Anaesthesia online edition 2013

NEURO PHYSIOLOGICAL BASIS OF THE
GENERALANAESTHETIC TECHNIQUES AND
MECHANISM OF ANAESTHETIC
COMPLICATIONS IN
PERI OPERATIVE PERIOD
BY
PROF. L.N.RAO, M.D., D.A., MAMS
(Prof. NARAHARI RAO LAKKARAJU)
Retired Professor of Anaesthesiology
Ex-President of Indian Society of Anaesthesiology (National)
Retired Commissioner Medical Services
(APVVP), Government of Andhra Pradesh, India
Phone : +91 9247417620
E-mails : 1) nara.rao87@gmail.com
2) rao.r89@gmail.com
2

1st
Edition : Consisting of only Complimentary copies
Published in : April 2012
Edition : 2nd Online Edition 2013
Printers : NEW HYDERABAD PRESS & ARTS
2nd Floor, Jamal Market, Chatta Bazar,
Hyderabad. A.P. India.
Cell: 9700698068, 9052442440
E-mail: mr4id@yahoo.com
3

GENERAL NOTE (ABOUT THE BOOK)
1. Inspiration to write this book (about the results of intensive
investigation into basic principles ofAnaesthesiology starting
from 1964) is purely due to the divine force called
parameswara, Allah the great, Lord Jesus Christ etc.
2. One of the greatest psychological books in the world
(Bhagavat Gita), gives us following message.“Yogasthah kuru
karmani sangam tyaktva Dhanunjaya ……..”
It means all human beings should act without attachment to
their work, because He, (the Lord) has allotted the duties to them.
They should not worry about the success or failure of the work
etc., etc., etc. Hence the authors feel that whether this book
succeeds or it fails to achieve it’s purpose is immaterial. We are
only doing our duty and nothing else.
3. This Edition of the book (which is only for providing
complimentary copies to the anaesthesiologists and others is
dedicated to Mrs. Sethu Laxmi, an anesthesiologist of South India
(In Tamilnadu, India). She was murdered by the relatives of a
patient who died in peri-operative period, (consequent to a peri
anaesthetic complication). May her soul rest in peace.
4. Anaesthetic complications (as indicated by our research) are
due to the patient’s personality factor (P-factor) and
anaesthesiologist has no role in the causation of such
complications (of course, he has to understand (P) factor and
treat the cndition to prevent catastrophy).
5. This book contains the results of research, conducted by Prof.
L.N. Rao and his co-research workers from 1964 onwards.
6. This book is divided into 3 sections.
4

SECTION-I
Deals with neurophysiological factors which produce ideal
operating conditions, (when general anaesthetic techniques are
used). Present concepts (about the fundamentals of the speciality),
and results of research for more than 25 years are dealt with, in
detail (for the purpose of highlighting the results of the research,
the research papers are also printed).
SECTION-II
Deals with patients personality factor (P-Factor) which, in fact,
causes all anaesthetic complications in peri-operative period in
vulnerable patients (this is the results of our research). (The
present concepts of anaesthetic complications are also discussed).
Method of treatment is also suggested.
SECTION III
Contains summary/conclusions/acknowledgments.
7. Author prays god that, information provided, in this book,
forms a nidus for further research in the basic principles in
Anaesthesiology so that the speciality of Anaesthesiology
becomes a broad based and independent speciality (like medicine/
surgery/gynecology etc) as desired by Dr.Haggard at the time of
inauguration of the journal “ANAESTHESIOLOGY” in 1940".
(refer the introduction).
(PROF. L.N. RAO)
5

P R O L O G U E
In the month of March, 2012, results of National Survey of
American Society of Anaesthesiologists concerning the impact
of peri-operative catastrophe, on the life of American
anaesthesiologists concerned were published. They were
published inAnaesth.Analg. (Vol.114) pages 596 to 603. (2012).
More than 500 Anaesthesiologists responded. Results of the
survey is given below:
1. 70% of the members were feeling guilty or serious. They were
still re-living the event (which happened on the day of catastrophe
in peri- operative period).
2. 88% said they required more time to recover emotionally
from the event.
3. 19% accepted that they did not fully recover.
4. 12% thought of changing their career.
Prof. L.N. Rao was in the process of printing this book when
we read the survey on-line. Our 1st
impression (about the survey)
was to express sympathy to the American Society of
Anaesthesiologists who had significant impact on them. After a
while, he also started wondering, why peri-operative catastrophe
should occur at all in a developed and affluent country like U.S.A.
If this survey was carried out in India or in any other developing
country, he could have taken it lightly.
Much later, it dawned on him that, peri-operative catastrophe
could still occur in a highly developed country (with all the
gadgets to monitor every aspect of vital functions of the patient),
because patients in U.S.A. (highly developed country) and India
(a developing country), would react in a similar way, (when they
are being operated under any of the techniques of Anaesthesia).
6

When we think about the catastrophe, it immediately gives us
an impression that some unexpected situation developed in peri-
operative period, and “event managers”, (the surgeon and his
staff and Anaesthesiologist and his staff) could not deal with the
situation. Hence the peri-operative catastrophe occured.
In normal course of events, when a patient is posted for surgery
(minor, major, elective or emergency), every aspect of his/her
vital functions are studied in detail and both the parties (surgical
personnel and anaesthesiology personnel) would be more than
familiar with the patients fitness for surgery and anaesthesia and
probable risk factor would be known to them. Catastrophe in
peri operative period could happen when some unknown factor
works against the patients’ welfare in peri operative period,
because, the anaesthesiologists would not know how to deal with
the unknown factor.
We, in this book, indicated some unknown factors (mostly
concerned with vulnerable patients) which could cause anesthetic
complications in peri-operative period. We strongly feel that a
thorough study about such factors might give the
anaesthesiologists a document to understand such factors and if
treatment is scientifically provided, peri operative catastrophes
may be avoided.
This is only a suggestion and we wish that, those who read
this book get advantage from our experience.
PROF. L.N. RAO
7

C O N T E N T S
SECTION-I
Deals with the research into the fundamentals of
Anaesthesiology, Papers published, results obtained, and the
special research paper (which is based on the results obtained
during research).
Page Nos.
A) Introduction 12
B) Evolution of Anaesthesiology as a speciality. 18
C) The necessity of research into the fundamentals of
Anaesthesiology. 22
D) Research papers published (about fundamentals of
Anaesthesiology) or presented to a gathering of
Anaesthesiologists. 27 - 122
D-1: RAO L.N. et all, increased afferent activity
(vagal, splanchnic etc) leading to hyperventilation
syndrome. Ind. J. Aneasth. 14, 226-232, 1966. 27
D-2: P.S.R.K. HARNATH, A. KRISHNAMOORTHY,
L.N. RAOAND K. SESHGIRI RAO, passage of gallamine
from blood into the liquor space in man and in dog., Brit.
J. Pharmacol., 48, 640-645, 1973. 28
D-3: L.N. RAO AND H. VENKATAKRISHNA BHATT,
Role of Thiopentone, Nitrous oxide, relaxant anaesthesia
in causing the syndrome of post operative paralysis in man.
Derr Anesthetist, 24, 73-77, 1975. 41
D-4: L.N. RAO, T.N. PRAHLAD AND H.
VENKATAKRISHNA BHATT, Central Nervous effects
of hyperventilation-a preliminary report, Ind. J. Medical
Sciences, 23, 665-670, 1969. 55
8

D-5: L.N. RAO AND H. VENKATAKRISHNA BHATT,
Vagal activity in canine: A possible connection to
hyperventilation syndrome. Anesthesia and Analgesia,
49, 351-354, 1970. 66
D-6: L.N. RAO, Patho-Physiological changes during
artificial over ventilation, XXIV congresso societa Italiana.
Anesthesia E Rianimazione (International symposium on
non operative resuscitation and Intensive care) (Book)
(Vol-I) pages 694-702, 1971. 75
D-7: L.N. RAO, Factors affecting awareness in patients
during and after general anesthetic techniques. (Research
paper presented at I.S.A.(National) at its annual conference
at Lakhnow, U.P. India. In December 1910. 98
E) Results of Investigations into the fundamentals of
anesthesiology. 118 -120
F) Special Research Paper (Result of Research for 25 years).
F-1: Letter from InternationalAnesthesia Research Society
(accepting the abstract of the papers) for their annual
conference in 2011. 121
Note: Since visa to visit Canada (Vancouvre) was denied
due to lack of time to process the visa papers Prof. Rao
could not present the paper in their annual conference
in 2011.
Hence, This Research Paper (F2) is Printed in this book for
information to all the anesthesiologists about the contents
of the paper. Titled “NEURO PHYSIOLOGICAL BASIS
OF REVERSIBLE DEPRESSION OF C.N.S. DURING
GENERALANAESTHETIC TECHNIQUES”. 122
9

SECTION – II
RELATIONSHIP OF ANAESTHETIC
COMPLICATIONS WITH PATIENT’S
PERSONALITY FACTOR (P-FACTOR)
A) Commonly observed complications in peri-operative period.
135
B) Interaction with patients pre-operative phase, and post
operative phases. 136
C) Study of concerned literature (about complications in
patients – (Due to their personality). 140
D) Mechanism of the development of “Shock Syndrome”
in some vulnerable patients. (an anaesthetic complication)
144
E) Papers published in journals/books (including those Articles
which were presented at various gatherings of Indian
Society of Anaesthesiologists). 147-232
E-1: L.N. RAO, G. ACHUTARAMAIAH AND K. GURUMOORTHY,
Clinical Signs of Neurogenic stress in surgical patients
during and after an operative procedure. Ind. J. Anesth. 23,
112-116, 1975. 147
E-2: L.N. RAO, The “Syndrome of depressed vital functions
in the post operative period in the man: Role of neuro
humors in its causation”. This is a chapter 29, in the book
“NEUROHUMORAL CORRELATES OF BEHAVIOUR”
Edited by Dr. Sharada Subramanyam. 1977., Thomson
Press (India) Ltd., Publication Division, pages 234-243,
Faridabad, Haryana, India. 159
10

E-3: L.N. RAO AND H. VENKATAKRISHNA BHATT, Stress
response during surgery and anesthesia, International
surgery, 57, 294-298, 1972. 175
E-4: L.N. RAO AND H. VENKATAKRISHNA BHATT, Syndrome
of post operative depression of vital functions in poor risk
patients: its treatment. Int. J. Clinicl. Pharmacol. Toxicology
& Therapy, 19, 18-22, 1981. 189
E-5: L. N. RAO, J.G. CHAR, H. VENKATAKRISHNA BHATT AND
HARI NARAYANA, Psychosomatic factors involved in the
development of bleeding tendency in the post operative
period. A Case report. Ind. J. Anesth. 23, 293-296, 1972. 203
E-6: L.N. RAO, Neurophysiological basis of the syndrome
of post operative depression of vital functions in some
operated patients under general anesthetic techniques.,
(This research paper was presented at Southern Zone
conference at Hyderabad. A.P. India in 2009). (It was a
conference of I.S.A. (National) for South Zone Members.)
211
E-7: L.N. RAO, Neurophysiological factors which lead to
awareness in patients during surgery under general
anesthetic techniques. 222
(This research paper was presented to the I.S.A. Branch
of Andhra Pradesh (India) on the occasion of their annual
conference in the year 2010, NELLORE. A.P., INDIA).
SECTION – III
A) SUMMARY AND CONCLUSION 233
B) ACKNOWLEDGMENTS 237
C) EPILOGUE 238
D) In praise of “IGNORANCE” 239
11

INTRODUCTION
Dr. Howard, W. Haggard in his inaugural address to the
founding fathers of prestigious journal of Anaesthesiology in
1940 (in U.S.A.) clearly outlined the criteria for medical/surgical
and allied specialities. (for the purpose of recognition as an
individual speciality).
He told the organizers of the journal that any speciality
which does not fulfill the three criteria (given below) cannot
claim to be a separate and individual speciality because without
fulfilling these criteria, the persons who are practicing the
speciality are treated only as skilled workers, and they cannot be
considered as specialists, even when they are highly successful
in their work pattern. Following are the criteria for becoming
specialists in independent/broad based specialties, in various
disciplines of medical sciences.
1.1 The persons (workers) practicing such a speciality should
have intellectual as well as manual occupation, when they are
treating the patients like medical/surgical specialties as well as
allied specialties.
1.2 The speciality (to which such individuals belong to) should
have fundamentals which should be easily understood by medical/
surgical fraternity thereby they should get prestige/recognition
from the members of medical/surgical faculty as specialists purely
on the basis of understanding of the fundamentals of their
speciality.
Neurophysiology & Anaesthesia 12

1.3 General public who are ultimate beneficiaries (due to the
use of such a speciality as a part of their treatment) should
understand the fundamentals of the speciality concerned.
2. He clarified his remarks further about the type of
fundamentals of a speciality which is regarded as a satisfactory
one, (if it fits to the following criteria).
2.1 In case of medical speciality common person is told about
the disease process and the type of treatment required by the
patient, for temporary or permanent cure. The common man
easily understands the fundamentals of medical speciality and
he reconciles to the situation even when the patient dies during
medical treatment.
2.2 In a similar way a common person understands the need of
an operation and also he understands the possible complications,
when surgery is done, which rarely ends up in death of the person
during or after the operation. Hence he reconciles to the situation
because he understands the principles of surgery and does not
blame the surgeon, unless gross evidence is presented about the
surgeon’s negligence during surgery or when his care was bad in
the post operative period.
2.3 Anaesthesiologist did not so far develop such a clear picture
about it’s fundamentals so that common man understands it.
Hence the difficulty is in calling it a broad based speciality or
independent speciality.

FUNDAMENTALS OFANAESTHESIOLOGY
(AS ON TODAY) WHEN COMPARED TO
SURGERY OR MEDICAL SPECIALITIES
3.1 Anaesthesiology as a speciality has revolutionized its
techniques in the later half of 20th
Century and unimaginable
situation has now developed in which anaesthetic techniques are
used to operate grossly ill patients with derangements of vital
functions of the body specially due to severe disease of kidneys,
heart, liver and other vital organs. Patients with end stage renal
disease, gross electrolyte imbalance and those patients who are
associated with severe restriction of blood supply to the head or
the heart are successfully anaesthetized. Anaesthesia is
successfully provided to beating heart surgery.
3.2 Anaesthsiologist in the role of consultant to help the
seriously ill patients during and after surgery (and in I.C.U.) is
highly respected consultant and every doctor in the medical
fraternity knows his contribution and respects him for the same.
However situation differs and a confused atmosphere ensues
when a fatality occurs in peri-operative period (1 hr. before
surgery to 48 hours or more after surgery). All persons in the
operating team speculate that technique of anaesthesia could be
one of the main factors in the causation of the fatality (or the
complication in peri-operative period).
3.3 Main reason for such a situation is due to the fact that signs
and symptoms of the abuse of anaesthetic drugs are exactly similar
to the signs and symptoms in a patients who develops anaesthetic
complication in peri-operative period, leading to paralysis and
coma in the operated patients in the post operative period.

3.4 Hospital administrators, judicial officers and other
investigating officers (investigating the cause of complication/
catastrophe occurring in post-operative period), like to exclude
primarily the abuse of anaesthetic drugs as the causatory factor
because patient who develops complication or dies in peri-
operative period, was in comatic condition with paralysis of
respiratory and other muscles with no sensation (of any type)
during the complication/or when fatality occurred.
3.5 Common persons including close relatives of the person
(who died in the peri-operative period) do not understand the
basic fundamentals of anaesthesiology. Since patient was found
to be deeply unconscious, with paralysis of respiratory and other
muscles with analgesia and reflex suppression, present when the
patient died, common man thinks that anaesthetist has used
excessive dose of anaesthetic drugs (abuse of anaesthetic drugs)
and anaesthesiologist’s explanation (about his innocence) would
not be believed by them. In under developed and developing
countries usually 30% to 40% of operating units are in semi urban
and rural areas and they are not equipped with respiratory care
units. Hence, people misunderstands the role of anaesthesiologist,
(in rural areas), when they see the anaesthetist struggling to keep
the patient alive in peri-operative period (by using artificial
ventilation and other supportive measures) and when they see
that surgeon disappears from the scene, only to visit the patient
periodically, they suspect that anaesthetist was the main culprit
because they feel that he abused the anaesthetic drugs and his
negligence has caused the fatality in the patient operated upon
and he is now trying to eliminate excessive anaesthetic drugs
from the body of the affected patient, used by him during the
operation.

3.5 In the well developed countries such a situation does not
cause much concern to the anaesthesiologist because comatic
and paralyzed patients in peri-operative period are routinely
treated in respiratory care units (in post operative ward). Hence
Anaesthesiologists of U.S.A., Canada, Japan, European countries
etc., do not face this problem seriously. In developing and under
developed countries only urban areas have respiratory care units
attached to the operating unit. Hence in most of operating units,
in semi urban and rural areas, anaesthetists are exposed to
harassment and recently one lady anaesthetist in south India was
murdered by patient’s relatives (when the operated patient died
in a comatose condition in peri-operative period).
3.6 Under such circumstances it is necessary that fundamentals
of Anaesthesiology are studied carefully and role of
anaesthesiologist in such a situation is rationalized. By this step
(by rationalizing the fundamentals of anaesthesiology) it becomes
easy for common man to understand the speciality better (similar
to that of medicine and surgery). Once they understand the
fundamental principles, they would not harass the anaesthetic
staff (when fatality occurs in peri-operative period).
3.7 As on today the fundamentals of anaesthesiology (with
regards to the reason for the operated patient to get paralysis and
comatic condition in peri operative period) are confused and
contradictory. Tremendous success of general anaesthetic
techniques is due to the use of skeletomuscular relaxants (with
some adjuvants) but unfortunately anaesthetists explain to the
patient’s relatives (relatives of affected patient who is paralysed

in the post operative period) that skeletomuscular relaxant drugs
which helped the patient earlier by producing ideal operating
conditions are now paralyzing the patient in the post operative
period. Such a blame to the same drug to cause peri operative
complications in the post operative period is unfortunate because
the actual meaning of the statement of the anaesthesiologist would
be understood by the relatives is that the good drug used during
surgery has turned poisonous in the post operative period. Hence
patient’s relatives do not agree with the anaesthetist’s explanation
and they would harass him/her for abuse of the anaesthetic drugs
during operation period.
*****

SECTION-I (B)
EVOLUTION OFANAESTHESIOLOGY
AS A SPECIALITY
1. It appears that many dentists and others tried to invent a
process of pain relief during dental surgery in the middle of 19th
Century (in the year 1846) (or about that time). One dentist
succeeded to show to the world that pain during surgery could
be relieved by using diethyl ether as a pain relieving agent. Many
others also claimed that they had discovered this fact earlier but
failed to get their claim recognized. Some persons in fact,
suffered during such controversy and they were harassed for their
claim. Unfortunately the anaesthesiologist working in semi-urban
and rural areas of many parts of the world even today, are being
harassed for a different reason. He/she is being harassed for
practicing the speciality of anaesthesiology in semi-urban and
rural areas in under developed or developing countries, for his
inability to convince the relatives of patients, (who developed
anaesthetic complication) that anaesthesiologists is innocent and
that such a complication developed in spite of his best efforts to
use the anaesthetic drugs as per rules. He fails to convince the
public that he did not abuse the anaesthetic drugs (because signs
and symptoms of anaesthetic complications are exactly similar
to those which appear in patients who developed complications,
when anaesthetist abused anaesthetic drugs).
2. Next stage of the development of anaesthesiology is the
intervening period that is from the introduction of diethyl ether
(as an anaesthetic drug) to the period when skeletomuscular
relaxant drugs were introduced into the specialty. During this
period, anaesthetic techniques were an artistic way of inducing

pain relief by selected individuals, who could produce anaesthesia
successfully for short operative procedures, by using diethylether
in addition to other anaesthetic drugs (as adjuvants), specially
the drugs like chloroform, Ethylchloride,ACE mixtures (mixture
of chloroform, diethylether with a preservative) etc. During this
period anaesthesia was an art rather than a scientific procedure.
1st
and 2nd
Hyderabad Commissioners reported that Chloroform
could safely be used during surgery, where as most of the
anaesthetists failed to use Chloroform safely because of its cardiac
toxicity. Hence it remained as such an art, practiced by few gifted
individuals until skeletomuscular drugs were introduced into the
speciality of anaesthesiology in the middle of 20th
Century.
3. Important developments took place after 1942 when rapid
expansion of anaesthetic services took place and large number
of persons (known as anaesthetists) (anaesthesiologists or
anaesthetic technicians), who using skeletomuscular relaxants,
(short acting and long acting types of skeletomuscular relaxant
drugs) provided anaesthetic services to various operative
procedures and by the end of 20th
Century anaesthetic services
become so common that operating units in various countries in
the world increased tremendously. Millions of operations under
general anesthetic techniques are carried out every day in the
entire globe. Such a success in the anaesthetic techniques was
possible, only because of the induction of skeletomuscular
relaxants into the speciality of anaesthesiology in the middle of
20th
Century.

4. As stated earlier, from the date of introduction of
skeletomuscular relaxants into anaesthetic practice, and upto this
day billions of operations were carried out in patients whose age
group ranged from few hours of life to 90 years of age or more,
(most of them successfully). However, in small number of
operated patients anaesthetic complications started developing
in peri operative period (One hour before surgery to 48 hours or
more in post operative period). During anaesthetic complications
patients continued to be unconscious with depression of vital
functions (paralysis of all muscles etc.), in addition to the
occurrence of coma in the affected patient. Aanesthesiologits
became a confused lot of persons. They started explaining the
cause of the post operative paralysis in operated patients to be
associated with the continued action of skeletomuscular relaxant
drugs on C.N.S. In the post operative period. Hence terms like
“central nervous action of curare”, “clinical syndrome of
incomplete reversal”, and “a stage of apparent recurarization”
were used to describe the anaesthetic complications which
develops in the peri operative period and continues into the post
operative period. Some others speculated that effect of antidote
to curare (drugs like neostigmine or its equivalent drugs) wears
off prematurely, leaving the skeletomuscular relaxant drugs to
act unopposed on CNS thereby leading to the paralytic condition
of the patient under comatose conditions. At this stage, it is
necessary to point out that anaesthesiologists even now believe
that skeletomuscular relaxant drugs not only act on the periphery
(on neuro muscular junction), producing paralysis of respiratory
and other muscles but also act on CNS causing analgesia,
unawareness during surgery, reflex suppression etc.,

thereby causing satisfactory conditions for safe surgery. They
(anaesthesiologists) feel that if anaesthetic complication develops
in peri operative period, it was due to the continued action of
skeletomuscular drug on CNS in the post operative period and
ventilatory support (as well as support of other vital functions)
in the post operative ward with ventilator therapy was enough to
treat such complications. This explanation and satisfaction with
ventilatory support to the affected patients appear to be doing
injustice to the speciality and to the anaesthesiologists because
30% to 40% of operative units in semi urban and rural areas of
the world (specially in under developed and developing world)
do not have respiratory care units attached to post operative ward.
When a patient is paralyzed in post operative ward in rural areas
anaesthesiologist has to struggles to keep the patient alive by
squeezing the ambu bag or any other device available for keeping
up satisfactory ventilatory function of the affected patient (in
addition to other supportive measures to keep him alive). Such
an act, on the part of anaesthetist therefore appears to the patient’s
relatives that anesthesiologist was irresponsible and had abused
the anaesthetic drugs during anaesthetic procedure, and caused
the anaesthetic complication in the peri operative period. Such a
situation undermines the image of the anaesthesiologist
concerned and he is harassed by the patient’s relatives.
5. Author therefore feel that research on fundamentals of
Anaesthesiology has to be vigorous so that anaesthesiologist
could claim to be specialist and not a skilled technician.
*****

SECTION-I (C)
NECESSITY OF RESEARCH INTO THE
FUNDAMENTALS OF THE SPECIALITY OF
ANAESTHESIOLOGY
1. As stated earlier (in the introduction) the fundamentals of
Anaesthesiology (if at all any fundamental principles exist for
the speciality) are not clear enough to be understood by doctor
fraternity (surgeons, physicians etc) and the common man, who
is the ultimate beneficiary, of surgery carried out on them under
regional or general anaesthetic techniques. He does not
understand it’s basic principles and it appears that main reason
for non development of the clarity of fundamentals of anaesthesia
appears to be the financial gains (for anaesthetizing patients),
with the help of skeletomuscular relaxants and getting away with
the consequences like post operative paralysis and comatic
condition in the post operative period by ventilating him (with
other support to vial functions) for 4 to 10 hours or more and
send the patient back to his original ward (after he is alright).
This statement may appear harsh but it appears to be true because
many changes in the techniques of anaesthesia were introduced
to make anaesthetic procedures convenient and safe, when
operations are carried out in sitting position, head low position,
lithotomy position, prone position etc. However, no
anaesthesiologist carried out research to find out the main basis
of various factors which produced ideal operating conditions and
nobody tried to find out the reason why some operated patients
develope coma and paralysis in the post operative period. This
situation (lack of research to find out the mechanism which

produced ideal operating conditions) (as well as various post
operative complication) could be due to the speculation by the
anaesthesiologist that skeletomuscular relaxant drugs act on CNS
to cause areflexia, analgesia, reflex relaxation of diaphragm and
other respiratory muscles etc., including occasional complication
during surgery and in the post operative period. Because of such
a speculation they blame the skeletomuscular relaxant drugs for
their prolonged action on CNS, (for causing post operative
depression of vital functions) when an occasional (operated)
patient fails to recover from anaesthesia for 4 to 10 hours or
more in the post operative period. Scientifically their argument
is not convincing because it is now known that skeletomuscular
relaxant drugs do not act on CNS. Hence common man believes
that anaesthesiologist has abused the anaesthetic drugs (during
the procedure of anaesthesia) and hence, the patient developed
coma and paralysis in the post operative period.
2. Awareness during surgery even when anaesthetic technique
is continuing, is another anaesthetic complication for which so
far no scientific explanation is available. At present
anaesthesiologist speculates that awareness during surgery was
due to light stage of anaesthesia and vigorous titration of
anaesthetic drugs would prevent the incidence of awareness
during surgery. They feel that light stage of anaesthesia was due
to carelessness of anaesthesiologist (who relaxed in his duties
during anaesthetic procedure). In under developed and
developing countries, patients (who claim to be aware during
surgery) are approaching family courts (its public grievance cell)
to award compensation to the affected patients who claim to be

affected functionally by awareness during surgery (such patients
express dissatisfaction with the operative procedure thinking that
operation was not satisfactorily done and their inability to work
efficiently in the post surgical period was due to the ineffective
surgery).
3. Some patients are observed to loose their memory
temporarily and in some rare cases, such a loss of memory is
prolonged for few weeks. During this period, they behave
abnormally and act as if they are different personalities in the
post operative period.
4. Apart from such complications, analysis of the currently
believed fundamentals lead to the following un-answered
questions about the very basis of the speciality of anaesthesiology.
(a) What is the mechanism by which a patient undergoing
operative procedure (under general anaesthetic technique) is
unaware during surgery and anaesthesia. Anaesthesiologists
believe that loss of proprioception (due to the paralysis of skeletal
and respiratory muscles) leads to a situation in which CNS is
deprived of proprioception (roughly 15% to 20% of all peripheral
impulses), thereby depressing the activity of CNS. They,
therefore speculate that unconsciousness ensues, purely due to
the loss of proprioception. However, their speculation cannot be
true because tactile sensation, sensation from bones and joints,
sensation from the viscera of abdomen, chest, head and neck etc
is still intact and sensation is transmitted through autonomic
nervous system (which is about 80% of the total sensation of the

body). Such sensory information reaches midbrain and the giant
cells of ascending reticulo alerting system (ARS) in the midbrain
receives such sensory information to cause intense activity of
various neurons of CNS. Hence CNS cannot be depressed due
to the lack of proprioception only. (unless ARS is depressed,
cerebral (cortical) cells are active and keep the other neurons of
various lobes active so that functions of CNS are not depressed.
(b) Consciousness in an individual depends on the activity of
cerebral cortical neurons in CNS, and the activity of cortical
neurons depend upon ascending reticulo alerting system (ARS).
Activity of ARS depends upon the volley of peripheral afferents
(which are mentioned in para (a)); The (Axons of ARS) directly
arbourise (connect) with the dendrides (inter connecting neurons),
of cerebral cortex so that during the activity of ARS, Acetyl
Choline (and probably other neuro humors) are released.
(Acetylcholine is the main transmitter of Cholinergic system).
As long as ARS is intact and is receiving information from
periphery, cerebral cortical neurons would be active to keep up
the consciousness of the individual. Hence it is necessary to
find out under what conditions, ARS stops its activity (and also
stops producing cholinergic transmitting hormones), to produce
unawareness during surgery under general anaesthetic techniques.
(c) What is the cause of the development of areflexia,
unawareness during surgery, analgesia and reflex relaxation of
respiratory muscles. (including diaphragm)

(d) Why some patients develop behavioural changes in post
anaesthetic period, in addition to the loss of memory in the
immediate/delayed post anaesthetic period.
(e) What is the mechanism, which causes “shock syndrome”
in some patients during spinal or general anaesthetic techniques
in peri operative period. (during or after surgery, which is the
main anaesthetic complication in some patients). (refer the article
“Clinical Signs of neurogenic stress” in Section II”. Page - 136
5. Our research team therefore looked into all these aspects
of the fundamentals of the speciality of anaesthesiology, which
includes the reason for some vulnerable patients to get “shock
syndrome” during all forms of anaesthetic techniques.
*****

RESEARCH PAPER
RAO L.N., RAMA RAO K.R.
AND
SQ. LEADER BHALLA
“Increased afferent activity
(vagal, splanchnic etc) leading to hyperventilation syndrome
during surgery under general anaesthesia”
Indian Journal of Anaesthesia, 1966, Vol. 14, Pages 226-232
NOTE: REPRINT NOT AVAILABLE
In this Article Prof. L.N. Rao in 1966, after intense study of
Neurophysiology put forward the theory that vagus, (Due to
receptor activity during IPPV) causes ideal
operating conditions during G.A.
D1 27

RESEARCH PAPER
PASSAGE OF GALLAMINE FROM
BLOOD INTO THE LIQUOR SPACE
IN MAN AND IN DOG
BY:
PROF. P.S.R.K. HARNATH, A. KRISHNAMURTHY,
PROF. L.N. RAO, AND K. KRISHNAMURTHY RAO
KURNOOL (P.O.) A.P. INDIA
British Journal of Pharmacology
1973, 48, 640-645
SPECIAL NOTE BY PROF. L.N. RAO
Please see Table-I of the paper which gives the correct picture of
concentration of gallamine in patients at the time of recovery. It is
obvious that 10 to 25% or more of gallamine concentration (when
compared to the paralysing concentration) is present at the time of
recovery of patient from anaesthesia.
D2 28

IN MAN AND IN DOG
BY:
P.S.R.K. HARNATH, A. KRISHNAMURTHY,
L.N. RAO, AND K. KRISHNAMURTHY RAO
Reprinted British Journal of Pharmacology
August 1973, Vol. 48, No. 4, p-640-645
COPYRIGHT © 1973
BRITISH JOURNAL OF PHARMACOLOGY
ALL RIGHTS REPRODUCTIN OF THIS REPRINT ARE RESERVED
IN ALL COUNTRIES OF THE WORLD
4 LITTLE ESSEX STREET, W.C.2
MACMILLAN JOURNALS LIMITED
LONDON
D2 29

IN MAN AND IN DOG
P.S.R.K. HARANATH,A. KRISHNAMURTY, L.N. RAO AND K. SESHAGIRIRIRAO
Department of Pharmacology and Anaesthesiology, Kurnool Medical
College, Kurnool 518002, A.P., India.
SUMMARY:
1. Patients receiving an intravenous injection of 2-3.8 mg/kg
gallamine showed gallamine-like activity in their lumbar
c.s.f. collected 15 and 70-100 min after the injection. The
activity assayed on acetylcholine contractions of frog rectus
muscle was equivalent to between 0.1 and 0.75 µg/ml
gallamine.
2. In anaesthetized dogs an intravenous injection as well as
an intravenous infusion of gallamine led to the appearance
of gallamine-like activity in the cisternal c.s.f. and, on
perfusion of the cerebral ventricles, in the effluent collected
from the cisterna magna.
3. After an intravenous injection of 1 mg/kg the activity in the
cisternal c.s.f. corresponded to between 0.2 and 1 µg/ml and
in the effluent to between 130 and 175 ng/min during the
first 15 min perfusion and then declined.
4. On intravenous infusion of gallamine at a rate of 10
(µg/kg)/min for 2 h the cisternal c.s.f. showed a uniform of
gallamine-like activity corresponding to between 0.4 and
0.67 µg/ml during the infusion. In the cisternal effluent the
gallamine-like acitivity rose initially to between 20 and
90 ng/min but declined before the infusion was ended.
Neurophysiology & Anaesthesia D2 - 30

5. The intravenous injection of gallamine caused respiratory
paralysis but did not affect arterial blood pressure; it s
intravenous infusion caused no respiratory paralysis and did
not affet arterial blood pressure.
INTRODUCTION:
Muscle relaxants like tubocurarine and gallamine, which are
quaternary ammonium compouinds, are expected either not to
pass from blood into cerebrospinal fluid (c.s.f.) or to do so with
difficulty. Previous reports on the passage of muscle relaxants
from blood into c.s.f. have been contradictory. The passage of
tubocurarine into c.s.f. was reported by Mahfouz (1949) and
Dal Santo (1964). but Cohen (1963) did not detect tubocurarine
in the c.s.f. in animal and human experiments after intravenous
administration of tubocurarine. Recently definite evidence was
obtained in man and dog for its passage into the liquor space.
The lumbar c.s.f. of patients who had received an intravenous
injection of tubocurarine was found to exert tubocurarine-like
activity when assayed on the frog rectus muscle contracted by
acetycholine. Similary, tubocurarine-like acitivity was detected
in thecisternal c.s.f. as well as in the effluent collected during
perfusion of different parts of the liquor space after an
intravenous injection and during an intravenous infusion of
tubocurarine (Devasankaraiah Haranath & Krishnaurty, 1973).
On the other hand, Dal Santo (1972) who studied the urinary
excretion and the distribution of labelled (14
C)-gallamine inected
intravenously into anaesthetized dogs, found no significant
radioactivity in the c.s.f.
In the present experiments the passage of gallamine from
blood into the liquor space was studied in man and dogs with

the methods used by Devasankaraiah et al. (1973) in their
experiments with tubocurarine. In patients, lumbar c.s.f. was
examined for gallamine-like activity after intravenous injection
of gallamine, and in anaesthetized dogs cisternal c.s.f. and
cisternal effluent collected during persufion of the cerebral
ventricles were examined for such activity after intravenous
injection or during intravenous infusion of gallamine.
METHODS:
Clinical procedures
Six male patients (33.1 to 50 kg), who were schedule for
surgery, were given atropine 0.6 mg as preanaesthetic medi-
cation. Anaesthesia was induced by intravenous
thiopentobarbitone sodium (150 to 250 mg). Gallamine (2 to
3.8 mg/kg) was then injected intravenously. As it produced
immediate respiratory arrest the trachea was intubated, con-
nected to a Boyle’s apparatus and controlled respiration was
applied. Anaesthesia was maintained with nitrous oxide and
oxygen. Supplemental doses of gallamine were administered
when necessary. Three samples are obtained by the lumbar
puncture, one before and two at different times after the in-
jection of gallamine. At the same time blood samples were
obtained in syringes containing 0.1 ml of heparin 5%.
Animal experiments:
Dogs weighing 6-16 kg were used. They were anaesthetized
with intravenous pentobarbitone sodium (30 mg/kg). The ex-
perimental procedures for recording arterial blood pressure and
respiration were the same as those described by Devasankaraiah
et al. (1973). The cerebral ventricles were perfused from alateral
ventricle to cisterna magna according to the method described
for casts by Bhattacharya & Feldberg (1958). The rate of

perfusion was 0.1 ml/mi, and the perfusion fluid was artificial
c.s.f. of the following composition (g/litre): NaCI 8.1; KCI 0.25;
CaC12
0.14; MgC12
0.11; NaHCO3
1.76; NaH2
PO4
0.072; urea
0.13; glucose 0.61. Gallamine solutions were either injected in-
travenously or infused intravenously at a rate of 0.4 ml/min with
a slow infusion pump.
BIOASSAY:
The samples of c.s.f. effluent or plasma were assayed bio-
logically for gallamine-like activity on acetylcholine-induced
contractions of frog rectus muscle as described for curare by
Burn (1952) and with the modification given by Devasankaraiah
et al. (1973). The preparation was usually sensitive to 0.5 µg of
gallamine. Control samples of c.s.f. and of plasma potentiated
the acetylcholine-induced contractions of the frog rectus muscle.
As the potentiating effect of plasma was strong, the values ob-
tained for the gallamine for the gallamine concentrations of
plasma are probably too low.
DRUGS:
In clinical administration Flaxedil brand of gallamine solu-
tions in vials (40 mg/ml) was used. For the experiments on dogs,
gallamine triethiodide (Flasedil) supplied through the courtesy
of May & Baker was used.
RESULTS:
Clinical Studies
As shown in Table 1, samples of lumbar c.s.f. withdrawn from
six patients during an operation 15 min after an intravenous in-
jection of 2 to 3.8 mg/kg gallamine exerted gallamine-like ac-
tivity on the frog rectus muscle equivalent to between 0.15 and

0.6 µg/ml. The activity of a second sample withdrawn at the end
of the operation 70 to 110 min after the injection was about the
same whether it had been necessary during this time to give
additonal injections of smaller amounts of gallamine or not. The
Table aslo shows that the gallamine concentration in plasma
collected 15 min after the injection varied widely from patient
to patient (between) 0.6 and 40 µg/ml) and decreased in plasma
collected 70 to 110 min after the injection.
Table 1. Gallamine-like effect (expressed in terms of gallamine µg/ml) in
lumbar c.s.f. collected from six male patients after its intraenous injection
Patient . Weight Dose of gallamine Gallamine conc. (µg/ml)
No. (Kg.) given (mg/kg) 15 min 70-110 min
1. 50.0 3.2 0.31 (0.6)
2. 36.3 3.3 0.6 (40.0) 0.75 (8.0)
3. 33.1 3.8 0.15 (2.5) 0.2
4. 40.0 3.0 0.5 (10.0)
5. 42.7 2.8 + 0.2 (20.0) 0.1 (3.3)
0.9 at 25’
0.9 at 75’
6. 40.0 2.0 + 0.3 (15.0) 0.35 (13.5)
2.0 at 15’
The figures in brackets refer to plasma concentration of gallamine (µg/ml)
Experiments on dogs:
Intravenous injection of gallamine:
An intravenous injection of gallamine (1 mg/kg) produced
immediate respiratory arrest and artifical ventilation was applied.
Respiration began to recover within 10 min but artificial
ventilation was continued for 40 to 50 min to ensure adequate
oxygenation. The arterial blood pressure did not chane during
this time.

As seen from Table 2 and 3, the gallamine concentration in
plasma was maximal 15 min after the injection when it was
between 0.7 and 6.7 µg/ml. It then declined. Table 2 gives the
gallamine-like acitivity of samples showed gallamine-like
acivity corresponding to between 0.2 and 1 µg/ml. The peak
concentration was obtained either in the 30 or in the 60 min
sample.
Table 2. Concentration of gallamine in consecutive samples of cisternal
c.s.f. and plasma of anaesthetized dogs after intravenous inection of
1 mg/kg gallamine.
Gallamine concentration (µg/ml)
Expt. Weight c.s.f. plasma
No. (Kg.)
15 min 30 min 60 min 15 min 30 min 60
min 1. 6 0.33 0.4 0.2
1.67
2. 12 04 0.33 1.0 3.0 0.5 nil
3. 13 0.33 056 033 075 0.75 0.3
In Expt. 2 of the Table, a fourth sample of c.s.f. (not includeed
in the Table) was collected 120 min after the injection. It no
longer exerted gallamine-like acitivity although a plasma
sample collected at this time showed gallamine acivity
corresponding to 1 µg/ml. Table 3 give the gallamine-like
acivity in the cisternal effluent colected during perfusion of the
cerebral ventricles. In all three experiments the output of
gallamine was maximal in the sample collected during the first
15 min after the gallamine injection when it was between 130
and 175 ng/min and declined to between 27 and 68 ng/min
in the second 15 min sample, but in the third 30 min
sample a further decline occurred in only one of the three
experiments.

TABLE 3. Output of gallamine in ng/min in cisternal effluent on perfu-
sion from lateral ventricle, and its plasma concentration in anaethetized
dogs after intravenous injetion of 1 mg/kg gallamine
Expt. Weight Gallamine output in effluent (ng/min) Plasma gallamine concn.
(µg/ml)
No. (Kg.) 0-15 min 16-30 min 31-60 min 15 min 30 min 60 min
4. 10 130 27 27 0.7 0.5 0.4
2. 10 175 63 67 1.4 1.0 0.7
3. 14 130 68 18 6.7 2.0 1.33
Intraenous infusion of gallamine:
A continuous intravenous infusion of gallamine for 2 h at a
rate of 10 (µg/kg)/ min din not affet arterial blood pressure nor
did it depress respiration; there was in fact some slight increase
in the respiratory amplitude as illustrated in Figure 1.
As seen from the results of Tables 4 and 5, the concentration
of gallamine in samples of plasma collected during the 2 h infu-
sion varied greatly from dog to dog. Larger dogs had hihger
plasma gallamine concentration than smaller dogs, proportional
to the total infused per minute. In the same dog, the plasma

Fig. 1. Recrod of respiration and blood pressure from a dog (6 kg) under
pentobarb itone anaesthesia. At the black dot gallamine i.v. infusion at 10
(µg/kg)/min was started. Records taken at the time noted under each panel
after commencement of infusion. (Time 1 min.)
Table 4. Concentration of gallamine in consecutive half hourly or hourly
samples of cisternal c.s.f. and plasma obtained from anaesthetized dogs
during continuous instravenous infusion of 10 (µg/kg)/min gallamine.
Gallamine concentration (µg/ml)
Expt. Weight c.s.f. plasma
No. (Kg.)
30 min 60 min 120 min 30 min 60 min 120 min
7 12.0 0.5 0.63 0.4 0.5 0.4
8 12.7 0.5 0.5 0.6 0.8 0.75 0.25
9 16.0 0.5 0.5 0.67 1.8 1.5 1.25
concentration of gallamine showed some fluctuations in the
samples collected different times of the infusion being higher
initially in three, and lower in two of the dogs than at the end of
the infusion. During the infusion gallamine-like activity appeared
in the cisternal c.s.f.As shown in Table 4, the activity was nearly
the same in all three dogs and in the samples collected 30, 60 or
120 min after the beginning of the gallamine infusion. As seen
from the results of Table 5, gallamine-like acitivity appeared
also in the cisternal effluent when the cerebral ventricles were
perfused during the infusion. The output of gallamine ranged
from 20 to 90 ng/min and declined during the 2 h infusion.
TABLE 5. Output of gallamine n ng/min in cisternal effluent on perfu-
sion from lateral ventricle of anaesthetized dogs during intravenous
infusion of gallamine, 10 (µg/kg)/min

Expt. Weight Gallamine output in Plasma gallamine concn.
effluent (ng/min) (µg/ml)
No. (Kg.) 0-15min 16-30min 31-60min 61-120min 15min 30min 60min 120min
10. 7.5 90 40 40 30 1.0 0.75 1.0 0.68
11. 6.0 90 60 54 34 0.5 0.5 0.67 1.012
12. 15.0 25 55 20 30 2.0 2.9 3.3 3.3
DISCUSSION:
The present experiments show that after the intravenous
administration of gallamine the lumbar c.s.f. obtained from
anaesthetized patients and the cisternal c.s.f. obatined from
anaesthetized dogs or, on perfusion of their cerebral ventricles,
the cisternal effluent exerted gallamine-like acitivity when tested
o the acetylcholine-induced contraction of the frog rectus muscle.
These findings agree with the results obtained by Devasankaraiah
et al. (1973) in similar studies with tubocurarine and suggest
that gallamine itself, or if not, a derivative of it which has re-
tained its biological activity, passed from the blood into the li-
quor space. The appearance of gallamine-like activity in the c.s.f.
of patients was obtained with doses of gallamine (2-3.8 mg/kg)
which are of the order (3.5 mg/kg) used in clinical anaesthetic
practice and are therefore of clinical interest.
It is not possible from the data available to give the reason
why Dal Santo (1972) in his studies in anaesthetized dogs onthe
urinary excretion and distribution in the body of (14C)-gallamine
could not detect any radioactivity in the cisternal c.s.f. after an
intravenous injection of a trace dose of 50 µCi gallamine
equivalent to 50x106 counts/min, particularly since in a previ-
ous similar study (1964) with (14C)-dimethy1-(+)-tubocurarine
injected intravenously in a trace dose equivalent to 25x106
counts/ min he could detect up to 20x10-5 of the injected amount
in the cisternal c.s.f. In his experiments with labelled gallamine
about 7 samples of c.s.f. were collected in 7 hours. In the present
experiments gallamine-like acivity was detected only in those

samples of c.s.f. collected during the first hour after a single
intravenous injection of gallamine, because a sample collected
after the second hour no longer exerted such activity. It is
possible that in the experiments of Dal Santo collection of the
samples of c.s.f. started too late after the injection of the
labelled gallamine, at a time when the gallamine that had passed
into the c.s.f. had disappeared, or if a derivative, had
passed into the c.s.f. that it was one which did not contain
radio-active carbon.
In the past, the passage of quaternary ammonium compounds
across the blood-c.s.f. barrier has been doubtful. The present
findings with gallamine and the earlier ones with tubocurarine
by Mahfouz (1949) Dal Santo (1964) and Devasankaraiah et al.
(1973) however suggest that this barrier is not absolute and that
small amounts of these muscle relaxants pass into the c.s.f.
Neither hypoxia nor a fall in blood pressure, nor histamine
release accounts for this passage, because in the experiments on
dogs with intravenous infusion of gallamine the appearance of
gallamine-like activity in the c.s.f., or in the effluent on perfu-
sion of the cerebral ventricles, occurred without changes in
respiration or blood pressure and gallamine, unlike (+)-
tubocurarine, does not release histamine.
The finding that 15 min after an intravenous injection of
gallamine, gallamine-like activity was detected in the lumbar
c.s.f. of patients and in the cisternal c.s.f. of dogs, sugest that
the gallamine passes equally well into the spinal and cerebral
c.s.f. space. On the other hand, the gallamine-like activity found
in the cisternal c.s.f. may well have passed, partly at least, from
the cerebral ventricles into the subarachnoid space. This con-
clusion is based on the finding that on perfusion of the cerebral
ventricles the highest values for gallamine-like activity were
found in the first 15 min samples after an intravenous injection
of gallamine and decreased steeply in the second 15 min sample,
whereas in the cisternal c.s.f. the highest values were found not

in the first sample collected 15 min but in the second one
collected 30 min after the injection, or there was a slight
decrease only in the second sample.
The concentration of gallamine in c.s.f. was always less than
in plasma, but a fixed ratio of the two concentrations cannot be
given from the results obtained. This is due to the fact that on
account of the strong potentiating effect which plasma exerts
on the acetylcholine-induced contractions of the frog rectus
muscle the values obtained for plasma concentrations were too
low and did not give the true concentrations of gallamine
in plasma.
This work was supported by a grant in aid frm the Indian
Council of Medical Research, which is gratefully acknowledged.
REFERENCES:
BHATTACHARYA, B.K. & FELDBERG, W. (1958). Perfusion of
cerebral ventricles: effects of drugs on outflow from cisterna and aqueduct.
Br. J. Pharmac. Chemother., 13, 156-162.
BURN, J.H. (1952). Practical Pharmacology, pp. 5-7-. Oxford: Blackwell.
COHEN, E.N. (1963). Blood-brain barrier to d-tubocurarine.
J. Pharmacol., 141, 356-362.
DAL SANTO, G. (1964). Kinetics of distribution of radioactive-labelled
muscle relaxants. I. Investigation with [14C]-dimethyl tubocurarine.
Anaesthesiology, 25, 788-800.
DAL SNATO, G. (1972). Kinetics of ditribution of radioactive labelled
muscle relaxants. IV. Urinary elimination of single dose of [14C]-gallamine.
Br. J. Anaesth., 44, 321-329.
DEVASNAKARAIAH, G., HARANATH, P.S.R.K. & KRISHNAMURTY,
A. (9173). Passage of intravenously administered tubocurarine into the
liquor space in man and dog. Br. J. Pharmac., 47, 787-798.
MAHFOUZ, M. (1949). The fate of tubocurarine in the body.
Br. J. Pharmac. Chemother., 4, 295-303.
(Received August 10, 1972)
*****

RESEARCH PAPER
“ROLE OF THIOPENTONE, NITROUS OXIDE
AND RELAXANT ANAESTHESIA IN CAUSING
THE SYNDROME OF POST-OPERATIVE PA-
RALYSIS IN MAN”
BY:
PROF. L. N. RAO MD, DA
AND
DR. H.VENKATAKRISHNA BHATT, PH.D
KURNOOL (PO), A.P. INDIA
DERR ANAESTHETIST
Vol. 24, 1975, 75-77
D3 41

THE SYNDROME OF POST-OPERATIVE PA-
RALYSIS IN MAN”
BY:
PROF. L.N. RAO, M.D., DA
AND
DR. H. VENKATAKRISHNA BHATT, PH.D.
DERR ANAESTHETIST,
Vol 24, 1975, 75-77
A Reprint from
Derr Anaesthetist, Vol. 24, 1975, Pages 75-77
42

THE SYNDROME OF POST-OPERATIVE
PARALYSIS IN MAN”
L.N. Rao and H. Venkatakrishna-Bhatt**
Departments of Anaesthesiology and Pharmacology, Kurnool Medical
College, Kurnool 518002 (Andhra Pradesh), India
Received: November 6, 1973
--------------------------------------------------------------------------
* This investigation was supported by a research grant from State Medical Research
Council of Government of Andhra Pradesh, Hyderabad 500 029. (India).
** At present working as Research Officer, Division of Medical and Industrial
Toxicology, National Institute of Occupational Health, Asarva, Opposite to New
Mental Hospital, Ahmedabad 380016 (Gujarat) India.
---------------------------------------------------------------------------
Summary: Forty-seven patients undergoing elective/
emergency surgery were investigated for the recovery pattern
by numerically scoring the state of consciousness, skeletomus-
cular tone, respiration and blood pressure after the neuromsucular
transmission at the level of thenar muscles returned to normalcy.
Anaethesia in them consisted of thiopentone induction and pas-
sive ventilation with nitrous oxide and oxygen mixtures (4½:2½l)
with consequent changes in PaCO2
(22.0 to 90 mm Hg) after
using 0.43 to 0.68 mg/kg d-tubocurarine or 2.3 to 3.8 mg/kg
gallamine. In this series twelve patients were selected at random
and biological assay of cerebrospinal fluid in them for curare/
gallamine after 15 min anaesthesia and at the recovery phase
was carried out on frog rectus muscle. All the patients recov-
ered satisfactorily and did not present clinical signs of de-
pression of central nervous system, even though twelve pa-
tients, in whom concentration of d’tc/gallamine was moni-
tored at 15 mts. of its, IV administration and later again moni-
tored at the end of anaesthesia revealed that d’tc or gallamine
concentration (at the time of their recovery from anaesthesia)

was still high in plasma and C.S.F. Inspite of containing signifi-
cant quantity (10% to 25%) or more of paralysing dose of d’tc
or gallamine, such patients recovered normally, these 12 patients
had the presene of curare (ranging from 0.05 to 0.33 µg/ml) and
gallamine (from 0.1 to 0.75 µg/ml) in the cerebrospinal fluid.
this study therefore indicates that thiopentone, nitrous oxide and
relaxant type of anaesthesia does not cause clinical syndrome of
post-operative paralysis even when such a technique of
anaesthesia is administered in poor-risk patients with associated
changes in acid-base balance, electrolytes etc. Significant quan-
tities of skeletomsucular relaxant drug (used during the tech-
nique) when found in cerebrospinal fluid and in plasma (refer
table-I of the research paper “Passage of gallamine from blood
to the liquor space in man & in dog” printed in this book), did
not induce post-operative paralysis in man.
*****
Some patients present a clinical syndrome of post-operative
paralysis [1] which is presumed to be due to electrolyte
imbalance, metabolic acidosis, antibiotic therapy, hypercapnia
and hypo-porteinaemia (due to prolongation of neuromuscular
block in poor-risk patients) [2-8]. More recently it has been stated
that when a high concentration of the relaxant drug is available
at the mynoeural junction at the end of an anaesthetic ptocedure
neuromuscular block continues inspite of administration of neo-
stigmine [9] and that the action of muscle relaxant could outlast
that of neostigmine [10]. However it is observed that
neuromsucular transmission need not be depressed on all occa-
sions in patients in whom the syndrome of post-operative pa-
ralysis characterized by depressed level of consciousness,
hyotonia of skeletal muscles and apnoea is present in the post-
operative period [11,13]. Moreover patients who are the
potential subjects for developing such a syndrome in the

postosugrical period (such as intestinal obstruction of some du-
ration) cannot be experimnetally made to manifest the same by
the administration of relaxant drugs preopoeratively [12]. It is
also observed that the level of consciousness, skeletomuscular
tone and respiratory efficiency could be improved by dehydra-
tion therapy [11,14]. These observations, therefore, sugest that
depression of the level of consciousness, skeletomuscular tone
and respiration in the postanaesthetic phase need not be due to
peripheral factors only (cntinued or abnromal action of drugs at
the myoneural junction), and that depression of the central ner-
vous system could coexist in them. Foster [15] postulated such
a possibility in some patients in whom hypokalaemia was present.
However, definite proof that a low serum potassium level can
casue depression of the central nervous system in such situa-
tions is lacking. Since recent studies reveal that commonly used
skeletomuscular relaxant drugs penetrate the blood -cerebrospi-
nal fluid barrier freely during anaesthesia in man [16,17], prob-
ably due to a change of the blood-brain barrier during hyperven-
tilation techniques [18], it is interesting to study the role of the
anaesthetic technique itself in contributing to postoperative de-
pression of the level of consciousness, keletomusucular tone and
respiration etc.
MATERIALS AND METHODS
Forty-seven adult patients of both sexes undergoing various
elective or mergency surgical procedures were studied for the
pattern of recovery from balanced anaesthetic proceduresAmodi-
fication of the postanaesthetic score chart devised by Aldrete
[19] was used. This enables a quantitative estimation to be made
of the state of skeltomuscular tone, consciousness, respiratory
efficiency etc. The pateints were anaestehtized with 250 to 400
mg thiopentone (2.5% - May & Baker, India). Orotracheal intu-
bation was facilitated by injection of a single dose of tubocurarine

0.43 to 0.68 mg/kg (Burroughs Wellcome India) or gallamine
2.0 to 3.8mg/kg (May & Baker, India). As a premeidation, only
atropine sulphate 0.6 mg (E. Merck) was intravenously admin-
istered prior to thiopentone. Passive manual ventilation was
maintained with a mixture of oxygen 2.51/min and nitrous ox-
ide 4.51/min using a closed circuit Boyle apparatus (Indian Oxy-
gen Company). By inclusion or exclusion of the Mark III soda-
lime absorber, and by regulation of the tidal volume, force and
rate of ventilation, PaCO2 levels were adjusted to lie between
22.0 and 90.0 mm Hg. After 45 to 90 min of anaesthesia (asso-
ciated withthe anticipated time of surgery), venous blood was
drawn from wrist veins (after warming the writst to 40º C with
hot packs) into paraffin and the pH immediately estimated. The
carbon-dioxide content was estimated with Van Slyke’s
manormetric apparatus (Gallenkepm, London) and PaCO2 was
calculated by solving the Henderson Hasselbalch equation, as
suggested by Woolmer [20]. Twelve patients were selected at
random from the series and curare/gallamine-like activity in
blood and cerebrospinal fluid was biologically assayed by the
method of Burn [21]. The samples of blood and cerebrospinal
fluid were collected at, 15 min after intravenous administration
of tubocurarine/gallamine, and at the end of anaestehtic proce-
dure [16, 17]. At the end of surgery, anaesthesia was stopped
and residual action of tubocurarine or gallamine was reversed
by using neostigmine 2.5 to 5.0 mg with atropine 1.2 mg. The
exant dose of neostigmine was calculated with the help of pe-
ripheral nerve stimulator (Meditronics Corporation -Ahmedaad,
India) [22], which allows stimulation at rates of 30 to over 300/
sec. As soon as nitrous oxide was cut off, neostigmine 2.5 mg
with atropine 1.2 mg was injected intravenously and ulanar nerve
was stimulated at the elbow at twitch and tatanic rates. The state
of neuromuscular transmission was judged by the activity of
thenar and hypothenar muscles (little and ring fingers) and if
necesary neostigmine 2.5 mg was again administered. At the

end of 15 min after the termination of anaetehsia, skeletomus-
cular tone was assessed by the patient’s ability to show wrinkes
in the forehead inaddition to his ability to move the limbs. Out
of 10 points (two each for satisfactory recovery of conscious-
ness, skeletomuscular tone, respiration, blood pressure and skin
colour), scoring of 7 points was considered to be an indication
of normal recovery of the patient under observation because
changes in blood pressue and skin colour were not related to the
direct or indirect efects of tubocurarine or gallamine. If a sub-
ject could breath deeply (by expanding the chest during such
efforts) when asked, it was considered that he has recovered
normal respiratory activity. The level of consciousness was
judged by his ability to open the eye-lids, show his tongue etc.
when asked to do so.
RESULTS:
In all 47 patients, (Table 1) the score was more than 7 out of
10 points by 15th minute after termination of anaesthesia. How-
ever it was 9 out of 10 in many patients, irrespective of the grossly
poor-risk nature of such cases, indicating that recovery from neu-
romuscular relaxant drugs, thiopentone and nitrous oxide ana-
esthesia was complete at the time of scoring. Hypocapinic,
isocapnic and hypercapnic type of passive ventilation did not
affect the recovery pattern at the end of anaesthetic procedure.
In the 12 patients in whom biologial assay for tubocurarine
or gallamine-like activity was carried out in blood and cerebrospi-
nal fluid, it was noted that both drugs penetrated the blood-cere-
brospinal fluid barrier and were found in cerebospinal fluid in
concentrations as high as 0.05 to 0.33 µg/ml of tubocurarine
and 0.1 to 0.75µg/ml of gallamine at the end of anaesthetic
procedure [16,17]. However their presence in plasma and cere-
brospinal fluid during and after the anaesthetic procedure, did
not influence the pattern of recovery because in all patients the

score was seven or more points. Presence of 10 to 25% or more
of paralysing dose of relaxant drugs (dtc or gallamine), in blood
& csf (at the time of recovery (16,17) did not affect the recovery
pattern in them (refer table-I of the reference article listed as 17)
(which is printed in this book).
Even though clinically and according to the method of scor-
ing all the patients recovered normally, they were found asleep
unless they were disturbed by questioning or by other means of
stimuli. They did not take any interest in the surroundings but
responded intelligently to simple commands and never indicated
a retardation of recent memory.
DISCUSSION:
The cerebral autoregulation is complete in awake man [23]
and has been shown to be intact during thiopentone, tubocurarine
and nitrous oxide anaethesia [24] withthe result that changes in
blood pressure and oxygen tension within physiological limits
do not influence the cerebral vascular flow [24,25]. Even when
the cerebrovascular flow is reduced during the technique of
hypocapnic ventilation [26], “the perfusion pressure” at all points
in the cerebral cortex is increased inspite of less total perfused
volume [27,28], thus making perfusion pattern of the entire
cortex uniform by cutting of regional imbalances [29]. These
facts (about the need based changes in the pattern of perfusion
of central nervous system under different conditions of ventila-
tion and blood pressure changes) could possibly explain the
observation that passive ventilation with low levels of PaCO2
keeps up satisfactory oxidative metabolism of brain in rats and
dogs [30,31] and man [32]. Since passive ventilation with PaCO2
between 22.0 and 90 mm Hg did not appear to affect the pattern
of recovery in the 47 patients in this study, the innocuous natue
of such a technique [33] is confirmed clinically.

Talbe 1: Score rate in 47 Patients during recovery phase
S. Risk Operation PaCO2 Score rate at (+) presence of
No. (class) (mm Hg) time of recoverya
muscle relaxant
1 3 Gastroenterostomy 30 8/10 +Gallamine in CSF
(Carcinoma stomach duodenal stenosis)
2 1 Laparotomy and release, of adhesions 28 9/10 ---
3 3 Laparotomy-drainage of pus and closure 32 9/10 ---
4 1 Laparotomy 23.9 8/10 ---
5 2 Repair of ventral hernia 25.6 6/10 ---
6 5 Choledochojujunnstomy for carcinoma 35 7/10 ---
of gall bladder
7 6 Ileo-ileal anastomosis for intestinal 26 7/10 +Tubocurarine in CSF
obstruction due to adhesions
8 5 L.S.C.S. 30 8/10 +Tubocurarine in CSF
9 5 L.S.C.S. 32 7/10 ---
10 5 Appendectomy 34 8/10 ---
11 1 Appendectomy 40 9/10 +Tubocurarine in CSF
12 1 Appendectomy 32 9/10 +Tubocurarine in CSF
13 2 Gastronenterostomy 33 8/10 +Gallamine in CSF
14 2 Gastronenterostomy 34 8/10 +Gallamine in CSF
15 1 Marsapalisation of hydatid cyst 32 8/10 ---
16 1 Radical masterctomy 26.2 8/10 ---
17 1 Gastronenterostomy --- 8/10 +Tubocurarine in CSF
18 1 Gastronenterostomy and appendectomy 23.9 7/10 ---
19 1 Urethrolithotomy 24.6 8/10 ---
20 1 Pyelolithotomy 29.6 8/10 ---
21 1 Vagotomy and gastro-jejunostomy 34 9/10 +Tubocurarine in CSF
22 1 Vagotomy and gastro-jejunostomy 23.9 9/10 ---
23 1 Vagotomy and gastro-jejunostomy 22 7/10 ---
24 1 Urethrolithotomy 43.5 9/10 ---
26 3 Ventral hernia (repair) 24.7 9/10 ---
27 2 Gastroenterostomy 90.5 8/10 ---
28 2 Gastroenterostomy 25 9/10 ---
29 3 Enteroenterostomy for T.B. strictures 32.5 9/10 ---
30 2 Laparotomy & resection of gastric ulcer 23.9 8/10 ---
and gastro-jejunostomy
31 2 Gastro-jejunostomy and appendectomy 26.4 9/10 ---
32 1 Nephrolithotomy 22 9/10 +Gallamine in CSF
33 2 Laparotomy 23.1 9/10 ---
35 3 Gastro-jejunostomy and ileotransverse 23 9/10 ---
colostomy
36 2 Gastro-jejunostomy and vagotomy 23 9/10 ---
37 2 Freyer postectomy 45 9/10 ---
38 2 Carcinoma Rt. Kidney exploration 26.4 9/10 ---
39 1 Gastro-jejunostomy and appendectomy 58.4 9/10 ---
40 5 Laparotomy 52 9/10 ---
41 1 Freyer prostectomy 52.8 9/10 ---
42 5 Laparotomy 60 9/10 ---
43 1 Gastro-jejunostomy and vagotomy 38 9/10 ---
44 1 Gastro-jejunostomy 64 9/10 ---
45 3 Laparotomy and enteroenterostomy 24 8/10 +Gallamine in CSF
46 6 Intestinal obstruction releasing of 54 9/10 ---
47 7 Intestinal obstructin releasing of 22 9/10 ---
contracting band
Preoperative risk was classified according to the regulations accepted by American Society of
Anesthesiologists. Score estimated 15 min after the end of anaesthesia.
& in plasma
& in plasma
& in plasma
& in plasma

It is thus far argued that alterations in the electroencephalographic
pattern indicate cerebral hypoxia due to changes in cerebral vas-
cular flow during such techniques. However, evidence is now
presented suggesting that changes in electroencephalographic
pattern are not reliable indicators of cerebral anaerobiosis[32].
Even though the question of passage of tubocurarine and
gallamine across the blood-cerebrospinal fluid barrier and its
action at the central nervous system is controversial [34-42],
attempts were made in this study to record the recovery pattern
in patients who exhitibed significant concentration of such drugs
in plasma and cerebrospinal fluid at the time of termination of
anaesthesia [16,17] so that the role of central nervous action of
tubocurarine and gallamine in causing depression of vital func-
tions in postopeartive period (such as areflexia, depression of
consciousness, hypotonia of skeletal muscles etc.) could be
assessed. However, it was found clinically and by the method of
scoring, hardly signs of nervous depression were present in
patients who exhibited significant quantities of tubocurarine
gallamine-like activity in the plasma and csf (cerebrospinal fluid)
at the end of operation. The type of score chart used in this study,
though not mathematical and exacting, was helpful to determine
quantitatively the recovery pattern of various vital functions in
the postoperative period similar to Apgar score chart used for
neonates. A significant number of patients in this study were
undergoing emergency or life saving surgery and derangements
in electrolytes, body water and acid-base balance were to be ex-
pected. However, in none of these was the score less than 7 out
of 10 and in a few of them the score was a shigh as 9
suggesting that recovery from the effects of non-depolarisation
block could satisfactorily takes places in patients suffering from
serious illness. These observations, therefore suggest that
technique of anaesthesia which is generally used for major

surgical procedures (thiopentone induction, nitrous oxide ana-
esthesia, skeletomuscular paralysis with tubocurarine or its
equivalents and passive ventilation with mild to moderate degreee
of change in PaCO2), does not per se cause the
syndrome of postoperative depression of vital functions in man.
Only side effects of such a technique could be the irresistible
desire to sleep (when undisturbed) in the immediate post-anes-
thetic period in patients who were exposed to such techniques,
and this could be due to the action of tubocurarine or gallamine
on the central nervous system [43].
REFERENCES:
1. Brechner, V.L.: Clinical syndrome of incomplete neuromuscular block
reversal: Doctor look at your patient. Anesth. Analg. 50, 876 (1971).
2. Scurr, C.F.: Carbon-dioxide retension simulating curarizaiton. Br. Med.
J. 1954/I, 565
3. Hunter, A.R.: Neostigmine resistant curarization. Br. Med. J. 1956/II, 919.
4. Foldes, F.F.: Neuromscular blocking agents in man. Clin.
Pharmacol. 1, 345 (1960)
5. Brookes, D.K., Feldman, SA.: Metabolic acidosis (a new approach to
neostigmine resistant curarization). Anesthesia 17, 161 (1962).
6. Bush, G.H., Baraka, A.: Factors afecting the termination of curarization
in human subjects. Brit. J. Anaesth. 36, 356 (1964).
7. Corrado, A.P.: Respiratory depression due to antibiotics: Calcium in
treatment. Anesth. Anagl. 42, l (1963).
8. Baraka, A.: The influence of carbon dioxide on the neuromuscular block
caused by tubocurarine chloride in the human subjects. Brit. J. Anaesth.
36, 272 (1964).
9. Baraka, A.: Irreversible tubocurarine neuromscular block in the human.
Brit. J. Anaesth. 39, 891 (1967).
10.Hannington-Kiff, P.g.: Residual poost-operative paralysis. Proc. J. Soc.
Med. 63, 73 (1970).

11.Rao, L.N., Venkatakrishna-Bhatt, H.: Stress response during surgery
and anesthesia in man: Its possible connection with the syndrome of
depressed vital functions in the post-surgical period. Indian J. Anaesth. 19,
365 (1971).
12.Wylie, W.D., Churchill-Davidson, H.C.: In: A Practice of Anaesthesia.
2nd Edition. P. 757. London: Llyod-Luke 1966.
13.Churchill-Davidson, H.C.: In: Recent Advanes in Anesthesia and
Analgesia. 9th Edition. Edited by C.L. Hewer. P. 98. London.
Churchill 1963.
14.Sikh, S.S., Agarwal, G., Branhbutt, P. Rai, P.: Recurarization and prolonged
unconsciousness. Indian J. Anaesth. 20, 91 (1970).
15.Foster, P.A.: Potassium depletion and central action of curare. Br. J.Anaesth.
28, 488 (1956).
16.Devasankaraiah, G., Haranath, P.S.R.K., Krishnamurthy, A.: Passage
of intravenously administered tubocurarine into the liquor space in
man and dog. Brit. J. Pharmacol. 47, 787 (1973).
17.Haranath, P.S.R.K., Krishnamurthy, A., Rao, L.N., Seshagiri Rao, K.:
Passage of intravenously administered gallamine into the liquor spae
in man and dog. Brit. J. Pharmacol. 48, 640 (1973).
18.Rangachary, S.S., Roth, A.D., Andrew, W.N., Mark, H.V.: Alterations of
blood brain barrier with hyperventilation. J. Neurosurg. 26, 614 (1965).
19.Aldrete, J.A.: Personal communication (1971).
20.Woolmer, R.: The measurement of pH and PCO2. In: Modern Trends in
Anaesthesia. Edited by F.T. Evans and T.C. Gray. 2, 31 - 55.
London: Butterworths 1962.
21.Burn, J.H. : Practical Pharmacology. P. 5 - 7. Oxoford: Blackwell 1952.
22.Bhatia, M.T., Shah, G.H.: Clinical trial with indigenous nerve stimulator.
Indian J. Anaesth. 18, 244 (1970).
23.Lassen, N.A.: Cerebral blood flow and oxygen consumption in man.
Physiol. Rev. 39, 183 (1959).
24.Smith, A.L., Neigh, J.L., Hoffman, J.C., Wollman, H.: Effects of general
anesthesia on autoregulation of cerebral blood flow in man. J. appl.
Physiol. 29, 665 (1970).
25.Kogure, K., Scheinberg, P., Fujishima, M., busto, R., Reinmuth, O.M.:
Effects of hypoxia on cerebral oxygen autoregulation. Amer. J.
Physiol. 219, 1393 (1970).

26.Kety, S.S., Schmidt, C.F.: The effects of active and passive
hyperventilation on cerebral blood flow, cerebral oxygen consumption,
cardiac output and blood pressure of normal young man. J. clin. Invest. 25,
107 (1946).
27.Ehrenfeld, W.K. Hamilton, F.N., Larson, C.P. Jr., Hickey, R.F., Severinghaus,
J.w.: effects of carbon-dioxide and systemic hypertension on down stream
cerebral arterial pressue during carotid endo-arterectomy.
Surgery 67, 87 (1970).
28.Fouracade, H.F., Larson, C.P. Jr., Ehrenfold, W.K., Hikcey, R.F.
Nowton, T.H. : The effects of carbon-dioxide and systemic hypertension
on central perfusion pressure during carotid endarterectomy.
Anesthesiology 33, 383 (1970).
29.Wilkinson, I.M.S., Brown, D.R.: The influence of anaesthesia and of
arterial hypocapnia on regional blood flow in normal human cerebral
hemisphere. Brit. J. Anaesth. 42, 472 (1970).
30.Cain, S.M.: An attempt to demonstrate cerebral anoxia
during hypervenitlation of anesthetized dogs. Amer. J. Physiol. 204,
323 (1967).
31.Miller,A.T. (Jr.), Curtin, K.E., Shen, A.L., Suiter, C.K. : Brain oxygenation
in the rat during hyperventilation with air and with low oxygen mixtues.
Amer. J. Physiol. 219, 798 (1970).
32.Allexander, S.C., Cohen, P.J., Woolman, H., Smith, T.C., Revich, M., Vander
Mollen, R.A.: Cerebral carbohydrate metabolism during hyocapnia in man.:
Studies during nitrous oxide anesthesia. Anesthesiology 26, 624 (1965).
33.Editorial. Brit. J. Anaesth. 41, 563 (1969).
34.Mahfouz, M.: The fate of tubocurarine in the body. Brit. J. Pharmacol. 4,
295 (1949).
35.Dalsanto, G.: Kinetics of distribution of radioactive labelled muscle
relaxants. I. Investigation with C14 dimethyl d-tubocurarine.
Anesthesiology 25, 788 (1966).
36.Dripps, R.D.: Abnormal respiratory responses to various “curare”
drugs during surgical anaesthesia: Incidence, etiology and treatment.
Ann. Surg. 137, 145 (1958).
37.Cohen, e.N.: Blood brain barrier to d-tubocurarine. J. Pharmacol. 141, 356
(1963).
38. Carmichael, e.a., Feldberg, W., Fleischauer, K.: The effects of tubocurarine
perfused through different parts of the cerebral ventricles. J. Physiol. (Lond.)
175, 303 (1964).

39.Whitacer, R.J., Fisher, A.J.: Clinical observations on use of curare in
anesthesia. Anesthesiology. 6. 124 (1945).
40.Dripps R.D., Severinghaus. J.W.: General anesthesia and respiations.
Physiol. Rev. 35, 741 (1955).
41.Smith. S.M., Brown, H.O, Toman, J.E.P., Goodman, L.S.: The lack of
central effects of d-tubocurarine. Anesthesiology 8, 1 (1947).
42.Churchill-Davidson, H.C.: Richardson, A.t.: Myasthenia crisis,
therapeutic use of d-tubocurarine. Lancer 1953/I, 1221.
43.Haranath, P.S.R.K. Shyamala Kumari, S.: Sleep induced by small doses of
tubocurarine injected into cerebral ventricles in dogs. Brit. J. Pharmacol.
49. 23 (1973).
Dr. L. Narahari Rao, M.D., D.A.,
Professor and Head
Department of Anaesthesiology
Kurnool Medical College,
Kurnool 518002
(Andra Pradesh)
India
*****

RESEARCH PAPER
“CENTRAL NERVOUS EFFECTS OF
HYPERVENTILATION”
A PRELIMINARY REPORT”
PROF. L.N. RAO
T.N. PRAHLAD
AND
DR. H. VENKATAKRISHNA BHATT PH.D.
INDIAN JOURNAL OF MEDICAL SCIENCES
VOL. 23, 1969, 665 - 670
D4 55

HYPERVENTILATION
L.N. Rao, T.N. Prahlad
AND
H. Venkatakrishna Bhatt
1). Abstract in Biological abstract Vol. 51. No. 20 Oct. 15, 1970. No. 113229.
2) Abstracted in Excerpta Medica (Physiology) Vol. 23, Nol. 23, Dec. 1970.
Abstract No. 7262
Reprinted frm “Indian Journal of Medical Sciences”
Vol. 23, No. 12, December 1969, pp 665-670
56

HYPERVENTILATION
L.N. Rao, T.N. Prahlad and H. Venkatakrishna Bhatt
Despite the fact that Bonwill5
and Beridge4
utilized the
technique of active hyperventilation for painless surgical
procedures, it’s use for similar purposes (to induce analgesia
during various surgical procedures) is now associated with the
possibilities of hypoxemic changes in persons exposed to such
techniques and thus a controversy exists about the safety of its
application. However, a critical review of the entire problem
reveals that such a controversy stems from the fact that the ex-
act mode of causation of analgesia during such techniques is not
known even today. Benjami Lee3
attributed the occurance of
analgesia during hyperventilation to be a form of hypnotism
whereas present day anesthetists ascribe it to the cerebral ef-
fects of hyperventilation, which, in turn are believed to be due
to a reduced cerebral blood flow. Many authors associate a
direct or indirect role for hypocapnia to be the cause for
analgesia and other aspects of the yperventilation syndrome
(Bonvellet & Dell6
, Cluttonbrock7
, Gray & Geddes8
, Sugioka &
Davis22
, Robinson & Gray17
, and Allen & Morris2
). This study
therefore aims to create conditons in which chances of
hypocapnia and cerebral hypoxemic conditions are minimized
so as to evaluate various factors causing generalized
analgesia during voluntary hyperventilation.
_____________________________________________________
1. Professor of Anesthsiology.
2. Department of Anesthsiology.
3. Department of Pharmacology.
Kurnool Medical College, Kurnool, Anadhra Pradesh, India.
Received for publication, November 9, 1968.

MATERIALS & METHODS
25 volunteers (8 doctors and the rest, surgical patients) were
selected to undergo active hyperventilation (rates of breathing
25 to 30/minute) for varying periods (10 to 30 minutes) while
they breathed (through a Magill’s circuit) a mixture of 2
per cent carbon dioxide and 98 per cent oxygen which was de-
livered at a flow rate of 20 litres/minute (the capafcity of the
reservoir bag being 6 liters). The average values of minute vol-
umes in these cases ranged between 25 to 30 litres/minute. The
fully opened expiratory valve allowed minimal instrumental re-
sistance to breathing and patients did not feel exhausted even
after 30 minutes. Pain threshold resonse was elicited in them
prior to, during and after a phase of hyperventilation which lasted
for 10 to 30 minutes by the following method:-
A disc 4 cm x 2.5 cm with blunt projections (6 mm long)
underneath the central portion of the disc, was placed over the
shin of tibia. The proijections were so blunt (due to fine polish)
that they did not elicit any other sensation than touch on the
skin. Prior to the application of the disc, 5 per cent lignocaine
ointment was applied locally to minimize touch sensation also
so that the patients felt only deep pressure sense over the shin of
the tibia. A sphygmomanometer cuff was then applied over the
disc and the mercury pressure raised in such a way that the per-
son concerned cried or showed other evidence of intolerable
bone pain. This was termed the pain threshold response. Later,
the same process of eliciting the pain threshold resonse was re-
peated 2 to 3 times during hyperventilation and in 13 cases the
post-hyperventilatory pain threshold response (1 to 8 minutes
after cessation of hyperventilation) was elicited to exclude the
influence of distracting elements on the pain threshold response
during hyperventilation.

RESULTS
Out of 25 volunteers, 4 were termed unpredictable because
of wide fluctuations between any two consecutive recordings of
the pain threshold response in the pre-hyperventilatory,
during hyperventilation, or in the post-hyperventilatory phase.
21 of these patients were found to be associated with constant
values during these phases: all of them did show significant evi-
dence of a raise in pain threshold resonse during hypervenitlation
(Figs. 1 & 2). Four out of these 21 cases did present further
evidence of the hyperventilation syndrome (apnea or respira-
tory irregularrity pattern after a phase of hyperventilation). In
13 cases, the pain threshold resonse was recorded in the post-
hyperventilatory phase (1 to 8 minutes after cessatin of such
attempts) only to exclude distracting influences
affecting the pain threshold response levels during active
hyperventilation. Except in one case, the rest did show evidence
of a sustained rise in the pain threshold response (Fig. 2).
One patient, who complained of abdominal pain before

Fig. 1:- Record of pain threshold response with 2% Co2 in O2, prior to
and during voluntary hyperventilation. Case X exhibited apnoea of 10 to 20
seconds in ost-hyperventilatory phase.
Case Y exibited waxing and waning type of respirations immediately
after hyperventilation.
Fig. 2:- Record of pain threshold resonse prior to, during and
after hypervenitlation. Interrupted lines indicate the record of pain thresh-
old obtained after hyperventilation. Case A was drowsy for a short time
after hyperventilation. The abdominal pain of which he complained earlier
was stated to have abated after hyperventilation. Case B was apneic after
hyperventilation and started breathing only when asked. However waxing
and waning type of respiration continued for sometime afterwards.
hyperventilation, volunteered that it had abated. To rule out the
possibility of ischemic pain influencing these patients,
the mercury pressure was raised upto 300 mm/Hg in a few of
these patients but they did not wince or show any other
evidence of pain perception.

DISCUSSION
Bonvallet & Dell6
and Gray & Geddes8
observed that
hypocapnia induces general analgesia during hyperventilation
(due to generalised reduction of the activity of the reticular sys-
tem). Robinson18
, however, felt that hypocapnia, instead of de-
pressing the reticular system directly (as was origfinally believed
by B onvallet & Dell6
) might interfere with the glycolytic en-
zyme activity so as to influence the cellular utilization of glu-
cose and consequent depression of the activity of central cells.
Others ascribed an indirect role for hypocapnia in causing vari-
ous aspects of the hyperventilation syndrome. Clutton-brock7
suggested that cerebral vascular flow, which was found to be
reduced by 32 per cent due to hyperventilation by Kety &
Schmidt10 possibly due to hypocapnia, results in cerebral hy-
poxemia and therefore generalised analgesia develops during
hyperventilation. Sugioka & Davis22
and Allen & Morris2
pro-
duced some evidence of cerebral hypoxemia during passive hy-
perventilation. Studdard20
, however, noted that, in spite of an
effective control of alveolar CO2
tension during hyperventila-
tion, EEG slowing did occur, revealing that such a change in the
EEG is unrelated to PaCO2
levels but is a direct sequel of such a
techniquje and most probably due to hypoxemia (due to cere-
bral vasoconstriction). The obvious deduction from these views
is that cerebral vaso-constriction, which may or may not be
realted to PaCO2
level during hyperventilation, should disap-
pear if vasodilation is induced by various methods (for instance
with the use of amyl nitrite). Though Clutton-b rock7 stated that
administration of amyl nitrite during hyperventilation reduced
the pain threshold, Robinson & Gray17
could not confirm these
results. Our experience inthis study brings out an as yet unex-
plored aspect of the hyperventilation syndrome in that even when
2 per cent CO2
was added into the breathing mixtures, the pain

threshold response was persistently raised during and after
hyperventilation. In this study we cannot rule out the possibility
of cerebral vascular constriction in spite of the presence of 2 per
cent CO2
in the breathing mixtures because these vessles might
still constrict under the influence of central nervous factors as
was originally postulated by Rao et al16
. The point, however, is
whether such a change in cerebral vascular tone could cause
temporary or permanent hypoxemic change in the central
nervous sytem inducing (as is now widely believed) some of the
beneficial aspects of the hyperventilation syndrome (for
instance analgesia). The clinical observation that such patients
(who are exposed to these techniques of hyperventilation for
any length of time) recover immediately and are oriented better
than others exosed to other techniques of anesthesia for similar
surgery, strongly suggests that it might not be so. Similarly, in
spite of 98 per cent O2
in the breathing mixtures (paCO2
in
cerebral vessels might be around 700 mm/Hg), the pain
thresho9ld resonse was persistently raised which contnued into
the immediate post-hyperventilatory phase, thereby indicating
that cerebral hypoxemia might not be the cause of analgesia
during hyperventilation.
At this stage, it is worthwhile to point out that slowing of the
EEG is not a specific phenomenon suggestive of low paCO2
,
high pH or cerebral hypoxemia during hyperventilation. Hughes
et al9
could not record any delta wave activity in the EEG during
upper abdominal surgery in spite of paCO2
levels as low as 12 to
14 mm/Hg. Similarly Kinnel11 could not find any evidence of
slower EEG waves during upper abdominal surgery in sptie of
the occurence of hypocapnia, unless extradural block was si-
multaneously given. It is now shown that EEG slowing could be
produced by somatic afferentation at slow rates and such
afferentation is found to be frequency dependent (Riotback19

and Pampeiano12
). Vagoaortic nerves are, however, found to be
independent of frequency and afferentation in them even at fast
rates is found to cause slowing of EEG activity (Padel & Dell13
).
Even mechnical irritation of the larynx is found to cause this
change in the EEG tracing (Vanreeth & Capon23
). On the basis
of the fact that vagal afferentation significantly increased dur-
ing hyperventilation, (Adrian1
) it is highly likely that slow EEG
waves observed during hyperventilation might be vagally ori-
ented and might not indicate hypoxemic conditions during the
same period. Similarly, on the basis of recent evidence that va-
gal afferentation could produce significant changes in cardio-
vascular, respiratory and skeletomuscular systems (Rao &
Bhatt14
) it could be pointed out that the entire hyperventilation
syndrome (namely analgesia, hypotonia of the skeletal muscles,
anea, EEG changes and various changes in cardiovascular tone)
is a neurophysiological phenomenon in which vagal and other
afferentations have a dominant role to induce its various param-
eters through the central nervous system (Rao et al16
, and Rao15
).
In 25 valunteers, the pain threshold resonse was eicited prior
to, during and after a phase of active hyperventilation (10 to 30
minutes) during which the person cncerned was breathing 2 per
cent CO2
: 98 percent O2
through a Magill’s circuit (total flow
rate 20 litres/minute). 21 cases whose records were considered
as predictable have shown evidence of a rise in the pain
threshold response during active hyperventilation. In 13 cases,
the pain threshold response was recorded after 1 to 8 minutes of
cessation of hyperentilation and it was found that except in one
case they did show evidence of sustenance of the raised pain
threshold response. These results indicate that hypocapnia might
not be the cause of analgesia during hyperventilation.

ACKNOWLEDGEMENT
This investigation was carried out with the aid of a State
Medical Research Grant from the Government of Andhra
Pradesh, India. We are grateful to Profressor T.C. Gray of the
Liverpool University, for his helpful suggestions. We are equally
obliged to the Superintendent, Government Genral Hospital, for
permitting us to experiment on human volunteers from various
wards.
REFERENCES
1. Adrain, E.D.: Afferent Impulses in Vagus and Their Effects on
Respiration. J. Physiol. (Lond.) 79:332, 1933.
2. Allen, G.D. and Morris L.E.: Central Nervous Effects of
Hyperventilation During Anesthesia. Brit. . Anesth. 34: 296, 1962.
3. Benjamin, Lee.: Quoted by 21.
4. Berridge, W.A.: Quoted by 21.
5. Bonwill: Quoted by 21
6. Bonvallet, M and Dell, P.: Proceedings the Societe d’Electro
encephalographicc et des Sciences Connexes de Longue Francaise.
Electroencepha. Clin. Neurophysil. 8: 170, 1956.
7. Clutton-brock, J.: The Cerebral Effects of Over-ventilation. Brit.
J. Anesth. 29: 111, 1957.
8. Gray, T.C. and Geddes, I.C.: Hyperventilation for Maintenance of
Anesthesia. Lancet. 1: 4, 1959.
9. Hughes, J.R., King, D.B., Cutter, .N. and Markello, R.: EEG in
Hyperventilation and Lightly Anesthetized Patients. Electroenceph.
Clin. Neurophysiol. 14: 274, 1962.
10.Kety, S.S. and Schmidt, C.F.: The Effect of Active and Passive
Hyperventilation on Cerebral Blood Flow, Cerebral Oxygen
Consumption, Cardiac Output and Blood Pressure of NormalYoung Men.
J. Clin. Invest. 25: 107, 1946.
11.Kennel, J.D.: The Influence of Afferent Block in Hyperventilation
Anesthesia. Anesthesia 17: 58, 1962.
12.Pompeiano, O. and Swett, J.E.: EEG and Behavioural Manifestations
Arch. Ital. Biol. 100: 311, 1962.

13.Padel, Y. and Dell, P.: Effects Bulbaires et Reticulaires des
Stimulations Endormantes Dutronc Vago-aortique. J. Physiol.
(Paris) 57: 269, 1965.
14.Rao, L.N. and Venkatakrishna Bhatt, H.: Skeletomuscular, Respiratory
and Cardiovascular Responses to Bilateral Vagal Stimulation - Its
Significance in Clinical Practive. Anesth. Analg. (In Press).
15. Rao L.N.: Apnoea During and After Hyperventilation Ind. J. Anesth.
15: 23, 1967.
16.Rao, L.N., Ramarao, K.R. and Bhalla: S.K.: Increased Afferentation
in Vagal Splanchnic etc. Leading to Hyperventilation Syndrome During
Surgery under General Anesthesia. Ind. J. Anesth. 14: 226 1966.
17.Robinson, J.S. and Gray T.C.: Observations on the Cerebral Effects of
Passive Hyperventilation. Brit. J. Anesth. 33: 62, 1961.
18.Robinson, J.S.: Hyperventilation - Modern Trends in Anesthesia Edn.
F.T. Evans and T.C. Gray, Vol II, Butterwoth, P. 82, 1962.
19.Riotback, A.L.: Electrical Phenomena in the Cerebral Cortex
During the Extinction of Orientation and Conditioned Reflexes, in
Jasper, H.H. and Smirnov, G.D. The Moscow Colloquium
of Electroencephalography of Higher Nervous Activity. Electroenceph.
Clin. Neurophysiol. Suppl. 13: 91, 1960
20.Studdard, J.C.: Electroencephalographic Activity During Voluntarily
Controlled Alveolar Hyperventilation. Brit. J. Anesth. 39: 2, 1967,
21.Sykes, S.: Essays on 100 years of Anesthesia. Vol. II. Livingstone Ltd.,
P. 67, 1961.
22.Vanreeth, P.C. and Capon. A.: Sleep Induced by Stimulation of
the LaryngealRegion. Electroenceph. Clin. Neurophysiol. 17: 725, 1963.
*****

RESEARCH PAPER
“VAGAL ACTIVITY IN CANINES:
A Possible Connection to Hyperventilation Syndrome”
BY:
PROF. L.N. RAO M.D. DA
AND
H. VENKATAKRISHNA BHATT, M.SC.
KURNOOL (P.O.) A.P. INDIA.
ANAESTHESIA, ANALGESIA
Current research, 1970, 49, 351-354
Reprint from:
ANAESTHESIAAND ANALGESIA
Vol. 49, 351 - 354, 1970
D5 66

“VAGAL ACTIVITY IN CANINES”
A Possible Connection to Hyperventilation Syndrome
L.N. RAO, M.D., D.A.
H. VENKATAKRISHNA-BHATT, M.Sc.,
Kurnool (P.O.) Andhra Pradesh, India*
*Department of Anesthesiology and Pharmacology, Kurnool Medical College,
Kurnool (P.O.) Andhra Pradesh, India.
This investigation was supported by a grant from State Medical Research,
government of Andhra Pradesh, India.
Reprinted from Anesthesia and Analgesia - Current Researchs, MAY-JUNE, 1970
During artifical ventilation, afferent impulses in the vagus
nerves are directly proportional to the amount of pulmonary
stretch1
. Some investigators believe the increased volume of the
afferent impulses contribute substantially to changes in the
skeletomuscular, respiratory, and cardiovascular systems which
occur during artificial ventilation.
Aserinsky and Debias2
obsrved that pulmonary stretch-
receptor activity during hyperventilation eliminates the
oculocardiac reflex. Daly and Hazzledine3
noted that hyperven-
tilation reduces or eliminates the ability to produce bradycardia
when the carotid body is stimulated. Dermkesian and Lamb4
stated that pulmonary stretch-receptor activity induced by
breathholding and artifical ventilation effects a vagal response
characterized by bradycardia and even cardiac arrest. They noted
that 1.2 mg. of atropine was effective in preventing such re-
sponses. Downes5
and Katz and Wolf6
indicated that hypotonia
during hyperventilation is a reflex phenomenon which is prob
ably mediated through vagal impulses. Rudomin7,8
observed that
laryngeal reflexes are depressed during artifical ventilation or
during electrical stimulation of the vagi. Siker9
attributed post

anesthetic respirartory depression and apnoea to vagal influence
on the respiratory center. Robson10
stated that at least in the ini-
tial phase of artifical ventilation the synchronization observed
between inspiratory neuronal discharge and the respirator is
caused by stretch phenomena.
In spite of the evidence put forth by these investigators that
stretch-receptor activity may be one of the most important fac-
tors in the hyperventilation syndrome, many clinical scientists
reject this theory. The present study was undertaken as an at-
tempt to elucidate the possible role of the vagus nerves during
artificial ventilation. The object of the study was to induce low-
intensity stimulation of the cervical vagi in anaesthetized dogs,
with the hope of evoking the skeletomuscular, respiratory, and
cardiovascular changes typical of the hyperventilation syndrome.
METHODS
Bilateral stimulation of the vagus nerves was performed 48
times in 8 anaesthetized dogs of the both sexes weighing 7.5 to
10.5 kg. Chloralose (110 mg./kg.) was administered intrave-
nously, and anesthesia was maintained with doses of 25 mg./kg.
every 30 minutes. A tracheotomy was performed, and respira-
tions were recorded on a kymograph using Mary’s tambour.
Blood pressue in the left femoral artery was recorded on the
same kymograph.
A hole in the right femur was drilled just proxmial to the
condyles, and the femur was stabilized with a supporting rod
attached to the ergographic stand.The tibia, proximal to the ankle,
was anchored to the isometric lever mounted on the ergographic
stand. Patellar-tendon reflex was elicited using an electrically-
driven hammer, powered by 4 to 6 volts of direct current and

tapping at the rate of six times per minute.
Bilateral stimulation of the vagus nerves was accomplished
by placing both cervical vagi in the groove provided for the nerve
stimulation. Four to 6 volts of direct current were fed into an
induction coil, and the resultant high-frequency, alternative
current was fed into the nerve stimulator. Usually, the period of
stimulation was 30 to 60 seconds. In a few cases, 0.6 mg. of
atropine was administered intravenously so that peripheral ef-
fects, such as bradycardia and subsequent hypotension, were
prevented.
Later experiments, using only stimulation of the central ends
of cut vagi, were performed to determine whether or not there
was any difference in results.
RESULTS
Bilateral vagal stimulation resulted in the depression or
elimination of the patellar reflex and in the cessation of respira-
tory activity (figure). There was severe bradycardia and hypoten-
sion. (When the central ends of cut vagi were stimulated). When
atropine had been administered prior to stimulation, there was
no bradycardia, but hypertension was observed.Apnea persisted
throughout the phase of stimulation and, in some cases, more
than 20 to 30 seconds into the poststimulatory phase. The patel-
lar reflex was reduced 75 percent during stimulation, and, in a
few cases, it disappeared completely. However, it reappeared
instantaneouslyu with cessation of stimulation, and its magni-
tude increased during the poststimulatory phase, returning to
normal within a few seconds. The administration of atropine
prior to stimulation did not prevent apnoea or depression of the
patellar reflex.

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