The Worst Ways to Cure Everything


 

 

 

Last month I started to read a fantastic book called Quackery, A Brief History of the Worst Ways to Cure Everything, by Kang and Pedersen. There is this exciting part about how mercury became one of the most prescribed drugs for many centuries, from Napoleon to Abraham Lincoln. Mercury is a potent cathartic and was considered to be effective only when people were drooling intoxicated with their colons empty. This treatment was so popular that they used the “quicksilver” to “treat” about everything, syphilis included. “A night with Venus, a lifetime with Mercury.”

Although it seems funny and absurd today, these bizarre medical histories made me think about what people (if there are any left) are going to say in the future regarding our era. Yes, we are going to be judged for fuck things up by giving unnecessary antibiotics on a daily basis and for the two things most doctors are proud of: overtreating and overdiagnosis.

Our current medicine is full of mercury, those cool and expensive treatments we try in every disease, which doesn’t make any sense, even if they have some physiological background. The problem is, RCTs don’t read physiology books. With that in mind, I decided to make a list of the TOP 3 worst ways to cure everything in our era! Here we go!

 

NUMBER ONE – HYPOTHERMIA

First, I’m not saying there will be no role for hypothermia in the future. All I’m saying is that we are addicted to things that seems cool enough to appear in Sci-Fi movies. If you talk with an Ice worshiper (not a Canadian one), probably you are going to hear some interesting facts about how hypothermia can act in almost every single pathway involved in neurological damage, from cytokines to metabolism, and how awesome it works in rats and lesser developed mammalians (cardiologists included).

That’s beautiful, but we are talking about decreasing the core temperature of a human being near to 32°C, deep sedation, intense monitorization, careful rewarming and, let’s say, some unwanted collateral effects: shivering, coagulopathy, infections, arrhythmias, thermal burns, etc. All those problems could be acceptable and managed if there was gold at the end of the rainbow, the problem is that, until now, there isn’t.

Here I list some of the most important hypothermia trials and their results:

-Hypothermia for Intracranial Hypertension after Traumatic Brain Injury. The EUROTHERM Trial [1].
>>>>> Results: The trial had to be stopped early due to safety concerns. The hypothermia group had worse neurological outcomes and higher mortality.

-Hypothermia Therapy after Traumatic Brain Injury in Children. [2]
>>>>> Results: No improvement in neurological outcomes and might increase mortality.

-Targeted Temperature Management at 33°C versus 36°C after Cardiac Arrest. The TTM Trial [3].
>>>>> Results: No difference in mortality or neurological outcomes.

-Therapeutic Hypothermia after In-Hospital Cardiac Arrest in Children. The THAPCA Trial [4].
>>>>> Results: Trial was stopped early due to futility. No significant benefits in survival with a favorable functional outcome at 1 year.

-Hypothermia for Neuroprotection in Convulsive Status Epilepticus. The HYBERNATUS Trial [5].
>>>>> Results: No difference in mortality or neurological outcomes.

-Induced hypothermia in patients with septic shock and respiratory failure. The CASS Trial [6]. Recently discussed here (link).
>>>>> Results: Although the trial was terminated early due to futility, there was a clear trend in mortality in the hypothermia group (44.2 %  vs. 35.8%, p:0,07).

Hypothermia is a very “cool” (funny choice of words) treatment. It’s sad we don’t have a disease to treat with it. But I think trials are gonna keep rolling, and there is a big box full of disease names to decide which we are going to freeze next year.

 

NUMBER TWO – ACETYLCYSTEINE

Probably the most ubiquitous magic powder we have in the history of medicine, it’s like a black suit, goes with everything. I can’t understand why doctors are addicted to it. The old mucolytic found its soulmate after Prescott and cols published in 1979 [7] a case series of 100 patients with paracetamol poisoning treated with acetylcysteine. The treatment group had better outcomes than the current treatment at the time (retrospective comparison).

After some experimental data about the possible effect on oxidative stress, the drug became an obsession among researchers. Let me list some of the most important trials; please note the range of diseases:

Contrast-induced nephropathy (main trials)
-Acetylcysteine for Prevention of Renal Outcomes in Patients Undergoing Coronary and Peripheral Vascular Angiography. The ACT Trial [8].
>>>>> Results: Negative.
-Outcomes after Angiography with Sodium Bicarbonate and Acetylcysteine. The PRESERVE Trial [9].
>>>>> Results: Negative.

Cancer
-A randomized trial of vitamin A and N-acetylcysteine in patients with head and neck cancer or lung cancer. The EUROSCAN Trial [10].
>>>>> Results: Negative.

COPD
-Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease. The BRONCUS Trial [11].
>>>>> Results: “Ineffective at prevention of deterioration in lung function and prevention of exacerbations in patients with COPD.”
Although small trials found mixed results, not a clear benefit in this population.

Non-paracetamol drug-induced liver injury
-N-acetylcysteine for non-paracetamol drug-induced liver injury: a systematic review. [12]
>>>>> Results: Evidence is limited and does not allow for any firm conclusions.

Miscellaneous
A quick PubMed search and you will find a massive list of diseases where NAC have been tested without apparent benefit or any positive effect. The disease range is incredible: myocardial infarction, chronic heart failure, sepsis, Alzheimer, diabetes, otitis, Sjögren, amyotrophic lateral sclerosis, obsessive-compulsive disorder, suicidal ideation in bipolar disorder, etc.

 

NUMBER THREE – STATINS

I know, statins might save people… So, why are statins here? Well, we are just not satisfied with giving statin for every single three-digit LDL and humans with any kind of arterial problems. It seems the goal is that one day, every single person in the world will be taking statins. It should be in the water we drink (I heard that one once). How far we went? Here’s our list:

Bacterial Infections
Small studies pointing to a possible beneficial effect. A PLOS ONE meta-analysis [13] found, after adjusting for publication bias, no benefit.

COPD
RCT published at NEJM [14] showed no benefit in exacerbation rates or time to first exacerbation.

ARDS
Two RCTs published at NEJM [16, 16] showed no benefit.

SAH
The STASH trial [17] found no benefit of simvastatin for long-term or short-term outcomes in patients with aneurysmal subarachnoid hemorrhage.

Delirium
Last year the MoDUS trial was published [18]. The rationale: delirium might have something to do with neuroinflammation, statins might work against inflammation. Piece of cake. Let’s run an RCT. Results: Nothing here.

Miscellaneous
We are talking about the worst ways to cure everything, so look at this and try to think: is there a strong rationale for using humans as ‘’guinea pigs’’ for this?
-Evaluation of anti-inflammatory effect of statins in chronic periodontitis. [19] INTERLEUKIN REDUCTION (?)
-Prophylactic statins as a possible method to decrease bubble formation in diving. [20] NEGATIVE
-Lovastatin for the Treatment of Adult Patients With Dengue. [21] UNDERPOWERED TO EFFICACY
-Atorvastatin for the Treatment of Plaque-Type Psoriasis. [22] NO BENEFIT

I love the concept that, if you have many drugs to treat a disease, there is probably no good drug at all. The reverse can also be true. If you have a drug in search of a disease, maybe this drug isn’t good for any disease. But the point is: if you have a drug, its gotta be profitable.

The problem is, when we use a p-value < 0.05, there is still a 5% chance of a false positive due to chance. Meaning that if you repeat the trial for 100 times, you may find a positive result in 5 of them. That’s what we are doing, testing a “placebo” like acetylcysteine 100 times in 100 different diseases.

I know science is a bitch. Fleming found out about how a fungus could be useful against Staphylococcus after forgetting some Petri dishes exposed in his lab when he took a trip to Scotland for a month [23]. Things happen by chance. But are we really thinking in equipoise or are we just shooting in every direction? Maybe in the future, somebody will use this as an introductory chapter about the worst ways to cure everything, or perhaps they will use it to show how I was wrong after they found out that statins are effective against brain death.

 

 

 

1- Andrews PJ, Sinclair HL, Rodriguez A et al. Hypothermia for Intracranial Hypertension after Traumatic Brain Injury N Engl J Med. 2015; 373(25):2403-2412.

2- Hutchison JS, Ward RE, Lacroix J et al. Hypothermia Therapy after Traumatic Brain Injury in Children N Engl J Med. 2008; 358(23):2447-2456.

3- Nielsen N, Wetterslev J, Cronberg T et al. Targeted Temperature Management at 33°C versus 36°C after Cardiac Arrest N Engl J Med. 2013; 369(23):2197-2206.

4- Moler FW, Silverstein FS, Holubkov R et al. Therapeutic Hypothermia after In-Hospital Cardiac Arrest in Children N Engl J Med. 2017; 376(4):318-329.

5- Legriel S, Lemiale V, Schenck M et al. Hypothermia for Neuroprotection in Convulsive Status Epilepticus N Engl J Med. 2016; 375(25):2457-2467.

6- Itenov TS, Johansen ME, Bestle M et al. Induced hypothermia in patients with septic shock and respiratory failure (CASS): a randomised, controlled, open-label trial The Lancet Respiratory Medicine. 2018.

7- Prescott LF, Illingworth RN, Critchley JA et al. Intravenous N-acetylcystine: the treatment of choice for paracetamol poisoning. British Medical Journal. 1979;2(6198):1097-1100.

8- ACT Investigators. Acetylcysteine for Prevention of Renal Outcomes in Patients Undergoing Coronary and Peripheral Vascular Angiography: Main Results From the Randomized Acetylcysteine for Contrast-Induced Nephropathy Trial (ACT) Circulation. 2011; 124(11):1250-1259.

9- Weisbord SD, Gallagher M, Jneid H et al. Outcomes after Angiography with Sodium Bicarbonate and Acetylcysteine N Engl J Med. 2017;

10- van Zandwijk N, Dalesio O, Pastorino U et al. EUROSCAN, a randomized trial of vitamin A and N-acetylcysteine in patients with head and neck cancer or lung cancer. For the EUropean Organization for Research and Treatment of Cancer Head and Neck and Lung Cancer Cooperative Groups. Journal of the National Cancer Institute. 2000; 92(12):977-86.

11- Decramer M, Rutten-van Mölken M, Dekhuijzen PR et al. Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): a randomised placebo-controlled trial The Lancet. 2005; 365(9470):1552-1560.

12- Chughlay MF, Kramer N, Spearman CW, Werfalli M, Cohen K. N-acetylcysteine for non-paracetamol drug-induced liver injury: a systematic review Br J Clin Pharmacol. 2016; 81(6):1021-1029.

13- Björkhem-Bergman L, Bergman P, Andersson J, Lindh JD. Statin Treatment and Mortality in Bacterial Infections – A Systematic Review and Meta-Analysis PLoS ONE. 2010; 5(5):e10702-.

14- Criner GJ, Connett JE, Aaron SD et al. Simvastatin for the Prevention of Exacerbations in Moderate-to-Severe COPD N Engl J Med. 2014; 370(23):2201-2210.

15- The National Heart, Lung, and Blood Institute ARDS Clinical Trials Network. Rosuvastatin for Sepsis-Associated Acute Respiratory Distress Syndrome N Engl J Med. 2014; 370(23):2191-2200.

16- McAuley DF, Laffey JG, O’Kane CM et al. Simvastatin in the Acute Respiratory Distress Syndrome N Engl J Med. 2014; 371(18):1695-1703.

17- Kirkpatrick PJ, Turner CL, Smith C, Hutchinson PJ, Murray GD. Simvastatin in aneurysmal subarachnoid haemorrhage (STASH): a multicentre randomised phase 3 trial The Lancet Neurology. 2014; 13(7):666-675.

18- Page VJ, Casarin A, Ely EW et al. Evaluation of early administration of simvastatin in the prevention and treatment of delirium in critically ill patients undergoing mechanical ventilation (MoDUS): a randomised, double-blind, placebo-controlled trial The Lancet Respiratory Medicine. 2017; 5(9):727-737.

19- Suresh S, Narayana S, Jayakumar P, Sudhakar U, Pramod V. Evaluation of anti-inflammatory effect of statins in chronic periodontitis Indian J Pharmacol. 2013; 45(4):391-.

20- Duplessis CA, Fothergill D, Schwaller D, Hughes L, Gertner J. Prophylactic statins as a possible method to decrease bubble formation in diving. Aviation, space, and environmental medicine. 2007; 78(4):430-4.

21- Whitehorn J, Nguyen CVV, Khanh LP et al. Lovastatin for the Treatment of Adult Patients With Dengue: A Randomized, Double-Blind, Placebo-Controlled Trial Clin Infect Dis.. 2015;

22- Faghihi T, Radfar M, Mehrabian Z, Ehsani AH, Rezaei Hemami M. Atorvastatin for the Treatment of Plaque-Type Psoriasis Pharmacotherapy. 2011; 31(11):1045-1050.

23- Richard G; The Alarming History of Medicine.

 

 

Photo Credit
-Venus belegert en ontset.


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