A COMPARATIVE STUDY OF THE

EFFECT OF CLONIDINE AND TRAMADOL ON

POST-SPINAL ANAESTHESIA

SHIVERINGINDIAN JOURNAL OF ANAESTHESIA

VOLUME 55, ISSUE3, MAY-JUNE 2011

BY: DR. HUNNY NARULA

MODERATOR: DR. CHANDRAKANTA SACHDEVA

INTRODUCTION: Shivering is known to be a frequent

complication, reported in 40-70% of patients undergoing surgery under regional anaesthesia.

Shivering is very unpleasant, physiologically stressful for the patient undergoing surgery, and some patients even find the accompanying cold “sensation to be worse than surgical pain.”

Aim:

The aim of this prospective double-blind randomized clinically controlled study was to compare the efficacy, potency, haemodynamic effects, complications and side effects of clonidine with those of tramadol for control of shivering.

RESULTING COMPLICATIONS ARE: Increased metabolic rate; Increased oxygen

consumption(upto100-600%) along with increased CO2 production;

Ventilation and C.O.; Adverse post operative outcomes such

as wound infection; Increased surgical bleeding; and Morbid cardiac events.

Also:

Arterial hypoxemia, Lactic acidosis, Increased IOP, ICT Interferes with pulse rate, BP, and ECG

monitoring. Shivering per se may aggravate

postoperative pain, simply by stretching of surgical incision.

MECHANISMS PROPOSED:

Neuraxial anaesthesia induced inhibition of autonomic thermoregulatory responses below the level of block

Heat loss l/t decreased core body temprature

Cutaneous vasoconstriction

SHIVERING THRESHOLD

Peripheral vasodilatation(sympathetic blockade)

Increased blood flow to the skin

Increased muscle activity

Rapid infusion of cold iv fluids

Cold temp. of OT

However, in the postoperative period,

muscle activity may be increased even with normothermia, suggesting that mechanisms other than heat loss with subsequent decrease in the core temperature contribute to the origin of shivering. These may be uninhibited spinal reflexes, sympathetic over-activity, postoperative pain, adrenal suppression, pyrogen release and respiratory alkalosis.

INCLUSION CRITERIA:

Approval from ethical committee & written informed consent,

80 ASA grade1 patients, of either sex Age 18-40yrs, Scheduled for elective abd.,

orthopaedic, and gynaecological surgeries e.g. inguinal herniorraphy, abd. or vaginal hysterectomy, K nailing, dynamic hip screw under spinal anaesthesia without any prior pre-medication

EXCLUSION CRITERIA:

Patients with known history of alcohol or substance abuse, hyperthyroidism, cardiovascular diseases, psychological disorder, severe diabetes or autonomic neuropathies and urinary tract infection.

Patients with KNOWN HYPERSENSITIVITY TO CLONIDINE and TRAMADOL.

Patients who developed post-spinal

anaesthesia shivering were randomly allocated to two groups:

Group C(n=40)

iv Clonidine(0.5mcg/k

g)

Group T(n=40)

iv tramadol(0.5mg/k

g)

METHOD OF THE STUDY: Subarachnoid block was given with inj.

Bupivacaine 0.5% (10-15 mg) at L 3-4 or L 4-

5 interspace using 25 gauge Quincke's needle, and blockage up to T 9-10 dermatome was achieved.

All operation theatres in which the operations were performed maintained constant humidity (70%) and an ambient temperature of around 21°C to 23°C.

Oxygen was administered to all the patients of both groups at a rate of 5 L/min with face mask, and patients were covered with drapes but not actively warmed. No means of active re-warming were used.

Intravenous fluids and anaesthetic drugs were

administered at room temperature. Preloading was not done in both the groups as

they did not want intravenous fluid to influence the onset of shivering mechanism.

Before beginning of spinal anaesthesia, standard monitoring procedures were established. Standard monitoring of pulse rate was done, and non-invasive blood pressure (NIBP), oxygen saturation (SPO 2 ), body temperature (axillary) were recorded before the commencement of surgery and thereafter at every 5 minutes from the baseline ie subarachnoid block (SAB), for 1 hour; and every 15 minutes, for the rest of the observation period.

GRADING OF SHIVERING was done as per Wrench, [6]

 which is as follows:

Grade 0: No shivering 

Grade 1: One or more of the following: Piloerection, Peripheral vasoconstriction, peripheral cyanosis with, but without visible muscle activity

Grade 2: Visible muscle activity confined to one muscle group

Grade 3: Visible muscle activity in more than one muscle group

Grade 4: Gross muscle activity involving the whole body

Patients who developed either grade 3 or grade 4 of shivering were included in the study. 

CONTD….

The attending anaesthetist recorded the time in minutes at which shivering started after spinal anaesthesia (onset of shivering), severity of the shivering, time to disappearance of shivering (in minutes) and response rate (shivering ceased after treatment in 15 minutes).

If the shivering did not subside by 15 minutes, the treatment was considered to be not effective.

Recurrence of shivering was also noticed until the patient left the operation theatre. Patients who did not respond or in whom recurrence of shivering occurred were treated with additional dose of clonidine (0.5 μg/kg IV) or tramadol (0.5 mg/kg IV) in the respective groups, if required.

Duration of surgery was noted, and

duration of spinal anaesthesia was recorded by assessing spontaneous recovery of sensory block using pin-prick method and

observing spontaneous movements of limbs in the postoperative period.

Side effects like nausea, vomiting, bradycardia (<50/min), hypotension (>20% of baseline), dizziness; and sedation score were recorded.

SEDATION SCORE was assessed with a four-point scale as per Filos:

 1. Awake and alert2. Drowsy, responsive to verbal stimuli3. Drowsy, arousable to physical stimuli4. Unarousable

 STATISTICAL ANALYSIS was done

using suitable statistical software, and Student t test and Chi-square test were applied for the interpretation of results. A  P value <.05 was considered statistically significant.

RESULTS:

Shivering disappeared in: 39(97.5%) patients in group C, and in 37(92.5%) pts in group T(out of 40 in

each group.)

BOTH THE GROUPS WERE FOUND TO BE EEFECTIVE IN REDUCING SHIVERING

One patient in group C (severity of shivering unchanged) and 5 patients (3- severity of shivering unchanged; 2- recurrence of shivering) in group T were given rescue doses of clonidine or tramadol, respectively.

Six (7.5%) patients out of a total of 80 patients received rescue doses.

The mean interval between the injection

of drug (clonidine and tramadol) and the complete cessation of shivering was 2.54±0.76 and 5.01±1.02 minutes, respectively (P=.0000001).

Time for onset of shivering and severity of shivering were not statistically significantly different between the two groups. However, the time interval between administration of drug after onset of shivering and disappearance of shivering was significantly shorter in the clonidine group(P=.0000001).

There was no statistically significant difference with respect to heart rate, mean blood pressure, axillary temperature and oxygen saturation between the two groups.

Complication rates were significantly higher in group T than in group C. Nausea, vomiting and dizziness were higher in group T [nausea - 31; vomiting - 8; and dizziness - 22) than in group C. More patients of group C (10 patients) were sedated than of group T (5 patients).

Complications in both groups:Bradycardia occurred in 2 patients of group C and 1 patient of group T. In group C, 3 patients suffered from hypotension, and 1 patient complained of dry mouth, both of which were not present in group T.

A limitation of this study is that the core

body temperature could not be measured. For measurement of core body temperature, the probe needs to be put in the oesophagus or near the tympanic membrane. Both these are uncomfortable and unacceptable who has been given spinal anaesthesia. Rectal temperature monitoring was a possibility but was not tried.

CLONIDINE:

Centrally acting selective α2 agonist. It exerts anti-shivering effects at three

levels: Hypothalamus, locus coeruleus and spinal cord.

At the hypothalamic level, it decreases thermoregulatory threshold for vasoconstriction and shivering, because hypothalamus has high density of α2 adrenoceptors and hence is effective in treating the established post-anaesthetic shivering.

Also reduces spontaneous firing in locus

coeruleus - a pro-shivering centre in Pons.

At the spinal cord level, it activates the a2 adrenoreceptors and release of dynorphine, nor epinephrine and acetylcholine. The depressor effects of these neurotransmitters at the dorsal horn modulate cutaneous thermal inputs.

Clonidine is highly lipid-soluble and easily crosses the blood-brain barrier..

TRAMADOL: Tramadol is an opioid analgesic with

opioid action preferably mediated via μ (mu) receptor with minimal effect on kappa and delta binding sites.

Tramadol also activates the mononergic receptors of the descending neuraxial inhibiting pain pathway.

The anti-shivering action of tramadol is probably mediated via its opioid or serotonergic and noradrenergic activity or both.

CONCLUSION: Both clonidine (0.5 μg/kg) and tramadol

(0.5 mg/kg) effectively treated patients with post-spinal anaesthesia shivering, but tramadol took longer time to achieve complete cessation of shivering than clonidine.

So they concluded that clonidine offers better thermodynamics than tramadol, with fewer side effects. The more frequent incidence of side effects of tramadol, like nausea, vomiting and dizziness, may limit it's use as an anti-shivering drug.

Prospective randomized data suggest that

high risk patients assigned to only 1.3 degree Celsius core hypothermia were three times more likely to experience adverse myocardial outcomes. Marked increase in plasma catecholamine level is perhaps associated with high-risk cardiac complications.

 Zavaherforoush et al. compared clonidine with pethedine and fentanyl for treating post-spinal anaesthesia shivering in elective Lower Segment Caesarean Section (LSCS) and also found it to be offering better thermodynamics than pethedine.

NORMAL THERMOREGULATION

THE PROCESSING OF THERMOREGULATORY RESPONSE HASTHREE COMPONENTS:

AFFERENT INPUT

CENTRAL CONTROL

(Hypothalamus)

EFFERENT RESPONSES

AFFERENT INPUT Information on temprature is obtained

from thermally sensitive cells throughout the body.

Warm receptors their firing rates when temp. increases, whereas cold receptors do so when temp. .

Cutaneous receptors rarely depolarise at normal skin temp.

The hypothalamus, other parts of the brain, spinal cord, deep abd. & thoracic tissues and the skin surface each contribute roughly 20% input to the central regulatory system.

Cold signals Warm signals

SPINAL CORD

Via A delta FIBRES

Via unmyelinated C fibres

MOST OF THE INF. Via Ant. Spinothalamic tract

C-fibres also carry pain

sensation,which is why sometimes

intense heat cannot be

distinguished from sharp pain.

No single spinal tract is critical for conveying thermal inf, consequently entire cord must be destroyed to ablate thermoregulatory

responses.

CENTRAL CONTROL

Preoptic region of the anterior hypothalamus is thedominant autonomic thermoregulatory controller inmammals.

Much of the excitatory input to warm sensitiveneurons comes from hippocampus, which links the limbicsystem (emotion, memory, and behaviour) tothermoregulatory responses

The hypothalamus,

other parts of the brain, spinal cord,

deep abd. & thoracic tissues

and the skin surface each

contribute roughly 20% input to the central regulatory

system.

Both sweating and vasoconstriction

thresholds are 0.3 – 0.5 degree higher in women than in men, even during the follicular phase of the menstrual cycle(first 10 days). These differences are even greater during the luteal phase.

Central thermoregulatory control is apparently intact even somewhat in premature infants. In contrast this control is sometimes impaired in elderly.

EFFERENT RESPONSES A core temp below the threshold for

response to cold provokes vasoconstriction, non shivering thermogenesis, and shivering. A core temp exceeding the hyperthermic threshold produces active vasodil. and sweating.

No thermoregulatory responses are initiated when the core temp is between these thresholds which is identified as interthreshold range, and is about 0.2 degrees centigrade in humans.

In general, energy efficient

effectors such as vasoconstriction are maximised before metabolically costly responses such as shivering are initiated.

Quantitatively, behavioural regulation is most imp. effector mech which includes dressing appropriately, modifying environmental temp, voluntary movements and acquiring positions that oppose skin surfaces.

EFFECTOR RESPONSES:1. Cutaneous vasoconstriction Most consistent Reduces the heat loss via convection

and radiation from the skin surface Total digital skin blood flow

thus vasoconstriction do not compromise the needs of peripheral tissue.

NUTRITIONAL(most capillary)

THERMOREGULATORY(arterio venous shunt)

Local α-adrenergic sympathetic nerves

mediate constriction in the thermoregulatory arteriovenous shunts, and flow is minimally affected by circulating catecholamines.

Roughly 10% of the cardiac output traverses the arteriovenous shunts; consequently shunt vasoconstriction increases mean arterial pressure approx. 15mmHg.

EFFECTOR RESPONSES:2. NON SHIVERING THERMOGENESIS: INC. metabolic heat production without

increasing mechanical work Х2 heat production in infants but

increase is only slight in adults. Skeletal muscle and brown fat tissues

are the major sources of non shivering heat in adults

Controlled primarily by norepinephrine from adrenergic nerve terminals in these tissues.

EFFECTOR RESPONSES:3. SUSTAINED SHIVERING: Augments metabolic heat production by

50-100% in adults. Shivering does not occur in newborns and

infants 4. SWEATING: mediated by post ganglionic,

cholinergic nerves, thus an active process. Prevented by nerve block or administration

of atropine. Only mechanism by which body can

dissipate heat in an environment exceeding core temprature.

EFFECTOR RESPONSES:5. ACTIVE VASODILATATION: Apparently mediated by nitric oxide Requires intact sweat gland functions, So largely inhibited by nerve blockade.

THERMOREGULATION UNDER GENERAL ANAESTHESIA

NON SHIVERINGTHERMOGENESIS

VASOCONSTRICTION

SWEATING

VASODILATATION

SHIVERING

33 35 37

39 41

THERMOREGULATORY THRESHOLD IN UNANAESTHETISED PATIENT (normal interthreshold range is near 0.3degrees)

SHIVERING

NONSHIVERINGTHERMOGENESIS

VASOCONSTRICTION

SWEATING

VASODILATATION

33 35 37 39 41

THERMOREGULATORY RESPONSE UNDER ANAESTHESIA(INCREASE FROM ITS NORMAL VALUE TO ABOUT 2-4 DEGREES)

All general anaesthetics tested so far markedly impair normal autonomic thermoregulatory control and cause:

markedly reduced cold response thresholds, and

slightly elevated warm response thresholds

and thus increasing the intrethreshold range about 20 folds to approx. 2-4 degrees C.

Temp. within this range do not trigger thermoregulatory defenses, and patients are thus by definition poikilotheric within this temp range.

Sweating is the best preserved major thermoregulatory defense during anaesthesia.

The drugs that are effective for post anaesthetic tremor and also for shivering during regional anaesthesia are:

MEPERIDINE(25mg iv), CLONIDINE(75mcg iv), DEXMEDETOMIDINE, TRAMADOL, KETANSERINE(10mg iv), MAGNESIUM SULFATE(30mg/kg iv), PHYSOSTIGMINE(0.4mg/kg iv),NEFOPAM(0.15mg/kg).

THANKS!!