Does Heart Rate Variablity (HRV) Predict Hypotension on Induction in Patients Undergoing Surgery for Cervical Myelopathy ?
Conditions: Heart Rate Variability
Sponsor: Lashmi Venkatraghavan

 
 
 
Does Heart Rate Variability (HRV) Predict 
Hypotension on Induction in Patients Undergoing 
Surgery for Cervical Myelopathy? 
 
Protocol Version: 2   
Protocol Date: October 2nd 2014 
ClinicalTrials.gov ID: NCT02360085 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Does Heart Rate Variability (HRV) Predict Hypotension on Induction in Patients 
Undergoing Surgery for Cervical Myelopathy? 
 
Investigators 
1.  Lashmi Venkatraghavan MD. Department of Anesthesia, Toronto Western Hospital. 
University of Toronto  
2.  Alastair Moodley MD. Department of Anesthesia, Toronto Western Hospital. University 
of Toronto. 
3.  Jigesh Mehta MD. Department of Anesthesia, Toronto Western Hospital. University of 
Toronto 
4   Alison Tedder MD. Department of Anesthesia, Toronto Western Hospital. University of 
Toronto 
5. Pirjo Manninen. MD Department of Anesthesia, Toronto Western Hospital. University of 
Toronto  
 Project Summary 
Cervical myelopathy is commonly associated with degenerative spinal disease. Dysfunction 
of the autonomic nervous system is also evident in many cases of cervical myelopathy.  
Autonomic dysfunction may result in haemodynamic instability and hypotension under 
anaesthesia.  It is important to maintain adequate mean arterial pressure in order to perfuse 
the spinal cord and prevent cord ischemia.  Heart rate variability, the physiological variations 
of the differences between heart beats, has been used to diagnose autonomic dysfunction. In 
patients with cervical myelopathy it may enable the anaesthetist to predict hypotension 
thereby allowing for early treatment and prevention of spinal cord ischemia. 

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Background  
Cervical myelopathy is commonly associated with degenerative spinal disease. It is a 
common cause of spinal cord dysfunction in the aging population.  The predominant 
pathology seen in these patients is spondylosis which includes degeneration of joints, discs 
and ligaments. (1).  Spinal cord ischemia may also contribute to these pathological processes 
but the exact mechanism remains unclear.  Magnetic resonance imaging may reveal disc 
herniation, osteophytic narrowing of the spinal canal and hypertrophic changes to the 
ligamentum flavum (2). Patients may present with a wide range of symptoms ranging from 
neck pain and decreases in dexterity in mild cases to sphincter dysfunction and complete loss 
of motor function in severe cases (3). Dysfunction of the autonomic nervous system is also 
evident in many cases of cervical myelopathy (4).  In many of these patients, the spinal cord 
is at risk of ischemia due to decreased blood flow as a result of compressive lesions.  Any 
further reduction in spinal cord blood flow may not be well tolerated. Mean arterial pressure 
(MAP) is one of the important factors that determine the adequacy of perfusion to the spinal 
cord and hypotension has been shown to be associated with poor outcome in patients with 
spinal cord injury.  
Autonomic nervous system dysfunction is often seen in patients with acute spinal cord injury. 
(5).  A recent study has shown autonomic nervous system involvement in up to 50% of 
patients with compressive cervical myelopathy (4). The autonomic nervous system (ANS) is 
responsible for the normal regulation of visceral organ function including the cardiovascular 
system. They are the primary regulator of heart rate and blood pressure. 
Surgical treatment of cervical myelopathy may involve anterior and/or posterior 
decompression of spinal cord with or without instrumented fusion. The main purpose of the 
surgery is to prevent further deterioration of spinal cord function. Patients with cervical 
myelopathy often pose a significant challenge to the anesthesiologists. In addition to 
challenges with airway management and patient positioning, the most important anesthetic 
consideration in these patients is to maintain the mean arterial blood pressure (MAP) >70 
mmHg during the surgery.  
Anesthetic induction may cause hypotension and this may be profound in some patients.  
Common causes of post-induction hypotension include vasodilatation, myocardial depression 
(6), hypovolemia and altered autonomic nervous system activity. Studies have shown that 

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patients with autonomic system dysfunction are more prone to anaesthesia induced 
hypotension. It has been shown that patients with autonomic dysfunction require increased 
vasopressor support to maintain blood pressure (7).  Hence patients with cervical myelopathy, 
because of their associated autonomic system dysfuction, are possibly more prone to 
hypotension on induction of anesthesia.  This hypotension may put these patients at risk for 
spinal cord ischmia.  Identifying patients at risk for hypotension can be useful to prevent 
hypotension and to prepare to treat hypotension sooner so that the risk of spinal cord 
ischemia can be minimized. 
Assessment of Autonomic Nervous System Function 
 Multiple methods have been used for the assessment of the ANS including, Valsalva test, 
isometric handgrip test, cold pressor test and active standing test. (8) Most of these tests are 
time consuming, labour intensive and are not easy to perform in the perioperative setting. 
Another method of assesment of  ANS tone which affects cardiovascular function may be 
assessed by an analytical method called heart rate variability analysis.  Guo et al. have shown 
that heart rate variability measurement is a simple useful alternative to conventional tests. (9).  
Heart Rate Variability (HRV) 
Under normal physiological conditions the interval between successive cardiac cycles is not 
static but varies in response to several factors that place changing demands on the 
cardiovascular system.  A decrease in the variability of the interval between cycles i.e. a 
decrease in heart rate variability has been shown to be associated with several pathological 
conditions that affect the autonomic nervous system (10).   
Heart rate variability may be analysed accord to either the frequency domain or the time 
domain. With regard to time domain analysis, the SDNN or Standard Deviation of normal R-
R intervals is calculated during the period of ECG monitoring, the N-N interval being the 
interval between two successive normal beats.  Using Fourier transformation, fluctuations in 
the frequency domain may also be analysed.  The low frequency (LF) band (0.04-0.15 Hz) 
relates to sympathetic and parasympathetic modulation.  The high frequency (HF) band 
(0.15-0.4Hz) largely reflects parasympathetic contribution.  The ratio between low frequency 
and high frequency (LF: HF) is used to determine sympathetic-parasympathetic balance (11). 
 Heart rate variability may be analysed using standard hospital electrocardiographic 
equipment and the relevant software to perform the analysis.  Power spectral analysis of the 

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electrocardiogram can be used to measure autonomic dysfunction. A short (5 minute) ECG 
recording can be analysed to provide several useful measurements of autonomic function. 
Therefore, heart rate variability analysis provides a non-invasive, bedside method of 
assessing the status of the autonomic nervous system that can be used in the perioperative 
setting without significant change to standard operating procedures.  
HRV as a predictor of Hypotension under Anesthesia 
Haemodynamic stability under anaesthesia depends in a large part on the integrity of the 
autonomic pathways that feedback into cardiovascular regulatory centres and control 
variables like heart rate, contractility and vascular tone.  As an indicator of autonomic 
function, heart rate variability may therefore have a role to play in predicting haemodynamic 
instability.  Studies show that heart rate variability may be used as a predictor of 
haemodynamic fluctuations under anaesthesia.  Hanss et al (12) have shown that the LF: HF 
ratio can be used to predict severe hypotension during spinal anaesthesia.  In a study of 
patients under general anaesthesia Huang et al (13) showed that spectral analysis of heart rate 
variability could be used as a sensitive predictor of hypotension and that heart rate variability 
may be superior to traditional tests of autonomic function. 
Heart rate variability is being increasingly used in the setting of general and regional 
anaesthesia as both a diagnostic and prognostic tool (8). 
At present the incidence of decreased HRV in patients with cervical myelopathy is unknown 
as well as whether this is predictive of hypotension on induction of general anaesthesia.  
Therefore, the aim of our study is to determine the incidence of abnormalities in HRV in 
patients undergoing surgery for cervical myelopathy and to determine whether decreased 
heart rate variability is predictive of hypotension on induction in these patients. 
References: 
1. A review of the pathophysiology of cervical spondylotic myelopathy with insights 
for potential novel mechanisms drawn from traumatic spinal cord injury. Fehlings 
MG, Skaf G.  Spine. 1998; 23:2730–7. 
2. Cervical Spondylotic Myelopathy: A Common Cause of Spinal Cord Dysfunction 
in Older Persons.  Young, WF. Am Fam Physician. 2000 Sep 1;62(5):1064-1070. 
3. Cervical Spondylotic Myelopathy: Pathophysiology, Clinical Presentation, and 
Treatment.   Lebl D, Hughes A, O’Leary PF. HSS J. Jul 2011; 7(2): 170–178 

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4. Subclinical autonomic nervous system dysfunction in compressive cervical 
myelopathy. Srihari G, Shukla D, Indira Devi B, Sathyaprabha TN. Spine (Phila 
Pa 1976). 2011 Apr 15;36(8):654-9. 
5. Autonomic dysfunction in spinal cord injury: clinical presentation of symptoms 
and signs. Karlsson AK. (12) Arch Med Sci. Mar 1, 2010; 6(1): 11–18. 
6. Comparison of etomidate, ketamine, midazolam, propofol, and thiopental on 
function and metabolism of isolated hearts. DF Stowe, ZJ Bosnjak, JP Kampine. 
Anesthesia & Analgesia, 1992 
7. Increased intraoperative cardiovascular morbidity in diabetics with autonomic 
neuropathy. Burgos LG, Ebert TJ, Asiddao C, Turner LA, Pattison CZ, Wang-
Cheng R et al. Anesthesiology 1989; 70: 591—7. Prog Brain Res. 2006; 152:1-8. 
8. Methods of evaluation of autonomic nervous system function Zygmunt A, 
Stanczyk J. Arch Med Sci. Mar 1, 2010; 6(1): 11–18. 
9. Heart rate variability as a measure of autonomic dysfunction in men with 
advanced cancer. Guo Y, Palmer JL, Strasser F, Yusuf SW, Bruera E. Eur J 
Cancer Care (Engl). 2013 Sep;22(5):612-6. 
 
10. Heart-rate variability and cardiac autonomic function in diabetes. Malpas SC, 
Maling TJB.  Diabetes 39:1177 81 
11. Heart Rate Variability. Bilchik KC, Berger,RD. Journal of Cardiovascular 
Electrophysiology. Volume 17, Issue 6, pages 691–694, June 2006  
12. Heart Rate Variability Predicts Severe Hypotension after Spinal Anesthesia. 
Anesthesiology. Volume 104 - Issue 3 - pp 537-545, March 2006.  Hanss R, Bein 
B, Weseloh H. 
13. Pre-operative measurement of heart rate variability predicts hypotension during 
general anesthesia.  Acta Anaesth Scand. Volume 50, Issue 5, pages 542–548, 
May 2006. Huang CJ, Kuol CH, Kuo TBJ, Hsu YW, Tsai PS 
14. Heart rate variability: standards of measurement, physiological interpretation and 
clinical use. Task Force of the European Society of Cardiology and the North 
American Society of Pacing and Electrophysiology. Circulation. 1996 March 
Hypothesis 
We hypothesise that decreased HRV is common in patients undergoing surgery for cervical 
myelopathy and that decreased HRV is a predictor of hypotension on induction of general 
anaesthesia. We also hypothesise that there is a relationship between severity of myelopathy 
and degree of abnormalities in HRV. 
Significance of the study 
Identifying patients at risk for hypotension can be useful to prevent hypotension and to 
prepare to treat hypotension sooner so that the risk of spinal cord ischemia can be minimized. 

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Proposed methodology 
Study design 
This is a single centre, prospective observational study. 
Trial Population 
The study participants will be recruited from patients with cervical myelopathy presenting for 
cervical spine surgery at Toronto Western Hospital. 
Inclusion Criteria 
Adults patients, aged 18 – 70 years with the history of cervical myelopathy, presenting for 
anterior or posterior cervical decompression and fusion. 
Exclusion Criteria 
1. 
Patients with arrhythmias or absence of sinus rhythm  
2. 
Diabetic patients 
3. 
Degenerative neurological disease e.g. Parkinson’s disease 
4. 
Complete SCI 
5. 
Inherited autonomic dysfunction 
Protocol 
1. Standard perioperative management 
Routine standard preparation of the patients will be carried out as per our institutional 
standard for all patients undergoing cervical spine surgery. All routine physiological 
monitoring (ECG, invasive arterial blood pressure, SPO2, end tidal CO2, temperature and 
depth of anaesthesia monitoring) will be performed.  The induction of anesthesia will be 
performed with propofol (2-5 mg/kg), fentanyl (3mcg/Kg) and rocuronium (0.6 mg/kg) for 
intubation of the patient’s trachea once peripheral nerve stimulation shows no muscle 
twitches.  After tracheal intubation, the lungs will be ventilated using volume-controlled 
mode to maintain PaCo2 between 33-35 mmHg.  Anesthesia will be maintained with total 
intravenous anaesthesia or balanced inhalational anaesthesia as per standard management. 
Hemodynamic management will target a MAP > 70 mmHg using standard inotropes and 

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vasopressors (phenylephrine and ephedrine). Prophylactic antibiotics (Cefazolin or 
Clindamycin), antiemetic (Ondansetron) and steroids (Dexamethasone) will be administered 
as per our routine practice.  Intraoperative, 25 mcg bolus dose of fentanyl will be given for 
additional analgesia as indicated by clinical judgment. After the skin closure, anesthetic 
agents will be turned off and the neuromuscular blockade will be reversed with neostigmine 
0.05 mg/kg and glycopyrrolate 0.01 mg/kg.  Patient’s trachea will be extubated after meeting 
the extubation criteria. Patients will be transferred to recovery room and standard 
postoperative care will be carried out. General care of the patients in the post-anesthetic 
recovery room will be as per our standard practice in terms of oxygen therapy, monitoring 
and assessment of neurological status, pain, nausea and vomiting and degree of sedation. 
Fentanyl 25 mcg i.v will be administered every 5 min to the maximum of 200 mcg to 
maintain a Numeric Pain Score (NRS) < 4 of 10. Morphine or hydromorphone will be used as 
additional analgesia after fentanyl. Nausea and vomiting will be treated with dimenhydrinate 
25-50 mg i.v.  Postoperative pain management will be provided with oral or parenteral opioid 
analgesia as per our standard of care   
2. Study protocol 
 Before general anesthesia, following a 10 minute stabilization period with the patient lying 
supine and breathing at a rate of 12 – 15 breaths per minute, a 5 minute ECG recording will 
be obtained.  ECG data will be downloaded onto a study laptop for later analysis  using 
LabChart Software (ADInstruments,Colarado Springs,CO,USA) to determine HRV values 
(Total power, high frequency, low frequency and low frequency : high frequency ratios).  
Hemodynamic data (heart rate, systolic diastolic and mean blood pressure) and depth of 
anaesthesia (Entropy) will be collected from the preinduction period until skin incision at 1 
minute intervals.  The study will be complete after skin incision.   
Data Collection and Management  
Data Collection  
The following data will be collected: patient demographics, surgical data including position 
technique, number of levels, duration, anaesthetic data including agents used, hemodynamic 
measurements from preinduction to surgical incision, Japanese Orthopaedic Association 
Score. The incidence of hypotension and the number of interventions required to keep mean 
arterial blood pressure above 70 mmHg will be recorded. 

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Data Management  
An electronic data management system will be used. All data will be entered directly on the 
electronic system. Pre specified automated data entry checks will be performed on all entered 
data to prevent the entry of impossible values or the omission of key data fields. All study 
databases will be in the password protected UHN server. Any data containing participant 
identifying details will be stored separately and securely from study documents.  
Analysis 
The incidence of low HRV as indicated by a total power below the normal range of 3466 ms2 
± 1018 ms2 will be determined as well as the incidence of hypotension. We will determine 
the correlation between low HRV, hypotension and the severity of myelopathy as determined 
by the Japanese Orthopaedic Association score. Non-parametric HRV within group data will 
be analysed with the Wilcoxon matched pairs test. Comparisons of non-parametric HRV data 
between groups will be performed using the Mann–Whitney test.  Student t test will be used 
for parametric data. 
Definitions: 
1. Heart rate variability 
The Task Force of the European Society of Cardiology and the North American Society of 
Pacing and Electrophysiology has standardized guidelines for the measurement of heart rate 
variability (14). These recordings will be analysed and power spectrum densities will be 
calculated for total power (TP) which is a measure of heart rate variability. Low frequencies 
(LF), high frequencies (HF) and LF: HF ratio will also be analysed. Based on HRV values, 
two groups will be designated: group L (low HRV) and group N (normal HRV) based on the 
normal range for total power i.e. 3466 ms2 ± 1018 ms2.  
2. Blood Pressure  
Hypotension will be defined as a mean arterial blood pressure less than 70 mmHg lasting 
more than 1 min as measured using arterial line. Non-invasive measurement will be taken if 
arterial line is not available. Based on the blood pressure, patients will be classified into 3 
groups  
Group 1: no episodes of hypotension i.e. mean blood pressures at or above 70 mmHg 

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Group 2: hypotension i.e. means blood pressures below 70 mmHg with minimal intervention 
( <5 interventions) 
Group 3: severe hypotension i.e. means blood pressures below 60 mmHg or MAP<70 mmHg 
needing multiple interventions or infusions of ionotropes. 
All interventions for the treatment of hypotension will be recorded. The interventions include 
phenylephrine 40 mcg, Ephedrine 5 mg, fluid bolus and decrease the anesthetic level 
(inhalational or intravenous).   Infusion of vasopressors and also total vasopressor dose will 
be recorded separately.  
3. Severity of myelopathy 
The Modified Japanese Orthopaedic Association score for severity of myelopathy will be 
used to determine the severity of myelopathy i.e.    
Mild (Modified Japanese Association Score - MJOA) ≥ 15 
Moderate (MJOA = 12) 
Severe (MJOA < 12).  
Sample size 
There is only one previous study that has looked at the autonomic dysfunction in patients 
with cervical myelopathy. They had a sample size of 30 patients and majority of patients had 
either moderate or severe myelopathy.  Currently there is no data on the incidence of low 
HRV in patients with varying severities of cervical myelopathy. We plan to recruit around 
100 patients with various degrees of cervical myelopathy for this study. Around 25 % of 
patients will be mild to moderate myelopathy and rest will be moderate to severe. Hence this 
sample size will provide us the useful information on the true incidence of autonomic 
dysfunction across different severities of myelopathy.  
Ethical Aspects  
Regulatory approval  
Regulatory approval will be sought from the local research ethics board and the study will not 
commence until it is obtained. 
Informed Consent  

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Prior to enrolment potential participants will receive written and verbal information regarding 
the nature and purpose of the study, what participation involves and potential benefit and 
risks. They will be given time to ask questions and it will be emphasized that participation is 
voluntary, that they are free to withdraw from the study at any time and that any decision to 
do so will not affect any treatment they would otherwise receive. Where the participant 
understands and accepts these terms, they will be asked to sign the consent form. 
Privacy and Confidentiality 
The laptop used in the study will contain only de-identified data and that it will be encrypted 
as per UHN policy 1.40.006 Storage, Transport & Destruction of Confidential Information.