杏吧原创

EVER since the First World War and the horrors of the trenches, physicians,
psychologists and psychiatrists have puzzled over how apparently healthy people
can end up bedridden, breathless and bothered by heart irregularities. This
condition has been given many names, including soldier鈥檚 heart, effort syndrome
and neurasthenia. Patients suffer a wide variety of symptoms and no physical
cause is obvious, so there is still no agreed definition or treatment.

But for forty years, one diagnosis has been in the ascendant鈥攃hronic
hyperventilation, or hyperventilation syndrome (HVS). A sufferer of this
hypothetical condition is believed to breathe excessively over long periods.
Persistent overbreathing removes too much carbon dioxide from the blood. This
increases blood pH and, says the HVS theory, triggers a combination of
symptoms that can include wind, diarrhoea, muscle pains, fatigue, heart
arrhythmia and anxiety.

HVS grew in prominence in the 1970s. Claude Lum, formerly a chest physician
at Papworth Hospital in Cambridge, claimed that up to 10 per cent of people
visiting outpatient clinics suffered from the syndrome. He also stressed that
HVS was not a product of other disease, but a 鈥減rimary disorder鈥�. In the
mid-1980s, this torch was picked up by Peter Nixon, a former NHS cardiologist
and prominent Harley Street consultant, who believed that HVS was a prime cause
of cardiac disorders, including heart attacks. Nixon has written more than 70
journal and newspaper articles blaming HVS for everything from chronic fatigue
to Gulf War syndrome.

But Nixon鈥檚 work on hyperventilation is now discredited and the very
existence of HVS is in doubt. His reputation collapsed in May after he
unsuccessfully sued for libel over allegations in a television documentary that
he had rigged hyperventilation tests. The court case revealed that Nixon鈥檚
research and diagnostic techniques were, at best, scientifically and ethically
dubious. After five days of cross-examination at the High Court in London, he
withdrew his case, agreed to pay costs of 拢765 000, and to retire
immediately from medical practice. In a bizarre twist, two prominent researchers
who supported Nixon provided the ammunition for a surprise attack in court on
recent studies which appear to show that HVS does not exist. The nature of the
clash suggests that some researchers have placed their faith in HVS ahead of
empirical science.

These events have confirmed long-standing worries among some specialists that
HVS was being written about in journals and diagnosed by doctors despite a lack
of rigorous scientific testing. Even New 杏吧原创 carried an
uncritical report of Lum鈥檚 and Nixon鈥檚 claims (鈥淭he hazards of heavy breathing鈥�,
3 December 1988, p 48). One of the chief critics of HVS is William Gardner,
senior lecturer in the department of thoracic medicine at King鈥檚 College School
of Medicine and Dentistry in London. There is a 鈥渄earth of data based on modern
quantitative criteria鈥�, he wrote last year in Chest (vol 109, p
516).

Dangerous diagnosis

鈥淢uch research in this area is bedevilled鈥�by the presentation of
scientifically unsound data lacking in rigorous quantitative proof and with
perpetuation of circular arguments,鈥� Gardner has argued. 鈥淣ot only is the term
hyperventilation syndrome of dubious value clinically, its use can be dangerous
in that it distracts from seeking the true causes of the increased respiratory
drive.鈥� So patients could be put at risk when HVS is diagnosed as the cause of
serious disease, while the real underlying problem goes untreated.

Back in 1979, in a bid to place HVS on a sound footing, two Dutch military
physicians reported that they had developed an objective diagnostic test. Their
hyperventilation provocation test (HVPT) uses a capnograph, which measures the
partial pressure of carbon dioxide in exhaled breath. The patient is asked to
hyperventilate for 3 minutes, which can halve the level of CO₂ in
blood. If the pressure of CO₂ in the breath does not then recover to at
least two-thirds of normal after 3 minutes or so the diagnosis is HVS.

But was this test valid, or could the stress of the test induce positive
results? To answer this would take a comparison with the best available test.
The 鈥済old standard鈥� would be to directly measure the level of CO₂
dissolved in arterial blood and show it to be lower than normal in HVS patients.
But until recently such checks could only be done in a lab, and were not
performed by many physicians. In the meantime, some researchers who used the
HVPT failed to obtain clear-cut results. They complained that it wrongly
identified non-sufferers as having HVS鈥攊t has a high false-positive
rate.

Nixon advanced a different view. The real problem with the HVPT, he said, is
too many false negatives. It is an 鈥渋nsensitive technique which causes the
rejection of many patients鈥�, he wrote in the Journal of the Royal Society of
Medicine (vol 81, p 277). So, in the same paper, published in May 1988, he
described an alternative鈥攖he 鈥渢hink test鈥�.

He connected patients to a capnograph and asked them to think about stressful
events in their life. If the pressure of CO₂ in their exhaled breath
fell by an arbitrary 10 millimetres of mercury, Nixon diagnosed HVS. The think
test produced twice as many diagnoses as the HVPT. This, he argued, suggested it
was the better test.

Laboratory workbooks that Nixon disclosed in court show that, soon after
inventing the think test, he had manipulated the procedure and achieved even
higher rates of diagnosis. In the May 1988 paper, Nixon stressed that no mention
of breathing should be made during the test, to avoid inducing the type of
response the doctor was looking for. Mentioning breathing, he told me in an
interview in 1991, meant that the results of the think test 鈥渄idn鈥檛 prove
anything鈥�. But his workbooks show that from January 1987 he had systematically
prompted patients to 鈥渓et your body show me how it was breathing鈥� as part of his
think test.

The nature of Nixon鈥檚 actual clinical procedures surfaced in the television
documentary, which I produced, and which was shown in 1994 on Britain鈥檚 Channel
4. In the programme, we secretly filmed Nixon being consulted by an AIDS
patient, Ian Hughes, who died last year. During the test, Nixon told Hughes to
鈥渟how me how you breathe when you鈥檙e angry鈥�. Then, after recording the dip in
partial pressure of CO₂from Hughes鈥檚 breath in response to this
request, Nixon announced his findings. 鈥淚t鈥檚 not some bloody virus [HIV] that
pulls you down, but the state you get into.鈥� Nixon recorded his diagnosis as
gross hyperventilation, and prescribed valium and an antihistamine, followed by
courses of physiotherapy and counselling to be purchased at his Harley Street
clinic.

In court, under cross-examination, it became glaringly clear that Nixon had a
poor grasp of scientific principles鈥攅ven when it came to his think test.
An analysis of his work by Kenneth MacRae, reader in medical statistics at the
Charing Cross and Westminster Medical School in London, revealed that Nixon鈥檚
methods had the primary effect of increasing the number of false positive
diagnoses.

There were other problems too. In his May 1988 paper, he reported on 54
patients, 16 of whom were positive on the HVPT, and 33 of whom had a positive
think test. But his test missed 9 of the 16 patients who were positive on the
HVPT. So the two tests seemed to be identifying different groups, making
comparison meaningless. In claiming to have a better test, Nixon had also failed
to compare his results with a gold standard test. In court, Nixon was presented
with MacRae鈥檚 analysis and asked: 鈥淵ou had no honest grounds for making the
claims you did about the efficacy of the think test?鈥� He said yes. 鈥淵ou agree
with me?鈥� the barrister asked. 鈥淵es,鈥� replied Nixon.

Worse followed. Nixon said he had not prepared protocols for his scientific
studies or, if he had, he hadn鈥檛 written them down. He admitted that at Charing
Cross Hospital and in private practice he experimented on patients without
ethical approval. He did not prepare informed consent forms or warn subjects
about the potential dangers, even though the tests carry the risk of inducing
heart attacks.

Nixon鈥檚 workbooks listed more than 4200 patients that he had tested since
1986, but he couldn鈥檛 say which patients had been included in which studies. He
also admitted reporting the same data differently in different places. In a
paper in the Journal of the Royal Society of Medicine (vol 79, p 76),
he said that 19 out of 27 patients tested for HVS using hypnosis were positive.
Later, in the American Journal of Clinical Hypnosis (vol 30, p 296), he
omitted three of the negative patients, improving his results to 19 out of 24.
This manoeuvre, he admitted in court, 鈥渓ooked rather suspicious鈥�. After his
fifth day of giving evidence, the judge鈥� who had earlier told him that he
appeared to have been, at best, medically negligent鈥攗rged him to consider
giving up his case, which he did.

During the court case, a subplot began to unfold involving researchers with
opposing views of HVS. In July last year, a group in Amsterdam published results
of a double-blind, placebo-controlled trial designed to investigate the validity
of the HVPT and the hyperventilation syndrome (The Lancet, vol 348, p
154). Hellen Hornsveld and her colleagues put 115 people with suspected HVS
through two provocation tests each, and asked them to list the symptoms they
felt. One of the two tests was a placebo, however, in which a team member fed
CO₂ to the patient at a rate that kept the partial pressure in their
exhaled breath constant鈥攕o the pH of the blood should not have
changed. The researchers also tested 40 healthy controls.

They divided the subjects into four groups: true positives, who reported
symptoms on the HVPT but not on the placebo test; false positives, who suffered
symptoms during both tests; a group that felt no symptoms during the HVPT; and
the healthy controls. Using standard test criteria, Hornsveld鈥檚 team found that
the HVPT identified 85 people as suffering HVS. But 56 of them were false
positives.

Time of attack

And that鈥檚 not all. The researchers fitted 15 true positives and 15 false
positives with small sensors that sit on the skin and constantly measure the
pressure of CO₂ in the blood. For two days the subjects went about
their business and recorded the time of any attack of symptoms. The results show
that only a few attacks were accompanied by hyperventilation. In these cases,
changes in breathing came after the onset of symptoms, so hyperventilation
appeared to be the result, not the cause. The team concludes that the notion of
HVS has 鈥渂ecome untenable鈥� and that the HVPT is 鈥渋nvalid as a diagnostic test鈥�.
It鈥檚 time to say 鈥渇arewell to the hyperventilation syndrome鈥�, says
Hornsveld.

During the court case, one of the Dutch team, pulmonary physician Paul van
Spiegel, travelled to London to interpret Nixon鈥檚 capnograph records of Ian
Hughes, and to explain to the court why these and other records did not support
Nixon鈥檚 diagnoses of HVS. Van Spiegel is a prominent member of a group of
scientific specialists known as the International Society for the Advancement of
Respiratory Psychophysiology (ISARP).

At the same time, two of ISARP鈥檚 top officials had sided with Nixon. Ronald
Ley, professor of psychology at the State University of New York, Albany, and
Beverly Timmons, a research fellow at St Bartholomew鈥檚 hospital in London, are
the two most recent presidents of ISARP. Without consulting the society鈥檚 board,
they agreed in 1994 that as soon as Nixon鈥檚 case had been resolved, he should
receive the society鈥檚 Award for Distinguished Contribution to Respiratory
Psychophysiology. Timmons wrote a letter, which Nixon produced in court, that
described Nixon as 鈥渢he obvious and most appropriate candidate鈥� for the
award.

In April this year, the two officials devoted a large part of the spring
issue of the society鈥檚 newsletter, Breathing, to criticism of the Dutch
study. Timmons claimed that the Dutch team鈥檚 sensors react slowly to changes in
blood levels of CO₂, so it is difficult to conclude that
hyperventilation does not precede an attack of symptoms. She also wrote that
asking patients to undergo two HPVTs was ethically unacceptable, because of the
test鈥檚 potentially unpleasant consequences. The Dutch study had, in fact,
received ethical approval.

Timmons brought advanced copies of the newsletter to court on the day van
Spiegel gave evidence, and sat in court as Nixon鈥檚 lawyers used it to challenge
the Dutch research. Other European members of ISARP did not receive the
newsletter until a week later. It was 鈥渁n ambush鈥�, says van Spiegel,
鈥渄iscrediting me and our team鈥檚 published research鈥�It is not acceptable
产别丑补惫颈辞耻谤鈥�.

Last month, Ley said that he had not read the Dutch study last summer when it
was published, nor had he attempted to publish his views in The Lancet,
which would have been the conventional place to criticise the research. He
declined to say whether he still supported the HVS theory. Timmons has declined
to talk to New 杏吧原创.

Van Spiegel and others are concerned at the appearance that Ley and Timmons
tried to harness ISARP鈥檚 reputation to Nixon鈥檚 cause. Kees Wientjes, chairman of
the Dutch chapter of ISARP, has asked them to account for their conduct. To
date, they have not replied to his questions and a clash seems inevitable. 鈥淎
scientific society that gives鈥攄ue to actions of its most prominent board
members鈥攖he impression to foster and promote certain scientific beliefs
and to discourage or even discredit research critical of such beliefs is
doomed,鈥� says Wientjes.

Schism

Wientjes says a 鈥渟chism鈥� has opened within ISARP between 鈥渁 camp of exponents
of the `classical鈥� belief in hyperventilation as a physiological problem
underlying an endless range of medical and psychological disorders, and a camp
of researchers primarily interested in an empirical and evidence-based
approach鈥�. The rival camps will meet next month to debate the definition of HVS.
Following the Nixon affair, 鈥渋t seems inevitable that the position of the
`believers鈥� is weakened鈥�, says Wientjes.

The story of Nixon and HVS raises questions about how to police the quality
and ethics of research, and the standard of peer review in medical journals. For
HVS, lessons need to be learnt quickly. If the clash between 鈥渂elievers鈥� and
empiricists continues, it bodes ill for medicine and patients. 鈥淎 clear
treatment strategy is vital,鈥� says Gardner. Without it, a host of 鈥渙therwise fit
and often young patients鈥� will become or remain chronically ill.

* * *

Theory and practice

THESE traces, which show the partial pressure of CO₂ in exhaled
breath, reveal how the think test was meant to work and how Nixon used it. The
top graph begins with a hyper-ventilation provocation test (HVPT). The level of
CO₂ returns to normal so this was negative. Nixon then asked the
patient to close her eyes and think about problems at work and her anger. She
hyperventilates and Nixon diagnosed HVS. The bottom trace is mine, made during
an undercover visit. I gave Nixon some imaginary stressful events in my life. He
asked about my 鈥渄ivorce鈥�, and then asked me to breathe as though I was in
despair or worried about my heart. When these had no effect, he asked me to
breathe as when I run. I panted, so my CO₂ pressure fell, and he
diagnosed hyperventilation.