Introduction: This retrospective single centred observational study assessed the safety and efficacy of sedation with Butorphanol and midazolam in critically ill mechanically ventilated patients in an Intensive care unit.

Method: Patients aged between 18 – 80 years admitted to the intensive care unit from July 2018 till December 2018 were included in the study. Medical records were identified by searching the pharmacy database and individual patient medicine cards for the given time period. Patients of the Cardiac care unit were not included in the study.Only those cases where proper documentation of baseline vitals, RASS, CPOT, CAM-ICU score, Age and sex had been documented were included in the study. The regimen consisted of butorphanol (0.48 mg/hour) and midazolam (2 mg/hour). Dose was titrated to achieve optimal sedation and analgesia.

Main outcome measures: Percentage of time within target RASS range. Secondary end points included level of analgesia, prevalence of delirium, adverse event like hypotension, bradycardia, patient self extubation etc.

Result: From this study we can safely conclude that the combination of Butorphanol and midazolam in there recommended doses are quite effective and safe agents for sedation and analgesia in ICU patients on mechanical ventilation.

INTRODUCTION:

Providing sedation and analgesia for Patient comfort is an integral component of bedside care for nearly every patient in the intensive care unit (ICU). For decades, y-aminobutyric acid (GABA) receptor agonists (including propofol and benzodiazepines such as midazolam) have been the most commonly administered sedative drugs for ICU patients worldwide. Practice guidelines for providing sedation in the ICU have identified the need for well-designed randomized trials comparing the effectiveness of different sedative agents for important clinical outcomes.

Butorphanol tartrate is a synthetic parenteral opiate agonist-antagonist. Specifically, Butorphanol is a kappa-receptor agonist and a partial agonist or mixed agonist-antagonist with low intrinsic activity at mu receptor .Because of limited stimulation at the mu-receptor, Butorphanol is believed to produce less respiratory depression and to pose a lower risk of physical dependence than morphine.²

There have been very few studies designed specifically to evaluate the safety and efficacy of Butorphanol for sedation and analgesia in mechanically ventilated patients³. Butorphanol with midazolam was being used routinely as sedative and analgesic for mechanicallyventilated patients in the ICU of our institute.Hence we decided to do a retrospective study on 122patients who had received the regimen.

METHODOLOGY:

This was a retrospective observational single centred study. 122 patients aged between 18 – 80 years admitted to the intensive care unit from July 2018 till December 2018 who needed mechanical ventilation were included in the study. Medical records were identified by searching the pharmacy database and individual patient medicine cards for the given time period. Patients of the Cardiac care unit were not included in the study. Only those cases where proper documentation of baseline vitals, RASS, CPOT, CAM-ICU score, Age and sex had been documented were included in the study.

TREATMENT PROTOCOL:

As per the ICU protocol Inj Butorphanol 6mg (3 ampules) was mixed with 25 mg Midazolam and rest Normal saline to be made a total infusion of 50 ml, was to be started by infusion, where each ml of the solution contained 0.12 mg/ml Butorphanol and 0.5 mg/ml Midazolam. A loading dose of 4ml was to be given followed by maintenance dose of 3.5 to 4 ml/hr. The regimen consisted of butorphanol (0.48 mg/hour) and midazolam (2 mg/hour). Dose was titrated to achieve optimal sedation and analgesia.

Rescue drugs that were allowed were Propofol, other opiods(like fentanyl and morphine) and muscle relaxants.

PATIENT MONITORING:

As per the ICU protocol all patient on mechanical ventilation were monitored closely for signs of agitation and pain using RASS, CPOT, HR, MAP, Respiratory rate. Additionally CAM-ICU score was used to detect presence of residual delirium every 24 hours and the result after 48 hours were included in the study. The nursing records and doctors ICU progress notes were evaluated for incidence of bradycardia, hypotension, allergy- anaphylaxis, during the study period. Other likely adverse events due to inadequate sedation like patient self extubation, vomiting, constipation were also noted from the nursing notes.

NEUROLOGICAL ASSESSMENT:

As per the ICU protocol daily sedation vacation was done before doing neurological assessment. For this rather than completely stopping the  study drug at once,  it was protocolized  to tapper down the infusion by 2 ml then wait for 10 minutes before doing the  neurological assessment,  then again tapper down the infusion by 2 ml then wait for 10 minutes before doing the neurological assessment.

RESULTS:

Target RASS level was achieved in 86% of the patients. Target CPOT level was achieved in 90% of the patients. Around 28% of the patient showed signs of delirium during the study period. Adverse events many included constipation (26%), vomiting (13%), Bradycardia (18%), Hypotension (19.6%). Around 21.3% of the patient required administration of rescue drugs during the study period.

DISCUSSION:

For patients on mechanical ventilation in the ICU, appropriate sedation and analgesia is one of the key factors to ensure patient’s comfort and improve the outcome.

Over sedation can lead to prolonged duration of mechanical ventilation /difficulty in weaning off, longer ICU stay and higher chances of complications. Under sedation can lead to anxiety, hyperactivity of the sympathetic system, delirium etc.

Our study showed that the combination of Butorphanol and Midazolam was quite effective and safe as a sedative and analgesic agent in ICU patients. The target sedation achieved with this combination was comparable with other agents commonly used in ICU like other opiods (fentanyl , morphine), alpha 2 agonist (dexmedetomidate)  and GABA receptor agonists ( including propofol).

As expected we observed that the incidence of delirium was quite high with this combination.

Additionally it was noted that the prevalence of over sedation was quite high. It seems intensivist preferred to oversedate their patients then undersedate, which might be partly due to fear of adverse events like patient self extubation, airway trauma etc.

CONCLUSION:

From this study we can safely conclude that the combination of Butorphanol and midazolam in there recommended doses are quite effective and safe agents for sedation and analgesia in ICU patients on mechanical ventilation.

REFERENCES

1. Riker RR, Shehabi Y, Bokesch PM, et al. Dexmedetomidinevs Midazolam for Sedation of Critically Ill Patients: A Randomized Trial. 2009;301(5):489–499. doi:10.1001/jama.2009.56
2. Clinical Key Drug Monograph Butorphanol
3. PANSE, Dr.Neha. TO COMPARE THE SEDATION AND ANALGESIA PRODUCED BY CONTINUOUS INFUSIONS OF DEXMEDITOMIDINE AND BUTORPHANOL IN CRITICALLY ILL PATIENTS ON MECHANICAL VENTILATION: A RANDOMIZED DOUBLE BLIND CONTROLLED TRIAL.. INDIAN JOURNAL OF APPLIED RESEARCH, [S.l.], v. 7, n. 12, aug. 2018. Available at: <https://wwjournals.com/index.php/ijar/article/view/7030/6971>

Author:

Dr Akash Boruah
Registrar Critical Care Medicine
Narayana Superspeciality Hospital, Guwahati

Dr Apurba Kumar Borah
HOD & In-charge Emergency and Critical Care Medicine
Narayana Superspeciality Hospital, Guwahati

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Tetanus is still a significant health hazard in developing countries, with high associated mortality. It is cause by Clostridium Tetani. This anaerobic bacillus produces Tetanospasmin which affects the central nervous system. It causes persistent tonic spasms. Spasms may be spontaneous or triggered by visual, auditory or emotional stimuli and can be severe enough to cause fractures or avulse tendons. Prolonged muscular action causes sudden, powerful, and painful contractions of muscle groups, which is called “tetany”. The incubation period is the time from spore inoculation to the initial symptom of tetanus. The onset period – the time from the first symptom to the first muscular spasm – reflects the progression of neurological manifestations caused by the tetanus toxin.Tetanospasmin disables release of neurotransmitter from presynaptic vesicles (particularly the inhibitory neurotransmitters GABA and glycine). The toxin is transported in the neurons into the central nervous system, which takes from 10–14 days. Recovery period is about 4-6 weeks.The progression of clinical symptoms of tetanus, such as respiratory failure and autonomic instability, are associated with high morbidity and mortality in the early hospitalization period. Later in the course of the disease, death results from complications of autonomic instability or prolonged ICU exposure.

Case Study :

A 50 year old male k/c/o diabetes type 2 for 3 years on OHA presented in hospital with h/o road traffic accident on 14/6/17. He had lacerated injury to his knee. On examination, he had diaphoresis, slow tongue movements and was unable to open his mouth fully. CT brain, MRI cervical spine and wound pus culture including clostridium tetani (aerobic and anaerobic) were sent to rule out tetanus. While inserting Ryle’s tube patient had cardiac arrest (which was most likely due to autonomic dysfunction). During the initial period of treatment patient was put on mechanical ventilation with volume control mode. Patient was handled with standard procedure for tetanus including debridement and care of lesion. Tetanus toxoid immunoglobulin 3000 units , inj. Metronidazole 500mg 6^thhrly, injMedazolam 5mg/kg as continuous infusion was started. Patient was shifted to isolation room with no lights to avoid any stimulation. Spasms were partially controlled by midazolam but additional muscle relaxant inj. Vecuronium 4mg/hr was added to the regimen for 2 day. Infusion of inj Magnesium Sulfate was stared as an effective adjunct in relaxation, sedation and controlling the autonomic disturbance in tetanus. Tab Baclofen 10mg BD was started for better was added  further for better control of spastic movement. More 5000 units of tetanus toxoid immunoglobulin was given (3000 units IM & 2000 units S/C). Patient required 4 weeks of ventilator support , having tracheostomy done on 12^th day. Intermittent stopping of sedations allowed us to reaccess the sensorium. Slowly the sedations were tapered off as events of spasm were stopped and weaning process was initiated on day 25^th. Gradually patient was put on T-Piece and weaned off from ventilator. Patient was shifted to wards on 30^th day.

Specific treatment :

Three  principles used while managing this case. 1)Prevent further toxin release. 2) Neutralise toxin present in the body outside the CNS. 3)Minimise the effects of the toxin already in the CNS.

Inj Metronidazole 500 mg iv 6 hourly was the drug of choice. Administration of tetanus toxoid immunoglobulin 150 mg/kg  IM within 24 hours of diagnosis of tetanus. Further intermittent doses of TIG was given IM/SC to further neutralize the effect of toxin.  Control rigidity and spasms with sedation, respiratory support given where necessary and control autonomic dysfunction achieved.

Discussion:

Benzodiazepines:

Benzodiazepines(GABA agonist) are the standard therapy for controlling muscle spasms in tetanus and have gained popularity over other agents due to their combined muscle relaxant, anticonvulsant, sedative and anxiolytic effects, which can be quite useful in managing a patient with tetanus. Midazolam, a relatively short acting benzodiazepine can be used as the continuous infusion @ 3mg/hr.

Muscle relaxant:

It should be added as the sedation alone is inadequate. InjVacuronium 0.1mg/kg IV should be used. Tab baclofen 10mg/kg BD can be added to control spasticity.Pancuronium may worsen autonomic instability by inhibiting catecholamine reuptake. Prolonged usage of muscle relaxants has been associated with critical illness neuropathy and myopathy.

Treatment of autonomic dysfunction:

InjMagnessium Sulfate @ 2mg/kg should be started.It is a pre-synaptic neuromuscular blocker, reduces catecholamine  release from nerves and the adrenal medulla, and reduces receptor responsiveness to released catecholamines. A loading dose of 5g should be given over 20 minutes, followed by an intravenous infusion of 2g/hr. By antagonizing calcium metabolism, magnesium causes weakness and paralysis in overdose. Monitoring of serum magnesium levels is important to prevent this: the normal serum magnesium level is 0.7 – 1.0 mmol/l, whilst an acceptable therapeutic level is 2 – 3.5 mmol/l.

General management:

Enteral feeding should be started by nasogatric tube to prevent malnutrition and autonomic gastrointestinal dysfunction. Prevention of ventilator associated pneumonia due to prolong ventilator support which was manage with appropriate antibiotic treatment. Care of wound should be taken to minimize bacterial growth. Measures to minimize the risks of thromboembolism, gastrointestinal haemorrhage and pressure sores should be applied.

Conclusion:

Tetanus is a dreaded disease with high mortality. But with a protocolized approach it can be treated effectively, which decreases the mortality and morbidity associated with it.

References:

http://www.anaesthesiauk.com/documents/tetanus.pdf

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4057067/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1737078/

https://associationofanaesthetists-publications.onlinelibrary.wiley.com/doi/full/10.1046/j.1365-2044.2002.02698_6.x

https://www.sciencedirect.com/science/article/pii/S1875957211000416

Author:

1. Dr. Sidhartha Das (Associate Consultant, Critical Care Medicine, Narayana Superspeciality Hospital, Guwahati)

2. Dr. Swapnil Thorat, (Fellow, Critical Care Medicine, Narayana Superspeciality Hospital, Guwahati)

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