The clinical scenario revolves around a 34 year old male patient who developed hyperthermia after surgery. His previous medication included linezolid and citalopram. Based on the brief clinical scenario, the patient's background condition could be further explained as follows :
Hyperthermia After Surgery
It was stated that patient developed hyperthermia symptoms after surgery. This could be due to a rare condition, postoperative malignant hyperthermia triggered by several factors including stress and the use of volatile anaesthetics and suxamethonium during surgery.1 It is a condition of high morbidity and mortality, and thus it is important to identify medications that have been administered to the patient prior or during a surgery process. This form of hyperthermia could be delayed up to 24 hours after administration of anaesthetics during surgery, thus patient monitoring is required.2
The pathophysiology of this form of autosomal dominant disease involves a MH-susceptible ryanodine receptor (type 1) RYR1 gene,3 located on sarcoplasmic reticulum in which its chromosome 19. The RYR1 gene subsequently undergoes mutation, encoding an abnormal RYR1 receptor which comprises of two sites, the A-site and the I-site. Both sites are highly sensitive to changes in Ca2+ concentration in which binding of Ca2+ to each site would lead to a different response in the opening and closing of receptor ion channels. The administration and exposure of triggering agents during surgery increases the affinity of Ca2+ for the A-site on RYP1 and reduces affinity of Ca2+ for the I-site. The high Ca2+ binding at the A-site leads to the opening of receptor ion channels, while low binding of cations to P-site leads to the reduction of ion channels closing. The sequestration of Ca2+ uses up a reasonable amount of adenosine triphophate (ATP). Membrane depolarization at neuromuscular junction activates dihydropyridine receptors located in skeletal muscle cells and opens up calcium channels on SR. A persistent release of Ca2+ into intracellular cytoplasm hence ensues, giving rise to a sustained muscle contraction.4 A rise in heat production and acidity in body fluids subsequently gives rise to hyperthermia.5
With relevance to its pathophysiology, the symptoms of postoperative hyperthermia are linked to the patient's hypermetabolic state. Patients with a genetic predisposition for the condition are at a higher risk of developing hyperthermia after surgery. The symptoms present include a rise in heat production, lactate levels and end-tidal carbon dioxide (ETCO2) of 55 mmHg/7.32 kPa and above. The presence of high circulating carbon dioxide in the blood, hypercarbia may be masked by rapid hyperventilation leading to a delay in diagnosis of up to a day. The classical early symptoms which propel an accurate diagnosis of postoperative hyperthermia are sinus tachycardia and a rise in carbon dioxide production. Contrary to its name, a rise in temperature at a rate of 1°C every 5 minutes may have a delayed occurrence. Other relevant symptoms include muscle rigidity and ache from unknown causes, predominantly in the jaw, unstable blood pressure, bleeding, production of dark brown urine as well as an increased in oxygen consumption.6 Clinical laboratory findings will reveal a creatine kinase level of more than 20,000 U/L, peak potassium to be 6.0 mmol/l and above. pH levels of less than 7.35 would be detected in the muscle tissue, signifying the metabolic acidosis condition in patient.6
If left untreated, postoperative hyperthermia would pose many complications to the patient's health. They include loss of consciousness, rhabdomyolysis, muscular deformity or myopathy, building up of fluid in the lungs, metabolic acidosis, damage to the heart, kidney and liver, disseminated intravascular coagulation which ultimately lead to death. Its severity for the complications vary due to the patient's demographics, types of anaesthetics given during surgery, form and dose of treatment given as well as time interval between presence of various symptoms and its subsequent treatment.7
Linking Hyperthermia after Surgery to Serotonin Syndrome
Patients has been administered with linezolid and citalopram, and these drugs would provide a certain risk to the lethal condition, serotonin syndrome which is linked to an increase serotonergic potentiation in the central nervous system (CNS). The neurotransmitter serotonin regulates alertness, appetite, depression, emesis, migraine and sexual activity. Clinical studies have revealed that an overactivity of 5-HT2A serotonin receptor plays a pivotal role in predisposing the patient to the drug reaction. The three symptoms linked to this condition include an alteration in mental status leading to confusion and anxiety, neuromuscular deformities which are involuntary, and an increase in autonomic activity.8 Hyperthermia is one of the symptoms characterised under the enhancement of autonomic activity. It is exhibted in patients diagnosed with moderate or severe serotonin syndrome.9 In moderate toxicity, the patient's core temperature would be as high as 40.0°C (104°F) and this would rise to 41.1 °C and above (106.0 °F) in critical cases.9 Other symptoms that could present alongside hyperthermia in the clinical diagnosis of serotonin syndrome are summarised in the following table:
Table 1 : Symptoms in Serotonin Syndrome 10
Seriousness
Autonomic Activity
Neuromuscular Deficits
Alteration in Mental Status
Other Symptoms
Mild
Afebrile
Increased heart rate
Mydriasis
Excessive sweating
Shiver
Akathisia
Tremor at regular intervals
Myoclonus
Overresponsive in reflexes that is mild
Anxiousness
Lethargy
Moderate
Increased heart rate
Diarrhoea with hyperactive bowel sounds
Excessive sweating with normal skin colour
Hyperthermia with temperature as high as 40.0°C
Overresponsive in reflexes
Inducible clonus
Ocular clonus
Myoclonus
Easily startled
Increased in disorientation
Loss of composure and hypervigilance
Rhabdomyolysis
Metabolic acidosis
Renal failure
Disseminated intravascular coagulation
Severe
Diaphoresis with normal skin colour
Hyperthermia with temperature higher than 41.1°C
Increased muscle tone (higher in low extremities)
Spontaneous clonus
Substantial myoclonus and overresponsive in reflexes
Delirium
Coma
As above
Note : Hyperthermia present as moderate and severe serotonin symptoms characterised under changes in autunomic activity.
Thus, it can be justified that the concurrent administration of linezolid, a weak monoamine oxidase (MAO) and citalopram, a selective serotonin reuptake inhibitor (SSRI) may augment the rise of temperature of the patient, increasing the risk of hyperthermia. The clinical course of this form of hyperthermia involves a more acute onset of action of one day to three weeks and resolution of one to five days.11 Hence, the diagnosis of hyperthermia due to serotonin syndrome could be reaffirmed by examining the presence of other relevant symptoms. Specific features which distinguish hyperthermia due to serotonin syndrome from other hyperthermic states are overresponsive reflexes, ocular and ankle clonus, which are more acute in lower extremities.5
The indications for both medications should be made clear in the patient's clinical scenario. Concurrent use of these two medications are common as resistant infections could be accquired from hospitals when patients diagnosed with depressive illnesses are admitted to the medical ward. Citalopram is administered to patients suffering from depressive illness or panic disorder. Linezolid is a synthetic oxazolidinone antibiotic used against a range of antibacterial-resistant gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VRE). It is also effective in treating pneumonia caused by Streptococcus pneumoniae as well as complicated skin and soft-tissue infections caused by Streptococcus pyogenes and Streptococcus agalactiae.12 Linezolid hinders the translation of mRNA into protein in the bacterial ribosome by binding to the 50S ribosome subunit which are the basis of the initiation complex in prokaryotic cells, distrupting the formation of the initiation complex. It also acts as a reversible, non-selective monoamine oxidase inhibitor in which the monoamine neurotransmitter availability is increased. Its weak inhibitory activity allows hyperthermia to be present when there is an overdose of administered medications to patients. The condition would be less common in patients who are under therapeutic doses of linezolid and citalopram.13 For a 35 year old patient, a maximum daily therapeutic dose of 40mg citalopram is given for diagnosis of depressive illness and panic disorder. Linezolid is give at a maximum daily dose of 1200mg.12
Conjuring a hypothesis based on patient's diagnosis of postoperative hyperthermia and his known medications
It is important to assess patient's medication charts and determine the types of medications that have been administered. As symptoms of hyperthermia appear right after surgery, it could be possible that the patient was suffering from postoperative malignant hyperthermia due to the use of volatile anaesthetics and suxamethonium. The condition could be augmented following surgery due to the inappropriate therapeutic medication of citalopram and linezolid used concurrently. Treatment options would be tailored according to these two important points.
TREATMENT OPTIONS WITH RELEVANCE TO PATIENT'S CLINICAL SCENARIO
Using SUPrimo, the University of Strathclyde Library's integrated search service, a selection of electronic journal papers were accessed to gain an in-depth understanding on serotonin syndrome. This search service encomprises various sources including British Medical Journal (http://www.bmj.com) and literature databases including MEDLINE. There were no guidelines for management of this form of hyperthermia, and hence treatment options were accquired from literature, with the majority of them at minimal high-level evidence.
2.1 Intravenous dantrolene for symptoms of postoperative hyperthermia
Once postoperative hyperthermia has been diagnosed, rapid intravenous injection of dantrolene sodium is administered to stop the sustained muscle constriction that occur alongside the rise in body temperature. Doses of 2-3mg/kg are given as an initial loading dose. Repeated maintenance doses of 1 mg/kg every six to eight hours for 24-72 hours after the initial episode, up to daily dose of 10mg/kg were then administered to the patient.12 Treament is continued till symptoms involving heart rate, carbon dioxide production and temperature are reduced. Dantrolene exhibits its action on skeletal muscle cells, disrupting calcium efflux into intracellular cytoplasm and relieving the sustained contraction on muscle cells. They are available in 20mg ampoules with 3g manitol each, requiring a mixture of 60ml with sterile distilled water. The intravenous line is flushed with sterile water prior to administration to prevent precipitation of drugs.12
Due to the route of administration of dantrolene sodium, the mixing and administration of dantrolene can only be carried out in hospitals and outpatient surgery centres under the direct supervision of a healthcare professional. Treatment is costly, as references to the latest edition of British National Formulary (BNF) 64 stated the price of £ 51.00 per vial.12 Relatively a safe drug, few adverse effects have been reported, and they are hepatotoxicity associated with duration and dose of treatment, pulmonary oedema, nausea, vomitting as well as central nervous system effects which are seizures, dizziness, insomnia and weakness. This form muscle weakness may last for a day even when dantrolene has been discontinued. It is advisable to administer dantrolene through the central venous line to minimise injection-site reactions, including thrombophlebitis.12 A clinical trial in its early phase have revealed similar efficacy in a standard dantrolene sodium injection when compared to a novel nanocrystalline dantrolene sodium suspension. The latter, however had a faster rate of preparation for administration to the patient.14
2.2 Adjunctive therapy for symptoms of postoperative hyperthermia
Hospitalized patient should be ventilated with 100% oxygen at a high flow rate of 10 L/min. This would alleviate the effects of metabolic acidosis and hypercapnia associated with symptoms of postoperative hyperthermia. This increases the uptake of oxygen. Surface cooling is carried out using a fan and removing the patient's clothes. Evaporation is initiated by sponging with lukewarm water.12 Ice packs can also be applied on areas where the major arteries are located, and this include the groins, side of the neck and the underarm region.7 The patient's stomach and rectum is lavaged with cold fluids to reduce the body temperature. Bladder lavage is avoided as the cold fluid might affect the amount of excreted urine output measured. Once the patient's body temperature returns to normal values (38°C) cooling is stopped to avoid the possibility of hypothermia.7
2.3 Patient monitoring to alleviate complications of postoperative hyperthermia
The risks of lactic acidosis and severe hepatotoxicity is minimised by close monitoring of the patient's hematocrit and platelet count, arterial blood gases, urine output, hepatic function, lactate as well as creatinine kinase levels. Core and peripheral temperature by nasopharyngeal, rectal, oesophageal routes should be monitored as well, as skin temperature is not a suitable measurement in this case. Other relevant laboratory testings include ECG, measurement of blood oxygen saturation SpO2, end-tidal CO2 (ETCO), arterial blood pressure and central blood pressure.12
2.4 Changes to patients' medication profile based on persisting serotonin syndrome
As the patient was administered with linezolid and citalopram which pose a substantial risk to the augmentation of hyperthermia due to moderate or severe serotonin toxocity, the medications need to be reviewed.
The intensity of therapy is related to the severity of the patient's condition. Once symptoms of hyperthemia persisted and medications have been reviewed, three options are established in which the changes to the patient's medication profile is made. Firstly, linezolid could be replaced with an alternative antibacterial therapy which has no monoamine oxidase inhibitory activity. Bacteria culture test is conducted to identify the causative microorganism linked to the infection. The alternative antibacterial agent chosen must not be resistant to the microorganism detected.15
Secondly, the serotonergic, precipitating drug, citalopram could be temporarily withdrawn from the medication profile. It is well established that linezolid therapy is not a long-term treatment option for most patients as it has a maximum treatment duration of 28 days.12 Patients receiving linezolid more than the recommended duration of four weeks are at a higher risk of haematopoietic disorders and optic neuropathy.12 If linezolid has to be administered to a patient who is already receiving citalopram, administration of citalopram is temporarily stopped for 14 days prior to commencing linezolid.16 In several cases, hyperthermia might still occur for several days after citalopram has been stopped. This is due to the fact that citalopram has a mean terminal-half life of 35 hours.17 Therefore a washout period is necessary once citalopram is stopped. Literature review on a case study involving an intubated patient suffering from depression was linked to a higher risk of infection.18 The patient required a more urgent administration of linezolid. Citalopram had a lower clinical priority. It was temporarily withdrawn and discontinued until linezolid treatment is completed and an improvement in symptoms was subsequently observed.18
The third established option is to continue the concurrent administration of both medications without a 14-day washout period and with cautious monitoring on patient's body temperature and other clinical symptoms. The choice between the second and the third option relies upon additional cost-benefit factor of the clinical scenario. It is necessary to determine the greater risk of recurrent mood disorder in comparison to serotonin toxicity, or vice versa. Literature review on a case study had revealed incidence whereby a patient diagnosed with chronic depressive illness was also found to be suffering from osteomyelitis.18 The patient's illness far outweighed serotonin toxicity caused by interaction between the two drugs. Hence, the subsequent treatment to this case study involved concurrent mantainence on linezolid and citalopram, with consequent follow-up treatment during the first four weeks to monitor the patient's toxicity levels.18 Concurrent administration is also possible due to the weak monoamine oxidase inhibition for linezolid leading to a minor interaction at therapeutic doses.
2.5 Adjunctive therapy for other symptoms present alongside hyperthermia due to serotonin syndrome
One of the symptoms that could present alongside hyperthermia due to moderate serotonin toxicity is persisting agitation. Chemical restraints are preferrable in overcoming this symptom, as physical restraints may further aggravate the patient's condition by causing lactic acidosis and which leads to worsening of hyperthermia. Hence, benzodiazepine, namely lorazepam is administered to control these symptoms, and indirectly adjust the slight increase in heart rate and blood pressure. In clinical studies, lorazepam was shown to increase survival rate in animal models, but does not stop them from dying.19
3. TREATMENT RECOMMENDATION WITH PHARMACOLOGICAL AND CLINICAL EVIDENCE
Figure 1 : Step-by-step treatment recommendation based on patient's clinical scenario
Alterations to medication due to presence of drug interaction.
Linezolid treatment necessary; could not be substituted.
Patient's rise in body temperature, leading to postoperative hyperthermia occurred after surgery. The step-by-step treatment recommendation is outlined in Figure 1, in which the most appropriate initial treatment would be the administration of intravenous dantrolene sodium. It is important to ensure that patient had been previously administered with volatile anaesthesia or succinylcholine during surgery. Clinical evidence have indicated that the mortality rates have fallen dramatically from 70-80% to 2-3% when dantrolene is administered to patients after an increased awareness among patients alongside an improvement in monitoring standards.6 After a successful treatment of loading and maintenance doses of intravenous dantrolene, monitoring of the patient at the intensive care unit for a day is necessary in case of recurrence of events.2
Adjuvant therapies for treatment symptoms that arise alongside postoperative hyperthermia are carried out as stated in section 2.2 and 2.3. As benzodiazepine is administered for persisting agitation, there is a high possibility of potentiation sedative effect due to concomittant administration of intravenous dantrolene, a muscle relaxant. This leads to an additive muscle relaxant action. This is a minor interaction with minimal clinical evidence, as a concrete relevant study could not be found. Continuous patient monitoring is still recommended to ensure that the patient does not exhibit additive skeletal muscle relaxant action.
Patient was already taking both linezolid and citalopram concurrently before symptoms of hyperthermia appear. Due to risk of serotonin syndrome, it is advisable to make changes to these two medications at the same time during administration of dantrolene sodium. The duration of treatment and severity of patient's condition are considered before subsequent changes are made. The length of medication for linezolid is shorter than citalopram in which citalopram treatment would last for 6 months to a year or longer depending on the patient's respond to the antidepressant. Bacterial culture test is carried out to identify the infection-causing microorganism in skin and soft tissue infection. Likewise, sputum culture test is carried out if patient is diagnosed with pneumonia. It is highly suggested to discontinue the administration of linezolid to patient after considering the number of doses left in the treatment regimen. The current clinical scenario is linked to findings from a case study on a 37-year-old male patient with cellulitis on his right leg.20 During a resolving MRSA infection, intravenous vancomycin, a glycopeptide was replaced with oral linezolid as a discharge medication. Symptoms related to serotonin toxicity then occur, requiring readmission of patient to the medical ward. As there was only one dose left in the 10-day planned therapy20, the oral linezolid treatment could be safely discontinued. No alternative medication to linezolid was administered to the patient in the specified case study as there was only one dose left in the 10-day planned therapy.20 However, if the MRSA infection was new and persistent requiring a substantial amount of antibacterial agent to treat the infection, the substitution of oral linezolid with newer oral antibacterials such as daptomycin, igecycline, telavancin or ceftaroline is initiated. Each medication in this line of new drugs however has specific indications and a varying degree of efficacy, and should be administered with caution.15 For instance, daptomycin is clinically approved for treatment of MRSA skin and soft tissue infections but ineffective against pneumococcal infections.21 Laboratory studies using animal models have shown that the failure was linked to an inactivation of antibacterial agent by lung surfactant.21
If the linezolid treatment for infection is necessary and could not be substituted due to safety reasons and antibacterial resistance, the administration of citalopram would be stopped for at least two weeks. Citalopram is discontinued by gradually withdrawing the administered dose and monitoring patient's symptoms of major depression including headache, lethargy and other physical complaints. Patient is then given the usual linezolid dose until the end of the duration of treatment which usually lasts for four weeks. It is vital to monitor the signs and symptoms of serotonin syndrome, including patient's elevated core and body temperature.13 In addition, large amounts of food containing tyramine is avoided when linezolid is administered to patient. Once the core temperature returns to normal values at 38°C and patient reaches the end treatment of linezolid, showing sufficient clinical improvements, the administration of citalopram is recommenced to treat the patient's symptoms of depressive illness. However, there is an ambiguity surrounding the choice of this treatment and concurrent administration of both medications. Findings from a 4-year retrospective study22 on 72 patients separated into two treatment groups indicated that only 2 patients (3%) were susceptible to a high risk of serotonin syndrome. Hence it is noted that the most appropriate choice of treatment relied on patient's specific condition for each clinical scenario with continuous monitoring of patient's condition.22
If treatment was carried out accordingly, symptoms could be resolved within half a day to a day. This is dependant on the severity of the patient's hyperthermia condition after the surgery process.
