Background

Cardiothoracic surgery involves excessive tissue manipulation and deep incisions often leading to postoperative pain, which delays healing and furthers complications. Pain is triggered in response to the cell trauma at the surgical site, causing a release of chemical substances such as bradykinin, histamine, serotonin, prostaglandins and hydrogen ions leading to stimulation of pain receptors called nociceptors.1 Excessive release of neurotransmitters can cause what is known as "central sensitization."2 When central sensitization occurs, the threshold of the pain fibers to a stimulus is reduced; consequently, pain sensation is transmitted more easily and subsequently becomes chronic pain.2 With the rapid development of pain and its long-standing effects, analgesic use has become common place in the postoperative period as well as to combat the side-effects associated with pain medications.

The consequences of ineffective pain management include an unopposed stress response which results in systemic complications because of excess cortisol and catecholamine release; a neuroendocrine response triggers hyperglycemia and retention of extravascular fluid both peripherally and in the lungs.3 Other precarious effects of prolonged stress response include myocardial ischemia because of an increased oxygen demand, coronary vasoconstriction, hypercoagulability and some extent of heart failure because of fluid accumulation.3,4 Immunosuppression of the adaptive immunity B and T cells can occur, further tempering the healing process, and also possible gastrointestinal complications such as postoperative ileus.3,4 Adequate pain control is imperative to help prevent or reduce these complications and the effects of pain, such as central sensitization, and therefore, commonly requires opioids. Investigation of other adjuncts for pain control such as ketamine, in postoperative surgical patients is particularly valuable to reduce complications relating to inadequate pain control or excessive opioid use.

Analgesics are medications administered to relieve pain or hyperalgesia and work via the peripheral or central nervous system. Opioids, such as morphine, are common and effective analgesics that at high doses can reduce the stress response but cause unwanted side-effects.3 Morphine binds to receptors throughout the body called [mu] opioid receptors (MOR). These receptors are G protein-coupled receptors that when activated cause a series of intracellular reactions resulting in attenuation of the pain response. Subsequently, the effects of pain discussed previously are reduced. Morphine is an excellent pain reliever, but an increased consumption is associated with increased levels of pain and causes side-effects, such as respiratory depression, urinary retention, nausea, vomiting and constipation.5 These side-effects often limit adequate pain management because of increasing adverse effects that occur in proportion with higher doses of opioids. Opioids bind to MOR in the pontine and bulbar respiratory centers of the brain, possibly leading to respiratory depression and subsequent cases of pneumonia, atelectasis and respiratory failure.1,5 Morphine patient-controlled analgesia (PCA) is routinely used for postoperative pain in the surgical cardiothoracic population.5 A PCA device is loaded with an intravenous pain medication and is programed with specific settings for each patient. The patient is handed a button that is attached to the PCA device. The intention of a PCA device is that when the patient feels pain, the patient presses the button and a dose of pain medication, determined by the provider, is delivered. Morphine, commonly used in a PCA device, is known to cause respiratory depression. Respiratory depression is an undesirable effect and even more so in the cardiothoracic surgical population. These patients are already predisposed to shallow breaths, because of the severe pain and increased morphine dosing, and respiratory depression can further impede accessory muscles and hinder the ability to breathe. This is why an additional adjunct medication might help mitigate morphine dosing requirements and its associated negative effects. Other opioids such as fentanyl and hydromorphone are also used in PCA devices but have different pharmacodynamics effects. Fentanyl, for example, is a shorter acting opioid in comparison to hydromorphone. The differences in pharmacodynamics make it difficult to assess the effects on morphine consumption if all opioids were included. For the purpose of this review, morphine will be used, as it appears to be the common opioid reported in the literature for this surgical population.

Ketamine was introduced clinically in 1970 and has been shown to have some benefits in treating postoperative pain at low doses. Low-dose ketamine has been defined in the literature as less than 1 mg/kg when given as an intravenous bolus or 20 [mu]g/kg/min or less for a continuous infusion.6,7 For the purpose of this proposed systematic review, low-dose ketamine will be defined in the same manner. Higher doses tend to have incidences of psychomimetic side-effects such as hallucinations and are not commonly used for postoperative pain. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, is believed to inhibit this excitatory receptor, hindering pain transmission.8 Ketamine does not cause respiratory center impairment, therefore circumventing major respiratory depression or atelectasis possibly caused by opioids, while providing exceptional analgesia.8 Ketamine is also known to have anti-hyperalgesic properties and is believed to have opioid sparing effects, thus allowing for potentially decreased consumption of morphine and avoidance of the adverse effects.6 Ketamine additionally prevents tolerance acquired with the continuous use of opioids, thus possibly decreasing doses, side-effects and improving the weaning process.9 Ketamine works via alternate pathways to opioids, enabling a multimodal analgesic approach.9 As discussed earlier, persistent stimulation of the sensory neurons during surgery leads to a release of neurotransmitters, including glutamate, which is one of the chemicals that causes central sensitization and is considered an agonist to the NMDA receptor.9 Ketamine, a NMDA antagonist, counteracts the alteration of calcium influx and enhanced sensitization by glutamate, therefore preventing acute pain and the development of chronic pain syndromes.9 When using a multimodal approach to treat pain, the goal is to reduce the amount of medication. In this case, the goal is to reduce opioid consumption, thus reducing unwanted side-effects; adding medications that do not utilize the MOR may be able to help achieve this. The two medications work synergistically to achieve pain control in hope to reduce the dose of morphine. Ketamine seems to avoid several complications that opioids have when used for postoperative pain such as respiratory depression, nausea and urinary retention. Ketamine appears to be a possible adjunct to a morphine PCA but necessitates further investigation to determine what effects, if any, ketamine has when added to morphine during the postoperative period, particularly with the cardiothoracic surgical population.

No systematic reviews were located when conducting an initial literature search using MEDLINE, EMBASE, JBI Database of Systematic Reviews and Implementation Reports, and the Cochrane Database of Systematic Reviews on this topic with this specific population. However, there is literature available on the effects of ketamine on morphine consumption, which includes randomized controlled trials.5,10,11 This systematic review will assess if adding ketamine to morphine PCA pumps has an effect on morphine consumption as a primary outcome, and additionally evaluate the effect on pain, nausea and vomiting as secondary outcomes. Providers may use any significant resulting data to adjust and improve postoperative pain strategies for cardiothoracic surgical patients and possibly reduce the delay in rehabilitation due to the associated side-effects of opioids. As mentioned above, reducing morphine consumption, while maintaining adequate pain control is a key element for the recovery phase of these patients. This could mean less risk for respiratory depression, better pain control and the possibility of fewer incidences of postoperative nausea and vomiting. Practitioners can then decide based on these findings if ketamine is an appropriate therapy for theses' patients. With this in mind, the following population, intervention, comparator, outcome and time question has been developed: In patients 15 years of age and older undergoing cardiothoracic surgery, does the addition of low-dose ketamine intravenously to a morphine PCA compared with a morphine PCA alone have an impact on morphine consumption during the 72 hour postoperative period?

Inclusion criteria

Types of participants

This review will consider studies that include inpatients over the age of 15 undergoing cardiothoracic surgeries. According to Etzioni and Starnes,12 cardiothoracic procedures are much more common in older adults, specifically past the third decade of life. However, data from the Center for Disease Control and Prevention13 indicates that cardiothoracic procedures are performed on patients as young as 15 years old, hence the decision to focus on patients from this age onwards. Patients undergoing procedures via thoracotomy technique will be included in the study, including minimally invasive direct coronary artery bypass surgeries. Patients who have chronic pain before surgery or have an epidural in place will be excluded as these patients have changes in pain perception that could alter the dose requirements of analgesics needed to adequately treat this population. Patients with an epidural in place are excluded because generally pain after cardiothoracic surgeries is treated with morphine PCA. The addition of neuraxial analgesia would also alter the dose requirements of morphine.

Types of intervention(s)/phenomena of interest

The intervention of interest is adding low-dose ketamine to a morphine PCA. This review will consider studies that evaluate morphine consumption with low-dose ketamine versus without low-dose ketamine. Low-dose ketamine is defined as less than 1 mg/kg as an intravenous bolus or less than 20 [mu]g/kg/min, for a continuous morphine PCA.

Outcomes

The primary outcome of this systematic review is morphine consumption in the first 72 hours postoperatively. Secondary outcomes that will be assessed will include pain measured via the visual analog pain scale, and the incidence of nausea and vomiting determined by postoperative nurse assessment and observation.

Types of studies

This review will consider both experimental and epidemiological study designs, including randomized controlled trials, non-randomized controlled trials, quasi-experimental, before and after studies, prospective and retrospective cohort studies, case control studies and analytical cross-sectional studies for inclusion.

Search strategy

The search strategy aims to find both published and unpublished studies. A three-step search strategy will be utilized in this review. An initial limited search of MEDLINE and CINAHL will be undertaken followed by analysis of the text words contained in the title and abstract and the index terms used to describe the article. A second search using all identified keywords and index terms will then be undertaken across all included databases. Third, the reference list of all identified reports and articles will be searched for additional studies. Studies published in English will be considered for inclusion in this review. Studies published after 1970 will be considered for inclusion in this review as this was the decade ketamine and PCAs were clinically introduced.

The databases to be searched include: MEDLINE, CINAHL, PubMed, EMBASE, Web of Science, Cochrane CENTRAL

The search for unpublished studies will include:

New York Academy of Medicine Grey Literature Report

MedNar

ProQuest Dissertations and Theses Global

Initial keywords to be used will be: ketamine, morphine consumption, patient-controlled analgesic pump, PCA, postoperative pain, cardiothoracic surgery.

Assessment of methodological quality

Studies selected for retrieval will be assessed by two independent reviewers for methodological validity prior to inclusion in the review using standardized critical appraisal instruments from the Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI) (Appendix I). Any disagreements that arise between the reviewers will be resolved through discussion or with a third reviewer.

Data extraction

Data will be extracted from studies included in the review using the standardized data extraction tool from JBI-MAStARI (Appendix II). The data extracted will include specific details of interventions, populations, study methods and outcomes of significance to the review question and specific objectives.

Data synthesis

Quantitative data will, wherever possible, be pooled in statistical meta-analysis using JBI-MAStARI. All results will be subject to double data entry. Effect sizes expressed as odds ratio (for categorical data) and weighted mean differences (for continuous data) and the 95% confidence intervals will be calculated for analysis. Study results will be evaluated as dichotomous data for the impact of ketamine on morphine consumption versus morphine consumption without ketamine co-administration. The categories will be either "no" where there is no effect on morphine consumption or "yes" where there is a decrease in morphine consumption with ketamine. Heterogeneity will be statistically assessed using the standard [chi]² and also explored using subgroup analyses based on the different study designs included in this review. Where statistical pooling is not possible, the findings will be presented in narrative form, including tables and figures to aid in data presentation, wherever appropriate.

Acknowledgements

Thanks to Dr Monica Jenschke and Dr Dru Riddle for the assistance and guidance through the systematic review compilation and protocol submission.

Appendix I: Appraisal instruments

MAStARI appraisal instruments

Appendix II: Data extraction instruments

MAStARI data extraction instruments

References