pain in PACU.

POSTOPERATIVE analgesia is vital in ensuring patients have positive outcomes. In this article, the use of Ketamine intra-operatively will be analysed to determine if it has merit in reducing postoperative pain in the post anaesthetic care unit (PACU). The physiology of nociceptive pain is described as well as the biological action of Ketamine and how it reduces pain. Three key studies are presented that support the use of Ketamine intra-operatively to reduce postoperative pain. The evidence for use of Ketamine is reviewed in the context of the PACU and its role in pain management.

Nociceptive Pain

Clarification of the type of pain experienced by the patient helps to choose the most appropriate drug to treat the pain. Nociceptive pain is defined as pain resulting from the on-going activation of primary afferent neurons by noxious stimuli (McCaffery & Pasero, 1999).

Nociceptive pain is caused by the patient's exposure to a type of painful stimulus and thus their experienced tissue damage. The two different types of nociceptive pain are somatic pain (originating from the musculoskeletal system) and visceral pain (originating from the internal organs of the body).

The basic mechanisms of nociceptive pain include four processes: transduction, transmission, perception and modulation (McCaffery & Pasero, 2011). Transduction occurs at the periphery where noxious stimuli cause tissue damage and activates the inflammatory mediators --prostaglandins, bradykinins, serotonin, substance P and histamine (Pasero & McCaffery, 2011). These substances activate the nociceptors and an action potential is created. Next, transmission occurs when action potential is transmitted to the dorsal horn of the spinal cord (Pasero & McCaffery, 2011). The nociceptors cease here and neurotransmitters connect the impulse toward the brainstem, thalamus and other centres in the brain for processing (Pasero & McCaffery, 2011). The third process is the perception or awareness of pain by the person. Finally, the pain impulses are changed or inhibited and this is known as modulation. Here the neurons that originate in the brain stem descend to the dorsal horn of the spinal cord and release substances that can inhibit the transmission of noxious stimuli, and produce analgesia (Pasero & McCaffery, 2011). Each individual modulation controls how each person experiences their pain (McCaffery & Pasero, 1999).

Action of Ketamine

In surgery, patients are often always exposed to some type (somatic or visceral) of nociceptive pain. This means that effective pain relief is imperative to produce good patient outcomes after surgery and reduce postoperative complications.

Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist. It binds to the NMDA receptors inhibitory interneurons. Ketamine then blocks NMDA receptor, glutamate mediated, nociceptive signals (Weinbroum, 2012). This prevents the peripheral afferent neurons transmitting nociceptive pain signals. In addition to this, when the NMDA receptors are blocked with Ketamine, changes occur in the calcium channels and this plays a role in preventing the transmission of pain (Weinbroum, 2012).

Ketamine may also be useful in the prevention of wind-up and central sensitisation. Woolf (2007) describes central sensitisation as an increase in the excitability of the central nervous system so that normal inputs now evoke exaggerated responses. Persistent activation of NMDA receptors by substances such as nitric oxide and substance P can amplify the pain signal (Hansen, 2005). Therefore if the NMDA receptors are being repeatedly stimulated, substance P is being released and this stimulates nerve growth and regeneration in the spinal cord (Hansen, 2005). Hansen (2005) goes on to say that remodelling and reconnection of nerves can cause allodynia or perceived pain in response to a stimuli that does not usually cause pain. Therefore the use of drugs that antagonize NMDA receptors (such as Ketamine) can reduce the development of chronic postoperative pain through NMDA receptor blockade and the reduction of wind-up and central sensitisation (Bell, Dahl, Moore & Kalso, 2010).

Ketamine therefore can be seen as a potential option in pain management as the blocking of the NMDA receptors may also improve the efficiency of opioids and reduce the development of chronic pain syndromes (Laskowski, Stirling, McKay & Lim, 2011).

Elia & Tramer (2005) note that the overall benefits and risks of Ketamine in postoperative pain management are not well understood, therefore accessing quality, high level evidence surrounding the use of Ketamine is important.

Side-effects

The use of Ketamine in the clinical setting can be somewhat limited by its side-effects. Hallucinations or bad dreams (known as the psychotomimetic adverse effects) as well as dizziness, blurred vision and nausea and vomiting can limit its clinical use (Bell et al., 2010).

Three studies that explore the use of Ketamine in the intraoperative setting to reduce postoperative pain will be reviewed. A Belgian randomised controlled trial by De Kock, Lavand'homme & Waterloo (2001) investigated whether intraoperative 'subanaesthetic doses' of Ketamine have a postoperative anti-hyperalgesic and an analgesic effect and whether systemic or epidural administration was preferable. This randomised, double-blinded controlled study included 100 adult patients undergoing curative surgical resection of rectal adenocarcinoma.

The participants were randomly divided into five groups as indicated in the table below. Before anaesthesia, an epidural catheter was inserted in all patients and all patients received a weight calculated epidural bolus of the same mix of Bupivacaine, Epinephrine, Sufentanil and Clonidine followed by an infusion of Bupivacaine, Sufentanil and Clonidine. All epidural anaesthesia was stopped at the end of the case and the epidural removed. Patients were connected to a Morphine Patient Controlled Anaesthesia (PCA) pump after they woke in the PACU. Patient characteristics in each of the five groups appeared to be similar and consistent with one another.

Results showed that IV intraoperative Ketamine at a sub-anaesthetic dose significantly improves postoperative analgesia by lowering early morphine consumption (De Kock, Lavand'homme & Waterloos, 2001). It also reduces mechanical hyperalgesia surrounding the surgical wound. Group three (Ketamine bolus 0.5mg/kg followed by an infusion of 0.25mg/kg/hr) had a useful dose for perioperative balanced analgesia and the systemic route of administration was more effective than the epidural route (De Kock, Lavand'homme & Waterloos, 2001).

Limitations of the study were the small treatment group (20 patients in each), inclusion of patients with adenocarcinoma only.

Study Two

A Japanese randomised controlled trial Kakinohana, Higa, Sasara, Saikawa, Miyata, Tomiyama & Sugahara (2003) investigated if intravenous Ketamine could reduce postoperative pain intensity and the consumption of morphine after elective open cholecystectomy. This study included 50 adult patients, undergoing elective open cholecystectomy randomised into two groups. Epidural catheters were inserted at thoracic (T) 7-8 or T 8-9. After a test dose, 4ml of 1% Lidocaine was administered to achieve loss of sensation up to T 4 level. Anaesthesia was induced in group one Propofol/Fentanyl group with 1.5kg/kg Propofol and 2mcg/kg of Fentanyl and 0.1ml of saline or in group two, Propofol/Fentanyl/Ketamine the same dose of Propofol and Fentanyl and 1mg/kg of Ketamine. Maintenance of anaesthesia was then achieved by an infusion of 5-10mg/kg of Propofol in group one and 5-10mg/kg of Propofol plus 1mg/kg/hr of Ketamine in group two. Epidural infusions of Lidocaine were ceased and a bolus of 2mg Morphine was administered with 6-8ml Bupivacaine 0.25% at the end of the case. Patient characteristics appeared to be similar in each of the two groups.

Results showed that group two--the Propofol/Fentanyl and Ketamine group--demonstrated a reduction of postoperative pain at rest and at movement throughout this study when compared with group one. Also Ketamine can reduce the pain intensity not only at five hours but also at 24 and 48 hours of the post-operative pain period.

The prolonged analgesic effect demonstrated in group two has significant implications in the PACU clinical setting. In reality, in the local PACU clinical environment epidural catheters are rarely used for elective open cholecystectomy patient. This makes it difficult to assess the intraoperative Ketamine dose in the clinical setting where no epidural was used. No limitation or bias were reported or referenced to within the study.

Study Three

Lastly a French randomised controlled study by Menigaux, Guinard, Fletcher, Sessler, Dupont and Chauvin (2001) explored how intraoperative small-dose Ketamine enhanced analgesia after outpatient knee arthroscopy. This study tested the hypothesis that a small intraoperative dose of Ketamine improves postoperative analgesia that lasts for several days, hence facilitating ambulation after arthroscopic meniscectomy (Menigaux et al., 2001).

Patients aged between 18-60 years were randomly assigned into a control group and a Ketamine group in this double-blinded study. Fifty patients were included in the trial with 25 randomised to each group and the choice of the number of particants was explained and justified. Patients were educated preoperatively in the use of the study questionnaires and then premedicated with 100mg of Hydroxyzine. The anaesthetic used was Propofol 2mg/kg and Alfentanil 20mcg/ kg and anaesthetic was maintained using a Propofol infusion titrated throughout surgery. However, patients assigned to the control group received 10ml of sodium chloride intravenously while the Ketamine group received 0.15mg/kg of Ketamine diluted in sodium chloride after induction of anaesthetic. All surgery was done by the same surgeon and at the completion of all operations, 20mls of 0.5% Bupivacaine and 5mg of Morphine was injected through the arthroscope into the knee joint. Morphine 3mg every five minutes was prescribed for use in PACU until the patient's pain score was reduced. Patients were also instructed to take Naproxen 550mg twice a day and Di-Antalvic six-hourly or as required for pain. Patient characteristics were similar in each group.

Results showed that patients who were given a single small dose of intra-operative Ketamine had less postoperative pain and that the benefit of this lasted over a full two-day period. In addition to this, fewer patients in the Ketamine group required morphine in the PACU and Di-Antalvic. It was also demonstrated that intra-operative small-dose Ketamine is an important adjunct to non-steroidal ant-inflammatory drugs (NSAID's), Paracetamol and a weak opioid. The most likely explanation for the results is that Ketamine provides pre-emptive analgesia by preventing central sensitisation to pain (Menigaux et al., 2001). There were no reports or reference within the study to any limitations or bias.

Discussion

The results of the three randomised controlled trials (Menigaux et al., 2001, Kakinohana et al., 2003, De Kock, Lavand'homme, & Waterloo, 2001) show that the use of a small-dose of Ketamine intraoperativly enhances postoperative analgesia and therefore offers significant benefits in the PACU environment if used appropriately.

There is still a sense of apprehension towards the use of Ketamine for analgesia, mainly surrounding the experiences of patients reporting psychomimetic effects such as hallucinations (Elia & Tramer, 2005).

However, Menigauz et al., (2001) state that small doses of intraoperative Ketamine do not cause dysphoric, psychotomimetic symptoms or nightmares.

Another consideration is the reduction in the volume of opioids used when intraoperative small dose Ketamine is used. Laskowski, Stirling, McKay & Lim (2011) conducted a systematic review of Ketamine use for postoperative pain management and reported that the use of IV Ketamine resulted in a significant reduction in the quantity of opioid administered and that Ketamine had an opioid sparing effect. De Kock et al., (2001) also state that IV Ketamine improves analgesia by lowering Morphine consumption.

Menigaux et al., (2001) also found that intraoperative Ketamine did not prolong emergence from anaesthesia. In contrast Kakinohana et al., (2003) reported that in the Ketamine group there was a prolonged time to extubation, thus further investigation is needed to address this aspect. This is an important consideration when working in the PACU because the prolonged stay of patients in PACU comes at a cost.

Minimisation of long term postoperative pain also encourages early mobilisation and return to work for the patient, offering benefit for both the patient and the healthcare system. Better pain relief during movement accelerates functional recovery after orthopaedic surgery, thus enabling patients to return to their normal activities more quickly (Menigaux et al., 2001). Ketamine does this by preventing the development of neuronal hyper-excitability and thus possible hyperalgesia (Menigaux et al., 2001).

De Kock et al., (2001) found that at six months, significantly fewer patients who had received Ketamine during surgery suffered from residual pain that required analgesic medication. Ketamine therefore appears to influence the development of chronic pain which has positive economic implications for primary and tertiary care costs. The question remains whether it is possible to introduce the intervention. While it is a financially viable option, Anaesthetists have strong preference and views surrounding the use of Ketamine and the associated side-effects. This issue would therefore have to be addressed before we see an increased use of Ketamine in the clinical environment.

Conclusion

Ketamine works well on the nociceptive pathways by blocking the NMDA receptors to promote short and long term analgesia. Three randomised controlled trial studies have been presented to support the use in the clinical environment and the merit of Ketamine in reducing postoperative pain, not only in the PACU immediately postoperative, but in time after the surgery.

It has also been shown to reduce the use of Morphine in the postoperative period. This is a positive move toward improving patient analgesia and reducing hospital costs through early mobilisation and rehabilitation. However, it comes with barriers which must be addressed before Ketamine is likely to become widely used in the clinical environment.

References

Bell, R F, Dahl, J B., Moore, R A. & Kalso, E A. (2006). Perioperative ketamine for acute postoperative pain (Review). The Cochrane Database for Systematic Review. 1. doi: 10.1002/14651858.CD004603.pub2.

De Kock, M, Lavand'homme, P & Waterloos, H. (2001). 'Balanced analgesia' in the perioperative period: is there a place for Ketamine? Pain. 92. 373-380.

Elia, N. & Tramer, M R. (2005). Ketamine and postoperative pain--a quantitative systematic review of randomised trials. Pain. 113. 61-70. doi: 10.1016/j. pain.2004.09.036.

Hansen, G R. (2005). Management of Chronic Pain in the Acute Care Setting. Emergency Medicine Clinics of North America. 23. 307-338. doi: 10.1016/j. emc.2004.12.004.

Kakinohana, M., Higa, Y., Sasara, T., Saikawa, S., Miyata, Y., Tomiyama, H. & Sugahara, K. (2003). Addition of Ketamine to propofol-fentanyl anaesthesia can reduce postoperative pain and epidural analgesic consumption in upper abdominal surgery. Acute Pain. 5(3-4). 75-79. doi: 10.1016/j. acpain.2003.12.001.

Laskowski, K., Stirling, A., McKay, W P. & Lim, H J. (2011). A systematic review of intravenous Ketamine for postoperative analgesia. Canadian Journal of Anaesthesia. 58. 911-923. doi: 10.1007/s12630-011-9560-0.

McCaffery, M. & Pasero, C. (1999). Pain Clinical Manual (2nd Ed). St Louis, Missouri:Mosby.

Menigaux, C., Guignard, B., Fletcher, D., Sessler, D I., Dupont, X. & Chauvin, M. (2001). Intraoperative Small-Dose Ketamine Enhances Analgesia After Outpatient Knee Arthroscopy. Anesthesia and Analgesia. 93(3). 606-612.

Pasero, C. & McCaffery, M. (2011). Pain Assessment and Pharmacologic Management. St Louis, Missouri:Mosby.

International Council of Nurses. (2012). Closing the Gap: from evidence to action. Retrieved from http://www.icn.ch/publications/2012-closing-the-gapfrom-evidence-to-action. 23 October, 2012.

Weinbroum, A A. (2012). Non Opioid IV adjuvants in the postoperative period: Pharmacological and clinical aspects of Ketamine and Gabapentinoids. Pharmacological Research. 65. 411-429. doi: 10.1016/j.phrs.2012.01.002.

Woolf, C. (2007). Central Sensitization, uncovering the relation between pain and plasticity. Anesthesiology. 106 (4). 864-867.

Lisa Greening is a Registered Nurse who has worked in the Post Anaesthetic Care Unit (PACU) for eight years. She graduated with her Batchelor of Health Science in Nursing in 2002, and has just completed her Post Graduate Diploma in Advanced Nursing through Auckland University
Group 1   10F/10M   67yrs +/- 9    No Ketamine
Group 2   11F/9M    65yrs +/- 10   IV Ketamine (bolus of
                                     0.25mg/kg followed by
                                     an infusion of
                                     0.125mg/kg/hr)
Group 3   8F/12M    69yrs +/- 6    IV Ketamine (bolus of
                                     0.5mg/kg followed by
                                     an infusion of
                                     0.25mg/kg/hr)
Group 4   8F/12M    69 +/- 6       Epidural Ketamine
                                     0.25mg/kg and
                                     0.125mg/kg/hr
Group 5   10F/10M   67 +/- 7       Epidural Ketamine
                                     0.5mg/kg and
                                     0.25mg/kg/hr

GROUP ONE--Propofol/Fentanyl   GROUP TWO--Propofol/Fentanyl/Ketamine
Age: 49.9 +/- 12               Age: 48.1 +/- 10.1
Sex M/F: 11/14                 Sex M/F: 10/15
Weight: 63.4kg +/- 12.1kg      Weight: 58.8kg +/- 9.1kg
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Title Annotation:clinical
Author:Greening, Lisa
Publication:The Dissector: Journal of the Perioperative Nurses College of the New Zealand Nurses Organisation
Date:Sep 1, 2013
Words:2660
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