Handheld computers in critical care Background Computing technology has the potential to improve health care management but is often underutilized . Handheld computers are versatile and relatively inexpensive , bringing the benefits of computers to the bedside . We evaluated the role of this technology for managing patient data and accessing medical reference information , in an academic intensive-care unit -LRB- ICU -RRB- . Introduction The rapid development of computing technology has had a major impact on health care , particularly in technology-oriented areas such as critical care . Electronic patient records require a major commitment by the institution , in hardware , software , training , and support . In many places , bedside care of patients still relies on paper records or nonintegrated computer systems that do not take full advantage of their data-management capabilities -LSB- 1 -RSB- . Even where there are advanced computerized systems , the bedside clinician may still rely on written notes for patient management and billing , and refer to pocket textbooks or printed management algorithms . For busy clinicians , the use of computers for hospital-based clinical care may be hampered by the computers ' inaccessibility . Handheld computing technology is versatile and relatively inexpensive -LSB- 2 -RSB- , combining many of the benefits of electronic patient records and paper charts . Handheld computers have been described in various medical situations ; early reports describe programmable calculators used to make complex calculations in intensive-care units -LRB- ICUs -RRB- -LSB- 3 -RSB- . Handheld devices are increasingly being used by physicians for a variety of functions , such as scheduling , accessing drug reference information , patient data storage and billing . However , there are few published reports describing the benefits of this technology -LSB- 4 , 5 , 6 , 7 -RSB- . In view of the potential advantages and increasing use of handheld computers in medicine , we evaluated the benefits and drawbacks associated with introducing this technology in an academic ICU . Materials and methods Hardware The Palm III series handheld device -LRB- Palm device , Palm Canada Inc , Toronto , Ontario -RRB- was used , as some of our staff were familiar with this equipment . It is a pocket-sized -LRB- 8 × 12 cm ; 165 g -RRB- computer with a 4-Mb -LRB- PalmIIIx -RRB- or 8-Mb -LRB- PalmIIIxe -RRB- memory . It has an infrared data association -LRB- IrDA -RRB- port that allows transmission of data between Palm devices and other IrDA-compatible devices such as printers , laptop computers and cellphones . The device has a monochrome 160 × 160 pixel liquid-crystal display screen -LRB- Fig. 1 -RRB- and allows the user to input data either by writing on the touch-sensitive screen with a stylus or by tapping on an on-screen keyboard . Handwriting is deciphered by Graffiti handwriting-recognition software -LRB- Palm Inc , Santa Clara , CA , USA -RRB- , which requires the user to learn specific characters . For users who preferred to enter data using a keyboard , two GoType keyboards -LRB- LandWare Inc , Oradell , NJ , USA -RRB- were found in the ICU . When the Palm device was placed in this keyboard , the user could type in the standard way . Software Each personal digital assistant -LRB- PDA -RRB- was installed with medical reference information as well as hospital and ICU specific guidelines -LRB- Table 1 -RRB- . This occupied approximately 2 Mb of memory . The applications that come with the PDA -LRB- Addressbook , Datebook , Memopad , To Do list -RRB- were used for essential telephone numbers as well as call and teaching schedules , but additional software was required for medical databases . The spreadsheet database program JFile -LRB- Land-J Technologies , Orlando , FL , USA -RRB- was used for reference information , such as drug doses and laboratory reference ranges . The text readers AvantGo -LRB- AvantGo Inc , San Mateo , CA , USA -RRB- and iSilo -LRB- www.isilo.com -RRB- , which convert word-processing and HTML documents , were used for textual medical reference information . CbasPad , a Tiny BASIC programming language interpreter and editor , was used to develop software to perform common critical-care calculations , such as calculated creatinine clearance and intravenous infusion rates . Additional software for medical reference data was introduced during the study period , including ePocrates qRx -LSB- 8 -RSB- , a drug information database . Patient data were entered into the Memopad using a customized template generated with MemoPlus -LRB- Hands High Software Inc , Palo Alto , CA , USA -RRB- . The information entered included demographic data , medical history , current diagnoses , therapy , procedures performed , and management plan . Data was transferred between medical personnel using the PDA 's infrared beaming ability . As hospital policy requires a paper record , daily notes were generated by Palmprint software -LRB- Stevens Creek Software , Cupertino , CA , USA -RRB- using infrared transmission to an HP Laserjet 6P printer -LRB- Hewlett Packard , Palo Alto , CA , USA -RRB- . Various software packages for patient data management -LRB- shareware or commercially available software -RRB- were evaluated during the study period . In the light of focus-group feedback , a more comprehensive reference database was developed . The electronic files for the Critical Care Handbook of the Massachusetts General Hospital -LSB- 9 -RSB- were provided by the publishers , and converted to a PDA-readable -LRB- iSilo -RRB- format . This 1.4-Mb file contained the full text of the book , with multiple hyperlinks , and some of the images . Hard copies of the book were also obtained . Study subjects PDAs were given to the ICU attending physicians , the rotating resident trainees , and other medical staff . Four to six residents -LRB- postgraduate years 2 to 4 -RRB- worked in the ICU at any one time . On the first day of their ICU rotation , residents were taught how to use the PDA in a 1-hour seminar . The principle investigator and research team were available for further help and troubleshooting throughout the study The research team was responsible for installing and updating software and schedules . Patient data was entered by residents , either during morning rounds or when patients were admitted to the ICU . The updated database was beamed to the on-call resident in the evening and transmitted back to the team in the morning , with new admissions added . Methodology An independent evaluation company -LRB- Smaller World Communications , Richmond Hill , Ontario -RRB- with experience in focus-group methodology was contracted to develop the qualitative methodology , collect data through focus-group meetings , and analyze the data -LSB- 10 , 11 -RSB- . A preliminary moderator 's guide was developed and tested on an expert panel , comprising two critical care physicians , an anaesthesiologist , three medical residents with experience in data management or PDAs , and a representative from Palm Canada Inc. . The moderator 's guide was designed to stimulate discussion about users ' familiarity with the technology , the benefits to patient management , and the drawbacks encountered . Finally , ideas were generated for new applications for the technology and improvements to the hardware and software . Three focus groups were held with the residents and staff who used PDAs in the ICU . Tapes were transcribed verbatim and the notes were analyzed for themes by a research analyst -LSB- 12 -RSB- . Interim reports from the meetings were provided to the investigators . On the basis of this feedback , ongoing improvements were made to the medical databases and patient-management software . The PDA reference database was evaluated objectively using a crossover study . The trainees ' rotation was split into two 3-week periods . One of the periods was allocated as a control -LRB- PDA-free -RRB- block and in the other the PDA was available . Two groups of trainees were studied : in one the PDA period preceded the PDA-free period , and in the other , the order was reversed . During the PDA period , trainees had access to the full PDA database as well as the electronic version of the Critical Care Handbook of the Massachusetts General Hospital -LSB- 9 -RSB- . The printed copy of the handbook was given to trainees during the PDA-free period . Objective evaluation was accomplished using a pair of standardized clinical scenario tests made up of 20 questions answered over 30 minutes . The questions were about common critical-care problems , drawn randomly from a pool of questions written by physicians in our ICU and at other teaching hospitals in the Toronto area . Trainees made use of the textbook -LRB- control period -RRB- or PDA database -LRB- study period -RRB- during the examination . To standardize for the possible difference in difficulty between the two tests , 11 General Internal Medicine trainees , not involved in the PDA study , wrote both the tests . This generated a mean and standard deviation for each test . Study trainees ' results were expressed as the standard deviation above or below this control mean , and compared using a permutation test , with P < 0.05 considered significant . Results During the 6-month study period , PDAs were used by 20 physicians -LRB- 4 attending physicians , 1 research fellow , and 15 rotating medical residents -RRB- and 6 paramedical staff -LRB- 3 respiratory therapists , 2 pharmacists , and 1 nurse educator -RRB- . The three focus groups had a total of 19 participants . Two residents who were unable to attend participated in telephone interviews . Each focus group had six or seven participants , a number within the recommended range -LSB- 11 -RSB- . Only five of the users -LRB- 19 % -RRB- had previous experience with the PDA computing format . Physical attributes Users found the PDA to be a convenient pocket size , allowing it to be available at all times . The screen was clear and easy to read , although not ideal for long text documents or large tables . Many users became proficient in text entry using Graffiti , while others preferred to use the GoType keyboards . Of the 19 PDA units used during the 6-month study period , only one had a technical malfunction requiring replacement . Two were damaged after being dropped and needed to have their screens replaced . No other problems were encountered . Medical reference databases Reference databases used regularly by medical residents included the critical-care drug dosing reference , ventilator weaning protocol , and electrolyte correction application . The calculation programs -LRB- creatinine clearance , ideal body weight -RRB- were found to be useful by the pharmacist and some residents . The ventilator weaning protocol was used by medical staff , as well as respiratory therapists , allowing regular assessment of whether patients met the criteria for extubation . Many databases were , however , not fully used . This appeared to relate more to inadequate training than to faults in the databases . In many cases , the PDA users were unaware that certain information was in their PDAs . This was because data were located on separate software programs -LRB- J-file , AvantGo , Cbas , Memopad -RRB- and may have been difficult to find . The PDA had a global ` Find ' function to search for keywords , but this does not incorporate some of the added software programs , such as AvantGo . A unified database program with a search capability was suggested as a useful addition . Patient-management software Patient information was managed using the text-based MemoPlus software and a customized template . This required text entry on the PDA . Several modifications to the template were made during the study period . Residents responsible for patient data entry described difficulty entering data for new patients and keeping patient information updated during busy weekends . Attending staff found the patient data useful , particularly when they were taking over care of patients at the beginning of their on-call duties . Transferring the care of critically ill patients to a new physician is time-consuming and potentially stressful . The PDA patient database improved the staff 's knowledge of patients , especially of previous medical problems in patients with complex conditions who had had a long stay in hospital . It also gave staff access to patient information when they were out of the ICU , aiding decision-making . During ICU rounds , the summarized chronological information was useful to find out how long intravenous lines had been in place and to review antibiotic therapy . Less benefit was noted in short-term patients . During night call , the patient summaries were of value when residents were called to see patients with whom they were not very familiar . In our ICU , a daily physician note is written in the patient record . The print function to create a daily note reduced duplication of work , but the process for entering patient data was found to be time-consuming initially . While residents did not feel that the patient-management application -LRB- MemoPlus -RRB- improved efficiency , it did increase their knowledge of the patients . During the study period , other commercially available patient-management software systems were evaluated . These had the advantage of easy data input using single keystrokes for date entry and ` pop-up ' lists of drugs and diagnoses . While this simplified data inputting , no system was found to be ideal for the ICU . Many of these systems did not support the infrared data transfer or printing functions . Other uses of the software Study participants used a variety of other applications on a regular basis . Having the call and teaching schedules easily accessible was considered a benefit . The telephone list of hospital numbers was found to be valuable and the To Do list was used by most users to keep track of their work . Teaching rounds and morbidity and mortality rounds were facilitated by using archived patient data . Many participants used the Memopad to take notes in teaching seminars . Suggestions for change The focus-group discussions generated a number of suggestions for improvement . The hardware unit was considered suitable , but a more robust one may be needed in view of the two damaged screens . Because most of the users had had no previous experience with the PDA , additional teaching sessions and follow-up training were suggested to make optimal use of the technology . This would have helped users to become more aware of the many databases available on their PDA . In this regard , the medical information on the PDA would clearly benefit from integration into a single , searchable program . The patient-management software would be more user-friendly if the data could be entered with minimal effort , using customized pull-down lists of drugs , diagnoses , and procedures . The demographic data could be entered and updated daily by a ward clerk . Alarms were suggested - for example , to warn of prolonged intravenous line duration or the end of a course of antibiotic therapy . While transmission of data between staff by infrared was found to be useful , synchronization with the hospital electronic patient record was considered the optimal situation . Objective evaluation Two groups of four trainees took part in each crossover study . Half of the residents had prior experience with PDAs . No difference was noted in their subjective preference for the PDA or printed copy of the handbook , and the individual 's preference did not correlate with previous PDA experience . Comparison of the test scores revealed no difference between the scores in the PDA-assisted test and the paper-assisted test , analyzed after correction for difficulty using the control mean and standard deviation . Discussion This study prospectively evaluated the benefits and drawbacks associated with the introduction of handheld computers in an academic-critical care environment . Who benefitted most ? The introduction of handheld computers was well received by all users , despite differences in their familiarity with these devices . The most favourable response was from the more senior staff , namely , the attending physicians and fellows . This may be because of the longer time they were involved in the study , allowing more familiarity with the PDA platform . They were also more likely to benefit from having patient data available while on call outside the ICU . Furthermore , they were usually not responsible for entering patient data . Clearly , two conditions that might enhance the acceptance of these technological changes are adequate education and ease of data entry . Although an initial education session was held , it was when the junior medical staff in the study were beginning their rotation in an unfamiliar environment . Making the devices more user-friendly The patient data applications assessed were not ideal but did enable us to identify several criteria for a user-friendly system . These include ease of data entry using shortcuts and lists , limiting the range of data stored to that essential for patient management , and the ability to transmit data easily between staff . It is important that this computerized patient database should decrease workload and not cause duplication in work . In our study , enabling residents to print a daily note from their handheld computer offset the additional work of data entry . Ideally , the handheld system should be integrated with the hospital electronic patient record , allowing direct entry of demographic data as well as access to laboratory data . A wireless capability may also have significant benefits with respect to medical information databases . This would allow access to Medline searches and evidence-based guidelines . While internet access is available from desktop computers in the ICU , the ability to perform these searches on rounds or while consulting outside the ICU may be beneficial . Databases on paper or on screen ? The comparison of paper and electronic databases did not reveal an advantage of one medium over the other . No significance difference was observed between the objective scenario test scores using the PDA or the paper database . The fact that equivalent results were obtained using this single database may suggest a potential benefit of using the PDA . The memory capability of the 8-Mb device would allow the trainees to carry five reference texts each of a size similar to that of the Critical Care Handbook of the Massachusetts General Hospital . What is needed Critical-care decision-making requires rapid access to strategic clinical data as well as to medical reference information . A patient in an ICU generates a large amount of data , and the number of information variables may exceed what clinicians can integrate and process -LSB- 13 -RSB- . Current information technology has the potential to realize the needs of the intensivist , but no customized product has been developed for this use . Handheld technology has a definite role to play , but systems need to be developed specifically for the critical-care environment to optimize real-time patient data management and communication between health care workers . Abbreviations HTML = hypertext markup language ; ICU = intensive-care unit ; IrDA = infrared data association ; Mb = megabytes ; PDA = personal digital assistant .

O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

computer communication networks
medical informatics
medical technology
microcomputers
point-of-care technology


Perturbation

of

hyaluronan

metabolism

predisposes

patients

with

type

diabetes

mellitus

to

atherosclerosis

Aims/hypothesis

Cardiovascular

disease

contributes

to

mortality

in

type

diabetes

mellitus

but

the

specific

pathophysiological

mechanisms

remain

to

be

established

We

recently

showed

that

the

endothelial

glycocalyx

a

protective

layer

of

proteoglycans

covering

the

endothelium

is

severely

perturbed

in

type

diabetes

with

concomitantly

increased

plasma

levels

of

hyaluronan

and

hyaluronidase

In

the

present

study

we

evaluated

the

relationship

between

hyaluronan

and

hyaluronidase

with

carotid

intima-media

thickness

-LRB-

cIMT

-RRB-

an

established

surrogate

marker

for

cardiovascular

disease

Introduction

Macro

and

microvascular

complications

are

a

major

cause

of

morbidity

and

mortality

in

patients

with

diabetes

mellitus

While

the

macrovascular

complications

in

patients

with

type

diabetes

mellitus

can

partly

be

attributed

to

the

increased

prevalence

of

classic

cardiovascular

risk

factors

such

as

dyslipidaemia

these

risk

factors

can

not

explain

the

increased

prevalence

of

atherosclerosis

in

type

diabetes

mellitus

-LSB-

-RSB-

Recent

data

demonstrated

that

hyperglycaemia

itself

may

play

a

causative

role

Thus

improved

metabolic

control

is

associated

with

a

decreased

macrovascular

event

rate

-LSB-

-RSB-

However

the

pathophysiology

of

glucose-associated

atherogenesis

remains

to

be

elucidated

-LSB-

-RSB-

In

recent

years

the

glycocalyx

has

emerged

as

a

potential

orchestrator

of

vascular

homeostasis

which

closely

determines

anti-adhesive

and

barrier

properties

of

the

vessel

wall

-LSB-

-RSB-

In

line

we

found

that

the

endothelial

glycocalyx

is

adversely

affected

by

both

acute

and

chronic

hyperglycaemia

in

volunteers

and

type

diabetes

patients

respectively

-LSB-

-RSB-

Hyaluronan

is

a

principal

constituent

of

the

glycocalyx

and

removal

of

the

glycocalyx

with

hyaluronidase

has

been

associated

with

increased

vascular

vulnerability

towards

atherogenic

insults

-LSB-

-RSB-

In

animal

models

of

type

diabetes

hyaluronidase

activity

has

been

shown

to

be

increased

and

this

correlated

with

increased

carotid

intima-media

thickness

-LRB-

cIMT

-RRB-

-LSB-

-RSB-

In

line

with

this

increased

accumulation

of

hyaluronan

within

the

arterial

wall

in

type

diabetes

patients

correlated

with

vascular

changes

-LSB-

-RSB-

We

recently

found

an

acute

increase

in

plasma

hyaluronan

coinciding

with

glycocalyx

perturbation

during

a

normo-insulinaemic

hyperglycaemic

clamp

in

healthy

volunteers

-LSB-

-RSB-

Moreover

we

observed

an

inverse

correlation

between

plasma

hyaluronan

as

well

as

plasma

hyaluronidase

and

glycocalyx

volume

in

patients

with

type

diabetes

-LSB-

-RSB-

In

this

concept

hyperglycaemia-induced

perturbation

of

hyaluronan

metabolism

characterised

by

increased

hyaluronidase

activity

with

subsequent

increased

plasma

hyaluronan

levels

may

indicate

increased

vascular

vulnerability

In

the

present

study

we

set

out

to

evaluate

the

potential

relationship

between

structural

changes

of

the

carotid

artery

and

hyaluronan

metabolism

in

patients

with

uncomplicated

type

diabetes

Subjects

and

methods

We

enrolled

non-smoking

Europid

patients

with

type

diabetes

all

without

clinical

signs

of

micro

or

macrovascular

disease

The

patients

were

recruited

from

the

Internal

Medicine

outpatient

clinics

of

the

Academic

Medical

Center

and

Onze

Lieve

Vrouwe

Gasthuis

in

Amsterdam

the

Netherlands

The

presence

of

macrovascular

disease

defined

as

ECG

abnormalities

or

a

history

of

cardiac

cerebral

or

peripheral

vascular

events

was

an

exclusion

criterion

for

the

study

Moreover

subjects

with

retinopathy

neuropathy

-LRB-

micro

-RRB-

albuminuria

or

hypertension

were

excluded

from

participation

All

patients

were

on

multiple

daily

injections

of

insulin

with

no

other

concomitant

medication

use

Matched

non-smoking

controls

-LRB-

selected

for

this

study

specifically

-RRB-

were

unrelated

volunteers

of

similar

age

and

sex

Investigations

of

both

study

groups

were

randomly

performed

during

the

study

period

Approval

for

the

study

was

obtained

from

the

Internal

Review

Board

of

the

Academic

Medical

Center

Amsterdam

and

all

subjects

gave

written

informed

consent

The

study

was

carried

out

in

accordance

with

the

principles

of

the

Declaration

of

Helsinki

All

measurements

were

performed

after

an

overnight

fast

and

in

a

quiet

and

air-conditioned

room

Blood

pressure

was

measured

in

triplicate

and

the

last

two

measurements

were

averaged

to

obtain

heart

rate

and

systolic

and

diastolic

blood

pressure

The

latter

were

averaged

to

calculate

mean

blood

pressure

At

baseline

blood

samples

were

collected

for

determination

of

lipids

high

sensitivity

C-reactive

protein

-LRB-

hsCRP

-RRB-

hyaluronan

and

hyaluronidase

The

markers

of

hepatic

function

ASAT

and

ALAT

-LRB-

aspartate

aminotransferase

and

alanine

aminotransferase

respectively

-RRB-

were

determined

since

chronic

liver

disease

is

known

to

be

associated

with

increased

plasma

hyaluronan

levels

-LSB-

-RSB-

After

centrifugation

-LRB-

within

h

after

collection

-RRB-

aliquots

were

snap-frozen

in

liquid

nitrogen

and

stored

at

°C

Clinical

chemistry

Total

cholesterol

HDL-cholesterol

and

triacylglycerol

were

measured

by

enzymatic

methods

-LRB-

Roche

Diagnostics

Basel

Switzerland

-RRB-

LDL-cholesterol

was

calculated

using

the

Friedewald

formula

ALAT

and

ASAT

were

measured

by

a

pyridoxal-phosphate

activation

assay

-LRB-

Roche

Diagnostics

-RRB-

was

measured

using

an

HPLC

-LRB-

Reagens

Bio-Rad

Laboratories

BV

the

Netherlands

-RRB-

on

a

Variant

II

-LRB-

Bio-Rad

Laboratories

-RRB-

Total

plasma

hyaluronan

and

hsCRP

levels

were

determined

in

duplicates

by

commercial

ELISA

-LRB-

Echelon

Biosciences

Salt

Lake

City

UT

USA

and

Roche

Bern

Switzerland

respectively

-RRB-

Plasma

hyaluronidase

levels

were

determined

with

a

previously

described

assay

-LSB-

-RSB-

Ultrasound

B-mode

protocol

for

cIMT

measurement

B-mode

ultrasound

imaging

was

used

to

visualise

three

carotid

arterial

wall

segments

comprising

common

carotid

bulb

and

internal

of

the

left

and

right

carotid

arteries

according

to

a

previously

published

protocol

-LSB-

-RSB-

Subjects

were

scanned

in

the

reclined

position

following

a

predetermined

standardised

protocol

An

Acuson

v

-LRB-

Siemens

Erlangen

Germany

-RRB-

equipped

with

an

linear

array

transducer

and

extended

frequency

software

was

used

B-mode

images

were

stored

as

compressed

jpeg

files

on

a

digital

still

recorder

-LRB-

SONY

P

-RRB-

All

scans

were

performed

by

the

same

sonographer

To

investigate

intra-sonographer

reproducibility

ten

study

subjects

were

scanned

in

duplicate

These

investigations

enabled

us

to

provide

robust

arterial

wall

thickness

measurements

-LRB-

SD

of

the

means

of

the

paired

cIMT

measurements

mm

CV

-RRB-

One

image

analyst

performed

the

analyses

off-line

with

semi-automated

quantitative

and

qualitative

video

image

analysis

software

Both

the

sonographer

and

the

image

analyst

were

blinded

to

the

clinical

status

of

the

subjects

These

images

provided

the

cIMT

data

Mean

cIMT

was

defined

as

the

mean

cIMT

of

the

right

and

left

common

carotid

the

carotid

bulb

and

the

internal

carotid

far

wall

segments

For

a

given

segment

cIMT

was

defined

as

the

average

of

the

right

and

left

cIMT

measurements

The

per-patient

averaged

means

of

the

cIMT

values

of

segments

was

used

for

the

primary

analysis

Statistical

analysis

Mean

values

of

continuous

variables

between

type

diabetes

patients

and

controls

were

compared

using

Student

's

t

test

for

independent

samples

In

the

case

of

a

skewed

distribution

the

t

test

was

performed

on

log-transformed

values

while

medians

and

interquartile

ranges

are

presented

Chi-square

tests

were

applied

for

comparison

of

distribution

of

dichotomous

data

Correlation

between

hyaluronan

and

hyaluronidase

was

calculated

by

Spearman

's

rank

coefficient

-LRB-

two-tailed

-RRB-

In

this

study

our

main

interest

was

to

find

predictors

for

type

diabetes-associated

atherosclerosis

and

vascular

dysfunction

The

relationship

between

the

dependent

variable

cIMT

on

the

one

hand

and

other

parameters

-LRB-

e.g.

plasma

hyaluronan

-RRB-

on

the

other

was

first

explored

univariably

using

linear

regression

analysis

For

clinical

variables

and

variables

which

revealed

statistically

significant

correlations

in

the

univariate

analysis

estimates

of

cIMT

adjusted

for

confounding

were

calculated

with

SPSS

version

-LRB-

Chicago

IL

USA

-RRB-

In

addition

several

multivariate

models

were

built

to

explore

the

effects

of

age

sex

and

the

statistically

significant

variables

on

cIMT

Throughout

a

two

tailed

p

value

was

considered

statistically

significant

Results

Clinical

characteristics

of

the

type

diabetes

subjects

and

matched

controls

are

listed

in

Table

There

was

no

significant

difference

between

type

diabetes

subjects

and

controls

with

regard

to

age

sex

BMI

systolic

and

diastolic

blood

pressure

liver

function

tests

and

cholesterol

profile

However

we

did

observe

increased

values

for

heart

rate

plasma

hsCRP

hyaluronan

and

hyaluronidase

in

type

diabetes

patients

A

significant

correlation

was

found

between

plasma

hyaluronan

and

hyaluronidase

activity

in

type

diabetes

-LRB-

r

p

see

Fig.

-RRB-

After

exclusion

of

the

highest

hyaluronidase

activity

levels

-LRB-

levels

U/ml

-RRB-

the

correlation

between

hyaluronan

and

hyaluronidase

levels

was

still

present

Liver

function

tests

-LRB-

ASAT

and

ALAT

-RRB-

were

not

significantly

associated

with

plasma

hyaluronan

levels

in

type

diabetes

Table

and

baseline

parameters

of

the

study

cohort

Type

diabetes

patientsControlsNumber

of

-LRB-

male/female

-RRB-

-LRB-

years

-RRB-

Duration

of

diabetes

-LRB-

years

-RRB-

Daily

insulin

dose

-LRB-

IU

-RRB-

Smoking

-LRB-

yes/no

-RRB-

-LRB-

-RRB-

Systolic

blood

pressure

-LRB-

mmHg

-RRB-

blood

pressure

-LRB-

mmHg

-RRB-

rate

-LRB-

beats/min

-RRB-

Total

cholesterol

-LRB-

mmol/l

-RRB-

-LRB-

mmol/l

-RRB-

-LRB-

mmol/l

-RRB-

Triacylglycerol

-LRB-

mmol/l

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

ASAT

-LRB-

U/l

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

ALAT

-LRB-

U/l

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Hyaluronan

-LRB-

ng/ml

-RRB-

-LRB-

U/ml

-RRB-

-LRB-

mg/l

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

cIMT

-LRB-

mm

-RRB-

Data

are

means

SD

except

for

triacylglycerol

ASAT

ALAT

and

hsCRP

which

are

expressed

as

median

-LRB-

inter-quartile

range

-RRB-

p

p

type

diabetes

patients

vs

controlsFig

Relationship

between

plasma

hyaluronan

levels

and

plasma

hyaluronidase

activity

in

type

diabetes

patients

b

Relationship

between

plasma

hyaluronan

levels

and

cIMT

in

type

diabetes

patients

Mean

cIMT

was

increased

in

the

type

diabetes

group

compared

with

controls

-LRB-

vs

mm

p

-RRB-

In

type

diabetes

subjects

plasma

hyaluronan

levels

-LRB-

Fig.

-RRB-

age

male

sex

duration

of

diabetes

and

mean

blood

pressure

were

positively

correlated

with

mean

cIMT

in

univariate

analysis

No

dose-dependent

relationship

between

insulin

dose

levels

and

mean

cIMT

was

found

in

these

patients

However

upon

multivariate

linear

regression

analysis

only

age

and

sex

remained

significantly

associated

with

cIMT

-LRB-

Table

-RRB-

Table

and

multivariate

associations

of

cIMT

with

various

risk

factors

in

patients

with

type

diabetesParameterUnivariate

β

coefficientp

valueMultivariate

β

coefficientp

valueFemale

sex

Duration

of

diabetes

Daily

insulin

dose

Mean

blood

Heart

Total

cholesterol0.0160.366LDL-cholesterol0.0210

Triacylglycerol

ALAT

hsCRP

p

type

diabetes

patients

vs

controls

Discussion

In

line

with

expectation

type

diabetes

patients

were

characterised

by

structural

changes

of

the

arterial

wall

In

addition

we

observed

significant

elevations

of

plasma

hyaluronan

and

hyaluronidase

activity

levels

in

type

diabetes

patients

whereas

hyaluronan

was

correlated

to

cIMT

These

present

data

imply

that

disturbances

of

hyaluronan

metabolism

may

be

associated

with

vascular

damage

in

type

diabetes

patients

Intima-media

thickness

in

type

diabetes

We

observed

a

significant

increase

in

cIMT

in

type

diabetes

patients

without

micro

or

macro-vascular

complications

compared

with

controls

and

confirmed

that

male

sex

is

associated

with

an

increased

cIMT

-LSB-

-RSB-

Despite

the

cross-sectional

design

of

our

study

this

finding

is

compatible

with

data

from

the

longitudinal

DCCT

study

-LSB-

-RSB-

LDL-cholesterol

was

not

associated

with

cIMT

progression

in

the

DCCT

cohort

underscoring

a

potential

role

for

hyperglycaemia

in

diabetic

atherogenesis

-LSB-

-RSB-

In

contrast

to

the

DCCT

findings

we

did

not

find

a

correlation

between

cIMT

and

glycaemic

status

This

apparent

discrepancy

may

have

several

explanations

First

a

single

determination

of

in

our

study

may

not

be

a

reliable

reflection

of

glycaemic

excursions

over

the

last

months

to

years

In

the

DCCT

was

evaluated

repetitively

in

a

prospective

cohort

of

type

diabetes

patients

all

receiving

an

intensive

treatment

regimen

-LSB-

-RSB-

Under

these

circumstances

was

predictive

of

cIMT

progression

over

the

next

years

Second

the

elderly

patients

in

our

cohort

may

have

been

exposed

to

longer

periods

of

poorly

controlled

diabetes

followed

by

more

intensive

treatment

regimens

only

in

the

last

few

years

As

a

consequence

their

present

levels

may

have

underestimated

long-term

glycaemic

exposure

Hyaluronan

metabolism

and

type

diabetes

Hyaluronan

is

the

principal

constituent

of

endothelial

glycocalyx

as

well

as

the

extra-cellular

matrix

-LSB-

-RSB-

Since

the

glycocalyx

is

a

principal

determinant

of

vascular

permeability

for

macromolecules

-LRB-

e.g.

lipoproteins

-RRB-

glycocalyx

loss

may

contribute

to

the

increased

transvascular

leakage

of

lipoproteins

in

patients

with

type

diabetes

-LSB-

-RSB-

Indeed

exposure

of

the

carotid

artery

to

atherogenic

challenges

in

mice

resulted

in

increased

plasma

hyaluronan

shedding

concomitant

loss

of

endothelial

glycocalyx

and

increased

cIMT

-LSB-

-RSB-

In

line

we

observed

that

patients

with

uncomplicated

type

diabetes

have

a

profound

reduction

of

endothelial

glycocalyx

which

was

associated

with

increased

plasma

hyaluronan

and

hyaluronidase

levels

-LSB-

-RSB-

In

fact

in

the

present

study

we

find

a

positive

correlation

between

plasma

hyaluronan

and

cIMT

thickness

Upon

multivariate

analysis

this

correlation

was

lost

most

likely

due

to

the

fact

that

age

and

sex

are

very

closely

associated

with

cIMT

thus

attenuating

the

predictive

value

of

hyaluronan

-LSB-

-RSB-

We

did

not

find

a

relationship

between

chronic

inflammation

as

measured

by

hsCRP

and

plasma

hyaluronan

in

type

diabetes

Therefore

further

studies

are

needed

to

evaluate

the

effect

of

other

inflammatory

markers

-LRB-

e.g.

leucocyte

count

-RRB-

on

hyaluronan

metabolism

in

these

patients.Collectively

the

present

finding

implies

that

hyperglycaemia

may

elicit

alterations

in

hyaluronan

metabolism

which

are

likely

to

reflect

glycocalyx

perturbation

The

latter

facilitates

a

wide

array

of

pro-atherogenic

effects

including

vascular

dysfunction

and

increased

permeability

of

the

vessel

wall

for

for

example

lipoproteins

In

line

aggregation

of

calcium

with

hyaluronan

-LRB-

and

other

subendothelial

glycosaminoglycans

-RRB-

could

enhance

ectopic

calcification

of

the

cIMT

which

is

increased

in

type

diabetes

patients

-LSB-

-RSB-

It

would

be

interesting

to

investigate

whether

therapeutic

intervention

aimed

at

this

disturbed

hyaluronan

metabolism

in

type

diabetes

has

the

potential

to

reverse

the

pro-atherogenic

state

in

these

patients

-LSB-

-RSB-

Study

limitations

Several

methodological

aspects

of

our

study

merit

caution

We

did

not

determine

fasting

plasma

glucose

levels

in

our

type

diabetes

subjects

therefore

we

were

only

able

to

study

markers

of

chronic

hyperglycaemia

-LRB-

-RRB-

on

vascular

dysfunction

Moreover

the

observational

nature

of

our

study

combined

with

the

use

of

surrogate

markers

of

future

vascular

disease

can

be

considered

a

weakness

However

solid

evidence

exists

that

changes

in

arterial

wall

function

are

predictive

of

cardiovascular

outcome

-LSB-

-RSB-

In

addition

reproducibility

of

the

measurements

was

excellent

since

a

single

ultrasound

machine

was

used

one

experienced

sonographer

performed

all

ultrasonography

and

images

were

analysed

by

a

single

reader

To

reduce

variability

further

image

analysis

software

automatically

investigated

each

measurement.Finally

endothelial

glycocalyx

also

comprises

other

glycosaminoglycans

such

as

syndecan

chondroitin

sulphate

and

heparan

sulphate

which

all

have

their

own

function

-LSB-

-RSB-

Since

hyaluronan

and

heparan

sulphate

are

important

in

shear

stress-mediated

nitric

oxide

production

which

is

inextricably

entangled

with

atherosclerosis

further

research

is

needed

to

explore

the

role

of

these

other

endothelial

glycocalyx

compounds

on

diabetes

mellitus

associated

vascular

dysfunction

O O B O O O O B I I I O O O O O O O O O B I I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

hyaluronan
hyaluronidase
type 1 diabetes mellitus


The autonomic nervous system at high altitude The effects of hypobaric hypoxia in visitors depend not only on the actual elevation but also on the rate of ascent . Sympathetic activity increases and there are increases in blood pressure and heart rate . Pulmonary vasoconstriction leads to pulmonary hypertension , particularly during exercise . The sympathetic excitation results from hypoxia , partly through chemoreceptor reflexes and partly through altered baroreceptor function . High pulmonary arterial pressures may also cause reflex systemic vasoconstriction . Most permanent high altitude dwellers show excellent adaptation although there are differences between populations in the extent of the ventilatory drive and the erythropoiesis . Some altitude dwellers , particularly Andeans , may develop chronic mountain sickness , the most prominent characteristic of which being excessive polycythaemia . Excessive hypoxia due to peripheral chemoreceptor dysfunction has been suggested as a cause . The hyperviscous blood leads to pulmonary hypertension , symptoms of cerebral hypoperfusion , and eventually right heart failure and death . Introduction High altitude places are amongst the most inhospitable on earth . According to WHO -LSB- 70 -RSB- in 1966 there were approximately 140 million people living at altitudes over 2,500 m and there are several areas of permanent habitation at over 4,000 m . These are in three main regions of the world : the Andes of South America , the highlands of Eastern Africa , and the Himalayas of South-Central Asia . This review is concerned with the effects of the altitude on visitors and the ways by which the permanent high altitude dwellers have adapted to their environment . The two main challenges to life at high altitude come from hypobaric hypoxia and the low ambient temperatures . Temperature decreases about 1 °C for each 150 m elevation , so that at 4,500 m temperature is roughly 30 °C lower than at sea level . Barometric pressure falls progressively with increasing altitude . Up to about 2,500 m there are few if any effects of hypoxia . Above 3,000 m some effects of hypoxia are likely to be experienced and above 4,000 m adverse effects would be experienced by most unacclimatized visitors . However , many people live and work at altitude with no apparent adverse effects . One such example is Cerro de Pasco a busy mining town of 72,000 population at 4,300 m in the Peruvian Andes , where much high altitude research has been undertaken . At this altitude barometric pressure is 450 mmHg and without hyperventilation alveolar oxygen tension would be only 34 mmHg . Autonomic control in visitors Most adaptive changes occur in the first days and weeks following arrival at altitude , and this is the period when acute mountain sickness with cerebral and/or pulmonary oedema may occur . Recent studies in animals and man have highlighted the role of the autonomic nervous system in adaptation and in particular the importance of sympathetic activation following high altitude exposure . Cardiovascular effects Acute hypobaric hypoxia results in an increase in resting heart rate and blood pressure and this is seen both during altitude exposure -LSB- 5 -RSB- and during simulated exposure using a hypobaric chamber -LSB- 68 -RSB- . Vogel et al. -LSB- 68 , 69 -RSB- demonstrated that the rate of ascent influenced the magnitude of the tachycardia . Gradual increases in altitude over two weeks resulted in larger heart rate changes compared with an abrupt ascent . Later , as subjects acclimatise at altitudes up to about 4,500 m , much of the increase in heart rate is lost and resting heart rates return towards their sea level values . Acute hypoxia also causes an increase in cardiac output both at rest and for given levels of exercise . This was seen both when breathing hypoxic gas at sea level -LSB- 34 , 68 , 69 -RSB- and on acute exposure to high altitude -LSB- 21 -RSB- . As subjects acclimatise to the altitude cardiac output decreases although the heart rate can remain high with a low stroke volume . This may be due to a loss of plasma volume -LSB- 23 , 54 -RSB- . The effect of hypoxia on the pulmonary circulation is rapid , resulting in an increase in pulmonary vascular resistance and pulmonary hypertension -LSB- 49 -RSB- . The maximum response occurs within 5 min -LSB- 65 -RSB- . Breathing 11 % oxygen for 30 min increases pulmonary artery pressure from 16 to 25 mmHg -LSB- 72 -RSB- . The effect of hypoxia on the pulmonary circulation is even more pronounced during exercise , as demonstrated in the Operation Everest II studies -LSB- 24 -RSB- where pulmonary artery pressure increased during near-maximal exercise at 8840 m to 54 mmHg . The mechanism of pulmonary artery vasoconstriction initially involves inhibition of O2 sensitive K + channels leading to depolarization of pulmonary artery smooth muscle cells and activation of voltage gated Ca2 + channels causing Ca2 + influx and vasoconstriction -LSB- 48 -RSB- . This process is immediately reversed by breathing oxygen . However , lowlanders exposed to high altitude for 2 -- 3 weeks develop pulmonary hypertension that is not completely reversed by oxygen breathing -LSB- 24 -RSB- suggesting remodelling of pulmonary arterioles . Remodelling involves proliferation of smooth muscle cells and thickening of the artery wall -LSB- 57 -RSB- . Sympathetic activity Acute hypoxia is a potent activator of sympathetic activity -LSB- 39 , 56 -RSB- . Studies in several species , including dogs , rats and rabbits , showed that hypoxia stimulated the sympathoadrenal system . Acute hypoxia in spontaneously breathing anaesthetized animals causes increases in sympathetic nerve activity , increased release of catecholamines , increases in heart rate and regional vasoconstriction -LSB- 28 , 60 -RSB- . However the effects of hypoxia on the human sympathetic nervous system are more difficult to determine and often indirect methods of assessment have been employed . One method of assessment of sympathetic activity in humans is from blood or urine levels of catecholamines . However , catecholamine levels are the net resultant of secretion , spill-over , reuptake and excretion -LSB- 59 , 18 -RSB- and results must be interpreted with caution . Mazzeo et al. -LSB- 40 -RSB- measured arterial noradrenaline and adrenaline concentrations in subjects at sea level , then after 4 h then 21 days at altitude -LRB- 4,300 m -RRB- . They reported an initial decrease in noradrenaline but by day 21 it had increased to 52 % above sea level values . Arterial adrenaline values doubled following acute altitude exposure then declined to only 26 % above sea-level by day 21 . In a later study , however , the same authors -LSB- 41 -RSB- measured 24 h urinary noradrenaline and adrenaline excretion and venous plasma catecholames in women at sea level and during 12 days of exposure to 4,300 m and reported increases in both urinary noradrenaline and adrenaline excretion after only one day at altitude and increases in plasma catecholamines on day 4 at altitude . During the 12 day period noradrenaline continued to increase as assessed both from urinary excretion and in the plasma samples . Adrenaline values however fell back to those recorded at sea level . Rostrup -LSB- 59 -RSB- reported initial decreases in both plasma noradrenaline and adrenaline which subsequently recovered . Results from simulated hypoxia are also conflicting with an increase in urinary adrenaline but no change in noradrenaline -LSB- 29 -RSB- or no change in either -LSB- 71 -RSB- . These results illustrate the difficulty in assessing autonomic activity from blood or urine catecholamines , but they do suggest that in the early stages of exposure to altitude there is an increase mainly in adrenaline , but that later it is noradrenaline that predominates . The changes in catecholamines are more consistent during exposure to chronic hypoxia . Calbet -LSB- 10 -RSB- measured systemic and skeletal muscle noradrenaline and adrenaline spillover in lowlanders after exposure to 5,260 m . After 9 weeks plasma noradrenaline and adrenaline concentrations were approximately 4 and 2 fold higher than the sea level values . These values were similar to those in patients with compensated chronic heart failure -LSB- 2 -RSB- . The heart rate at maximal exercise is reduced at altitude . In Operation Everest II maximal heart rates decreased from 160 at sea level to 118 at 8,848 m -LSB- 54 -RSB- . Given the evidence for elevated catecholamines at altitude , at least during chronic exposure , this suggests a down regulation of the cardiac β - adrenergic receptors . Studies in rats following prolonged exposure to hypobaric hypoxia have shown a decreased β-adrenergic receptor density -LSB- 30 , 67 -RSB- . Short exposures to hypoxia -LRB- 1 -- 15 days -RRB- did not affect β-adrenergic receptor density . However by 21 days there was a 24 % reduction . Leon-Velarde et al -LSB- 35 -RSB- exposed rats to a simulated altitude of 5,500 m for 21 days and also found a 24 % reduction in β-adrenergic receptor density in both left and right ventricles . They also reported an increase in α1-adrenergic receptor density in the left ventricle , although Morel et al -LSB- 48 -RSB- , who exposed rats to 5,500 m for 15 days , found no change in α1-adrenergic receptor density in either left or right ventricle . Density of adenosine receptors has also been shown to be decreased by 46 % following 30 day exposure to 5,500 m simulated altitude in the rat while muscarinic receptor density increased by 49 % -LSB- 31 -RSB- . Changes in receptor density have also been estimated indirectly in man by determining the rate of isoprenaline infusion required to increase heart rate by 25 beats/min . The required rate increased with increasing exposure to altitude and this was attributed to a down regulation of the β-adrenergic receptors -LSB- 56 -RSB- . Platelet α2-adrenergic receptor density decreased after 4 weeks exposure to 5,050 m -LSB- 19 -RSB- . Changes in α2-adrenergic receptor density on platelets may indicate a similar change in the central nervous system -LSB- 53 -RSB- . In the central nervous system α2-adrenergic receptors are known to play an important role in cardiovascular regulation -LSB- 22 -RSB- . Stimulation of these receptors in the ventrolateral medulla has been shown to reduce sympathetic and increase parasympathetic outflow -LSB- 55 -RSB- . If a change in the density of these receptors occurred it may explain many of the effects of altitude on the autonomic system . The effect on the parasympathetic system has been assessed in humans from the responses to muscarinic blockade . Following short exposures to hypoxia the changes in heart rate following muscarinic blockade became smaller -LSB- 11 -RSB- . However , Boushel et al. -LSB- 8 -RSB- exposed subjects to an altitude of 5,260 m for 9 weeks and then studied the effects of muscarinic blockade both at rest and during exercise , and suggested that there was an enhanced parasympathetic activity and that this was responsible for the reduction in heart rate seen during chronic adaptation to altitude . Muscle sympathetic nerve activity Several studies have examined the effects of acute hypoxia on muscle sympathetic nerve activity and reported increases in discharge -LSB- 17 , 27 -RSB- . Chronic hypoxia also enhances sympathetic activity and Hanson and Sander -LSB- 27 -RSB- reported that , following exposure to an altitude of 5,260 m for 4 weeks , activity remained elevated 3 days following descent . Heart rate variability Cardiac autonomic nerve activity is often assessed noninvasively from spontaneous changes in heart rate . This is influenced by respiration -LSB- 9 -RSB- and this complicates many studies of hypoxia due to the concomitant respiratory stimulation . High frequency R -- R interval power is considered to be associated with cardiac parasympathetic activity whereas the low frequency components are associated with both parasympathetic and sympathetic activity . The ratio of low to high frequency power is said to be an index of the `` sympathovagal balance '' . Power in both high and low frequency bands were found to decrease at altitude although the ratio of low to high frequency power increased -LSB- 32 , 16 , 17 -RSB- . The increase in the ratio is believed to imply that the sympathetic activity is dominant compared to parasympathetic . These findings imply that acute exposure to hypoxia causes decreased parasympathetic and increased sympathetic tone and during acclimatization there is a progressive shift toward still higher sympathetic tone . Arterial baroreflex Studies in humans of baroreflex control at altitude or simulated altitude have yielded contradictory results . Sagawa et al. -LSB- 61 -RSB- , using the neck chamber method , reported that acute exposure to simulated altitude of 4,300 m had no effect on carotid baroreflex set point for heart rate control but there was a 50 % reduction in the gain of the reflex . Halliwill and Minson -LSB- 25 , 26 -RSB- , on the other hand , using nitroprusside and phenylephrine , found that hypoxic breathing increased set point but did not change gain . Studies of `` spontaneous '' baroreflex gain have indicated that it decreases at altitude or simulated altitude -LSB- 5 , 6 , 7 , 63 -RSB- . Interpretation of these findings is complicated by the differences in baseline blood pressures and heart rate . Recently , Cooper et al. -LSB- 15 -RSB- reported that although acute hypoxia did not change baroreceptor control of heart rate it did decrease the gain of the vascular resistance response without changing `` set point '' . Mechanisms for sympathetic activation at high altitude The increase in sympathetic activity at altitude is caused by both the direct and indirect effects of hypoxia . The role of chemoreceptors is reviewed by Marshall -LSB- 39 -RSB- . Hypoxia acts directly on vascular smooth muscle in the systemic circulation causing relaxation and therefore hypotension . This , in turn , would lead to baroreceptor-mediated sympathetic excitation . Alterations in baroreflex function : an increase in `` set point '' and possibly a decrease in gain , are likely to contribute . An additional mechanism for exciting sympathetic activity may also arise through stimulation of pulmonary arterial baroreceptors . Hypoxia induces pulmonary hypertension and we have recently reported that , in the anaesthetized dog , increases in pulmonary artery pressure increase systemic vascular resistance -LSB- 38 , 46 -RSB- . Autonomic function in high altitude residents Healthy highlanders Healthy high altitude dwellers show excellent adaptation to their environment . These adaptations are likely to be associated with altered gene expression as the expression of genes associated with vascular control and reactions to hypoxia have been found to be high in altitude dwellers -LSB- 1 -RSB- . Different communities , however , seem to adopt different adaptation strategies -LSB- 4 -RSB- . For example Andeans hyperventilate to decrease end-tidal and arterial CO2 levels to as low as 25 mmHg and have haemoglobin levels well above those at sea-level . Ethiopian highlanders , on the other hand , have CO2 and haemoglobins levels similar to sea-level dwellers -LSB- 13 , 33 -RSB- . Despite the successful adaptation of permanent residents , some differences do occur . The carotid body shows age-related hyperplasia but blunted responses to hypoxia -LSB- 62 -RSB- . High altitude dwellers have been reported to show earlier cardiovascular degenerative changes with aging . Arterial wall stiffness is greater and blood pressures are higher -LSB- 51 , 52 -RSB- . High altitude residents , both healthy subjects and patients with chronic mountain sickness -LRB- see below -RRB- have higher catecholamine levels when measured at altitude than following descent to sea level -LSB- 20 -RSB- . Baroreceptors , however , appear to function normally at altitude -LSB- 5 -RSB- . We -LSB- 45 -RSB- examined cardiac and vascular responses to neck chamber pressures and found that responses were unaffected by descent to sea-level . Moore et al. -LSB- 47 -RSB- also studied baroreceptor function in anaesthetized dogs , which allows better control of relevant variables . There was no difference in the gain of the baroreflex control of vascular resistance between lowland animals and animals reared at altitude -LRB- 4,330 m -RRB- . Set point , however , was lower in high altitude animals which seems surprising in view of the known hypertensive effect of hypoxia . Blood volumes are larger in high altitude dwellers . In Andeans this is due to a large packed cell volume whereas in Ethiopians plasma volume was large -LSB- 12 , 13 -RSB- . Probably as the result of the large blood volumes , tolerance to orthostatic stress was greater than that in sea-level residents -LSB- 12 , 14 -RSB- . Patients with chronic mountain sickness Chronic mountain sickness -LRB- CMS , Monge 's disease ; -LSB- 43 -RSB- -RRB- is a condition frequently found in long-term residents of high altitudes particularly in the Andes where it is a major public health problem . It also occurs in residents on the Tibetan plateau , although not in Ethiopians -LSB- 13 -RSB- . Patients with CMS develop excessive polycythemia and various clinical features including dyspnoea , palpitations , insomnia , dizziness , headache , confusion , loss of appetite , lack of mental concentration and memory alterations . Patients may also complain of decreased exercise tolerance , bone pain , acral paraesthesia and occasionally haemoptysis . The impairment of mental function may be reversed by phlebotomy -LSB- 42 -RSB- . Physical examination reveals cyanosis , due to the combination of polycythemia and low oxygen saturation , and a marked pigmentation of the skin exposed to the sun . Hyperaemia of conjunctivae is characteristic and the retinal vessels are also dilated and engorged . The second cardiac sound is frequently accentuated and there is an increased cardiac size , mainly due to right ventricular hypertrophy . As the condition progresses , overt congestive heart failure becomes evident , characterized by dyspnoea at rest and during mild effort , peripheral oedema , distension of superficial veins , and progressive cardiac dilation . A clinical score was devised in the attempt to assess the severity of the syndrome and to compare CMS cases within and between different countries in the world -LSB- 37 -RSB- . CMS is most likely the result of several influences acting on subjects living at high altitudes . Hypoventilation associated with aging has been proposed as one of the main underlying mechanisms -LSB- 64 -RSB- . Many of the clinical features may be attributed to the excessive polycythemia which leads to hyperviscosity of the blood and consequently impaired blood flow and impaired oxygen delivery to several organs including the brain -LSB- 44 -RSB- . Sime et al. -LSB- 64 -RSB- reported a blunted ventilatory response to hypoxia -LRB- VRH -RRB- in subjects with CMS and suggested this as the basic underlying cause . However , the same effect may also occur in some subjects without CMS -LSB- 3 , 62 -RSB- . The function of the peripheral chemoreceptors has been shown to be abnormal -LSB- 36 -RSB- . Studies have been carried out to examine the plasticity of chemoreflexes to both long and short term changes in blood gas tensions of chronically hypoxic high-altitude natives with blunted respiratory responses to hypoxia . It was found that natives who had migrated to live at sea level had ventilatory responses to acute hypoxia -LRB- few minutes -RRB- which had become similar to those of sea-level controls -LSB- 21 -RSB- . However , responses to sustained hypoxia -LRB- 20 min -RRB- remained markedly blunted . These results may explain the apparent discrepancy in previous studies . Recent studies have examined cardiovascular and cerebrovascular control in subjects with CMS . Bernardi et al. -LSB- 6 -RSB- assessed baroreflex function and the chemo - and baroreflex interactions in Andean subjects with and without CMS . They found that subjects with CMS showed a reduction in the responses to stimulation of peripheral chemoreflexes . In addition , these subjects also showed a reduction in the baroreflex control of heart rate and blood pressure . The reduction in the arterial baroreflex correlated with an increase in CMS score , and with an increase of haemoglobin levels . They interpreted these findings as suggestive of a functional , reversible central depression rather than of the presence of an organic dysautonomia in CMS . They further suggested that the observed baroreflex alteration might be involved in the causation of some of the symptoms of CMS . In another study on subjects with CMS , performed at high altitude , the same authors showed that increasing oxygen saturation for an hour by a slow breathing pattern or by oxygen administration was associated with increased arterial baroreflex sensitivity -LSB- 33 -RSB- . The major mechanism for the control of blood pressure is through regulation of peripheral vascular resistance , but most studies have examined only the control of heart rate . We have recently studied the responses of forearm vascular resistance to carotid baroreceptor stimulation in high altitude residents with and without CMS , both at their resident altitude and shortly after descent to sea level . Results showed that baroreflex `` set point '' was higher in CMS , but only at altitude . At sea level , values were similar -LSB- 45 -RSB- . Cerebrovascular control Cerebral blood flow is known to be less in CMS patients than in healthy controls and this is attributed to the high viscosity of the blood . Villafuerte et al. -LSB- 66 -RSB- estimated that the ideal haemoglobin level for maximal oxygen delivery is 14.7 g/dl , a value similar to that of sea-level dwellers . The cerebral circulation normally shows an efficient autoregulation whereby changes in cerebral perfusion pressure have minimal effect on flow . Claydon et al. -LSB- 14 -RSB- assessed autoregulation from the correlation between flow and pressure during orthostatic stress , where a significant correlation with a high coefficient indicates poor autoregulation . Results of this study showed that cerebrovascular autoregulation was impaired in CMS patients . These findings are compatible with those of Roach et al. -LSB- 58 -RSB- who reported reduced cerebrovascular sensitivity to carbon dioxide in the presence of hypobaric hypoxia in subjects with CMS . Norcliffe et al. -LSB- 50 -RSB- determined the cerebrovascular responses to hypoxia and hypercapnia , separately and together , in CMS patients and normal high altitude dwellers . CMS patients did not respond differently from the normals , but in both groups at altitude the sensitivity of the cerebral circulation to hypoxia was less than that in sea level residents . Shortly after descent to sea level , however , sensitivity increased . Sensitivity to hypercapnia during hypoxia decreased after descent .

O B I I O O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B I O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O

altitude
mountain sickness
hypoxia
polycythemia
respiration
chemoreceptors
baroreceptors
autonomic nervous system