Greater numbers of meta-analyses are finding their

way into medical journals [8]. Indeed, an emerging

topic is the meta-analysis of meta-analyses (a meta-

meta-analysis) [9]. Part of the explosion of interest

has been the automation of statistical testing. The

‘heavy lifting’ is no longer the calculation of effect

sizes and confidence intervals, but the searching for,

acquisition of, and inputting of data from relevant

clinical trials. The Cochrane Collaboration, a global

network of researchers maintains an informative

website (http://www.cochrane.org/), and distributes a

handbook that describes in detail the process of pre-

paring systematic reviews of healthcare interventions.

Software called ‘Review Manager’ produces the

attractive graphics that readers of Cochrane reviews

are familiar with. Searching for a particular abstract

or summary can be carried out at http://www.

cochrane.org/reviews/. It’s worth a look.

Disclosures

Leslie Citrome, is a consultant for, has received

honoraria from, or has conducted clinical research

supported by the following: Abbott Laboratories,

AstraZeneca Pharmaceuticals, Avanir Pharmaceuticals,

Azur Pharma Inc, Barr Laboratories, Bristol-Myers

Squibb, Eli Lilly and Company, Forest Research

Institute, GlaxoSmithKline, Janssen Pharmaceuticals,

Jazz Pharmaceuticals, Pfizer Inc, and Vanda Pharma-

ceuticals.

L. CitromeDepartment of Psychiatry,

New York University School of Medicine,New York, NY, USA

Clinical Research and Evaluation Facility,Nathan S. Kline Institute for Psychiatric Research,

Orangeburg, NY, USAEmail: citrome@nki.rfmh.org

References1 Edwards SJ, Clarke MJ, Wordsworth S, Borrill J. Indirect compari-

sons of treatments based on systematic reviews of randomised con-

trolled trials. Int J Clin Pract 2009; 63: 841–54.

2 Guyatt GH, Rennie D. Users’ Guides to the Medical Literature: Essen-

tials of Evidence-Based Clinical Practice. Chicago, IL: AMA Press,

2001. Table 1A-1, page 7.

3 Khoshdel A, Attia J, Carney SL. Basic concepts in meta-analysis: a

primer for clinicians. Int J Clin Pract 2006; 60: 1287–94.

4 Jones D. Of medicine and meta-analysis. Nat Rev Drug Discov 2008;

7: 376–7.

5 Lam RW, Kennedy SH. Using metaanalysis to evaluate evidence:

practical tips and traps. Can J Psychiatry 2005; 50: 167–74.

6 Whittington CJ, Kendall T, Fonagy P, Cottrell D, Cotgrove A,

Boddington E. Selective serotonin reuptake inhibitors in childhood

depression: systematic review of published versus unpublished data.

Lancet 2004; 363: 1341–5.

7 Citrome L. Compelling or irrelevant? Using number needed to treat

can help decide Acta Psychiatr Scand 2008; 117: 412–9.

8 Nasrallah HA. Meta-analysis trends in schizophrenia over three

decades (editorial). Schizophr Res 2009; 108: 1–2.

9 Delgado-Rodriguez M. Systematic reviews of meta-analyses: appli-

cations and limitations. J Epidemiol Community Health 2006; 60:

90–2.

doi: 10.1111/j.1742-1241.2009.02091.x

ED ITORIAL

Cola-induced hypokalaemia: a super-sized problem

Consider this curious case: a 44-year-old ostrich

farmer from the Australian outback developed

sudden onset of muscle weakness after returning

home from an evening of kangaroo-shooting. He

had difficulty in getting out of his bath and was

unable to stand while waiting for help to arrive. His

respiratory status deteriorated, and he required intu-

bation and mechanical ventilation. He was found to

be profoundly hypokalaemic with a serum potassium

level of 1.4 mmol ⁄ l. He had been drinking 4 l of

Coca-Cola per day over the past 3 years, and drank

up to 10 l to slake his thirst when he went for kan-

garoo-shooting at night. He was advised to curtail

his cola drinking, and his potassium level norma-

lised, his weakness resolved, and he made a full

recovery (1).

My own patient’s case was less dramatic, but

equally puzzling. He was a 51-year-old man with

chronic obstructive pulmonary disease (COPD),

hypertension and idiopathic gastroparesis. Over the

course of 2 years, he had persistent hypokalaemia

in the 2.7–3.3 mmol ⁄ l range and complained of

ongoing generalised weakness and 2–3 loose stools

per day. I stopped his hydrochlorothiazide and other

drugs that might cause hypokalaemia, with no effect.

Oral potassium supplements did not help. Labora-

tory testing ruled out renal potassium wasting, which

in the absence of diuretic treatment seemed to point

to a gastrointestinal (GI) cause. One day he showed

up at my office with a 2-l bottle of Pepsi-Cola in the

basket of his electric scooter. I asked him how much

he drank, and he said that he sipped it continuously,

Linked Comment: Tsimihodimos et al. Int J Clin Pract 2009; 63: 900–2.

Editorials 833

ª 2009 Blackwell Publishing Ltd Int J Clin Pract, June 2009, 63, 6, 831–838

4 l per day. He was not willing to stop drinking cola,

but he did agree to reduce his intake to 2 l per day.

His potassium then rose to the normal range, and

his weakness improved (2).

In 2007, worldwide consumption of soft drinks

reached 552 billion litres or 82.5 l per person (3).

This is projected to rise to 95 l per person by 2012.

In the United States, annual soft drink consumption

has been estimated to be 212 l per person. Sugar-

sweetened soft drinks have been shown to cause

obesity, type 2 diabetes, dental decay and metabolic

syndrome. They appear also to increase the risk for

osteoporosis, gout, gastroesophageal reflux disease,

hypovitaminosis C, albuminuria and chronic kidney

disease (CKD). Case reports have linked soft drinks

with secondary hyperparathyroidism, oesophageal

perforation, haematuria, swallow syncope, pseudo-

porphyria, tongue erosions, hyponatraemia and

gastritis. The only therapeutic use of soft drinks is

described in a few case reports of the successful use

of Coca-Cola to dissolve phytobezoars.

In their review of cola-induced hypokalaemia,

Tsimihodimos et al. make a compelling argument

that potassium depletion should be added to the

long list of soft drink-related health problems. In the

cases they describe, chronic consumption of 3–10 l

of sugar-sweetened cola per day led to severe hypo-

kalaemia, hypokalaemic myopathy, and in some

cases, hypokalaemic paralysis. One patient developed

hypokalaemic nephropathy and subsequent nephro-

genic diabetes insipidus. In all cases, the patients’

symptoms improved, and the hypokalaemia resolved

with potassium repletion and reduction or cessation

of cola drinking.

The proposed mechanisms of cola-induced hypo-

kalaemia run practically the whole gamut of electro-

lyte physiology. First, the large glucose load can

cause both an osmotic diuresis, with increased renal

potassium wasting, and hyperinsulinaemia, causing

intracellular redistribution of potassium. Second,

drinks containing large amounts of high-fructose

corn syrup send boluses of largely indigestible fruc-

tose into the GI tract, which causes potassium wast-

ing via an osmotic diarrhoea. Third, caffeine has

been shown to cause beta adrenergic stimulation,

increase Na+ ⁄ K+-ATPase via cellular phosphodiester-

ase inhibition, and produce metabolic alkalosis,

diuresis and increased renin levels, all of which may

contribute to hypokalaemia. The caffeine in a few

cups of coffee can lower serum potassium by as

much as 0.4 mmol ⁄ l (4). Based on case reports of

hypokalaemia from both caffeine-free soft drinks and

caffeine products (such as coffee and tea) without

sugar or high-fructose corn syrup, any or all of the

above mechanisms may be at work in various indi-

viduals drinking various beverages. However, soft

drinks that combine large amounts of high-fructose

corn syrup with caffeine, such as regular colas, might

deplete potassium stores more effectively because of

concurrent osmotic and caffeine-mediated potassium

wasting. With his 4 l per day Pepsi-Cola habit, my

patient was ingesting 396 g of fructose, enough to

cause a chronic low-grade osmotic diarrhoea, and

400 mg of caffeine, the equivalent of about seven

cups of coffee.

One might argue that people who drink 3–10 l of

cola per day are outliers, and that excessive soft

drink consumption at this level is so rare that it is

not a public health issue. The problem is that we

have every reason to think that it is not rare. We

know, for instance, that for the period from 1999 to

2002, the 95th percentile of soft drink consumption

for US male teenagers was 83 ounces per day, and

for female teenagers, 61 ounces per day (5). This

means that several million US teenagers were con-

suming two or more litres per day. Consider, too,

the marketing of the soft drink. In the 1950s, soft

drinks were sold in six and 1 ⁄ 2 ounce bottles.

Twelve-ounce cans were introduced in the 1960s,

followed by the 20-ounce plastic bottle in the 1990s.

Today we find 24-ounce bottles in vending

machines, which have apparently become the new

standard for individual servings. Two 24-ounce bot-

tles, two standard servings, equals 1.42 l. Another

new development is the popular ‘Hugo’, a 42-ounce,

410 calorie super-sized soft drink sold at McDon-

ald’s. Two of these behemoths in a day would total

a whopping 2.48 l. Then (for the very thirsty), there

is the 64-ounce ‘Big Gulp’ sold at 7-Eleven stores.

With aggressive mass marketing, super-sizing of soft

drinks, and the effects of caffeine tolerance and

dependence, there is very little doubt that tens of

millions of people in industrialised countries drink

at least 2–3 l of cola per day. It follows that the

serum potassium levels of these heavy cola drink-

ers are dropping, in some cases, to dangerous low

levels.

Low potassium is well-tolerated in healthy adults

(6), but even mild-to-moderate hypokalaemia is

believed to increase the risk of morbidity and mor-

tality in patients with cardiac ischaemia, heart failure

or left ventricular hypertrophy (7). The Heart Out-

comes and Prevention Evaluation study showed

that even modest hypokalaemia (serum potassium

< 3.5 mmol ⁄ l) increases the likelihood of myocardial

infarction, cardiovascular death and stroke in high-

risk patients (8). As our heavy cola drinkers age and

develop obesity, hypertension and diabetes, they will

become more vulnerable to the potentially lethal

effects of chronic hypokalaemia.

Worldwide

consumption

of soft drinks

is projected to

rise to 95 litres

per person by

2012

834 Editorials

ª 2009 Blackwell Publishing Ltd Int J Clin Pract, June 2009, 63, 6, 831–838

Another concern is that even moderate chronic

cola consumption has been found to be associated

with CKD. A comparison of 465 patients with newly

diagnosed CKD and 467 community controls in

North Carolina showed a twofold increased risk of

CKD in patients who drank two or more cola drinks

(16 ounces) per day (9). Chronic hypokalaemia

causes increased renin levels, increased sympathetic

tone and altered nitric oxide metabolism. Over time,

these changes can lead to vasoconstriction, salt-sensi-

tivity, polydipsia, polyuria and tubulointerstitial

injury. This hypokalaemic nephropathy is reversible

if promptly treated with potassium repletion, but in

long-term cases, it can lead to chronic renal insuffi-

ciency and sometimes progress to end-stage renal

disease. In the North Carolina study, it was not clear

what role hypokalaemia may have played; other pos-

sible causes of cola-associated CKD include diabetes,

hypertension and phosphoric acid-induced kidney

stone disease.

Most government responses to soft drink health

concerns have focused on protecting children from

youth-targeted advertising and in-school vending

machines. This same focus seems to hold in the

medical profession, where paediatricians are generally

more aware of the health risks of soft drinks, and

probably more likely than internists to discuss them

with their patients. In addition to the usual questions

about alcohol, tobacco and illicit drug use, internists

need to start asking their adult patients about soft

drink consumption. Cola drinks need to be added to

the physician’s checklist of drugs and substances

(such as liquorice) that can cause hypokalaemia.

More work is needed on the epidemiology of cola

consumption, hypokalaemia and cardiovascular dis-

ease rates. Finally, the soft drink industry needs to

promote safe and moderate use of its products for

all age groups, reduce serving sizes and pay heed to

the rising call for healthier drinks. The tale of the

thirsty kangaroo-hunter reminds us of the wisdom of

Aristotle: ‘In all things, moderation’.

Disclosures

The author has not received funding or honoraria

from any source.

C. D. PackerLouis Stokes Cleveland VA Medical Center

Associate Professor of Medicine,Case Western Reserve University School of Medicine,

Cleveland, OH, USAEmail: clifford.packer@med.va.gov

References1 Mudge DW, Johnson DW. Coca-Cola and kangaroos. Lancet 2004;

364: 1190.

2 Packer CD. Chronic hypokalemia due to excessive cola consump-

tion: a case report. Cases J 2008; 1: 32.

3 Just-drinks [Internet]. Worcester, UK: Aroq Ltd; c2009. Global: soft

drinks consumption rises in 2007 – research; 5 December 2008.

http://www.justdrinks.com/article.aspx?id=95766 (accessed 6 March

2009).

4 Passmore AP, Kondowe GB, Johnston GD. Caffeine and hypokale-

mia. Ann Intern Med 1986; 105: 468.

5 Jacobson MF. Liquid Candy: How Soft Drinks are Harming America’s

Health [Internet], 2nd edn. Washington, DC: Center for Science in the

Public Interest; c2005. Liquid Candy Supplement. Soft Drink Con-

sumption:1999–2002. Table 3, Percentile distribution of consumption

of non-diet carbonated soft drinks and fruit juices by 13- to 18-year-

olds, excluding non-consumers (oz. ⁄ day). http://www.cspinet.org/

new/pdf/liquid_candy_final_w_new_supplement.pdf (accessed 6

March 2009).

6 Walsh CR, Larson MG, Leip EP, Vasan RS, Levy D. Serum potas-

sium and risk of cardiovascular disease: the Framingham heart

study. Arch Intern Med 2002; 162: 1007–12.

7 Gennari FJ. Hypokalemia. N Engl J Med 1998; 339: 451–8.

8 Mann JF, Yi QL, Sleight P et al. Serum potassium, cardiovascular

risk, and the effects of an ACE inhibitor: results of the HOPE study.

Clin Nephrol 2005; 63: 181–7.

9 Saldana TM, Basso O, Darden R, Sandler DP. Carbonated

beverages and chronic kidney disease. Epidemiology 2007; 18:

501–6.

doi: 10.1111/j.1742-1241.2009.02066.x

ED ITORIAL

Upper gastrointestinal cancer and economicdeprivation – data from a London (UK) Cancer Network

The epidemiology of a cancer gives clues to its

aetiology. Survival defines the success of our health-

care systems in terms of both prevention and treat-

ment. In their paper in this edition of IJCP,

Gossage et al. (1) describe findings from one of

the UK’s 34 Cancer Networks, the London Cancer

Network. They show that between 1993–1995 and

2000–2002, the incidence of oesophageal cancer in

the most affluent males rose by 51% compared

with a 2% rise in the least affluent males. The fig-

ures for gastric cancer showed a different pattern,

falling by 32% in the most affluent and 7% in the

Linked Comment: Gossage et al. Int J Clin Pract 2009; 63: 859–64.

Editorials 835

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