Free eBook on Acid Base

Benjamin Abelow's book: The Painless Guide to Mastering Clinical Acid-Base is available again as a free download in recognition of the new class of incoming nephrology fellows. We have highlighted this book in the past. It is a great primer on Acid-Base for trainees - easy to read and very informative. 

The details on how to access the offer are below. It will be available for a limited time only. 

To download a free ebook copy of The Painless Guide to Mastering Clinical Acid-Base, follow the numbered steps below. You will be downloading directly from Amazon, where you can also read editorial reviews of the book. The ebook is a Kindle file type. Apps are available for all devices: phones, tablets, and laptops, including Apple, Android, and Windows. The ebook will be available for free for three days, Sunday, July 8 - Tuesday, July 10. 

To Download:

1.  During the period Sunday, July 8 - Tuesday, July 10 click here: https://www.amazon.com/Painless-Guide-Mastering-Clinical-Acid-Base-ebook/dp/B06XRM56TY

2.  Be sure you’re on the page for the e-book (Kindle) edition, not the paperback. During the three days in questions, it should say, "Kindle Price: $0.00."

3.  Click on “Buy now with 1-Click.” (Do not click on “Read for Free,” as that leads to the “KindleUnlimited” program, which has a monthly fee.)

4.  If you don’t already have a Kindle app on your device, you can easily download one. Just go to your usual on-line source for apps and search “Kindle.” The apps are available for all types and makes of devices. You can download to multiple devices associated with your Amazon account.

An Under Recognised Cause of Metabolic Acidosis

The MUDPALES mnemonic for raised anion gap acidosis was drilled into me from medical school.  However recently after working through each category I became stumped when nothing ticked the box to identify the cause. 

The lady I had been asked to see was in her 80s and had fractured her hip.  On admission she had normal renal function and acid base status.  Post-operatively she was started on regular analgesia including paracetamol (acetaminophen) and developed a Staphlococcus Aureus wound cellulitis treated with flucloxacillin.  Over the following 2 weeks she developed a raised anion gap acidosis and positive urinary anion gap.  Renal function, lactate and ketones were normal.    

A cause of metabolic acidosis not in MUDPILES is pyroglutamic acidosis.  Pyroglutamic acid (also called 5-oxoproline) is a by-product in the gamma-glutamyl cycle.  This pathway is involved in the synthesis of glutathione, and is shown above from a recent paper.

Glutathione provides negative feedback on the cycle by inhibiting the enzyme gamma-glutamyl-cysteine synthase.  An acquired deficiency in glutathione, as with alcohol or paracetamol, results in loss of this negative feedback and increased production of 5-oxoproline leading to a metabolic acidosis.  Other drugs affect the cycle at different points including flucloxacillin which inhibits 5-oxoprolinase similarly resulting in build-up of 5-oxoproline. 

Urine amino acid screens show high levels of 5-oxoproline, though this test is not always available.  Our patient improved with withdrawal of paracetamol and flucloxacillin and oral bicarbonate which was stopped after a week.  Some cases have been treated with N-acetylcysteine to replenish glutathione levels. 

I think this is probably an under-recognised cause of metabolic acidosis with many of the risk factors being prevalent in our inpatients (poor nutrition, chronic alcohol use, renal failure, infection, paracetamol use).  A different mnemonic for causes of raised anion gap metabolic acidosis may be helpful like GOLD MARK:

·         G – glycols (ethylene and propylene)

·         O – 5-oxoproline (pyroglutamic acid)

·         L – L-lactate

·         D – D-lactate

·         M – methanol, ethanol

·         A – aspirin/salicylates

·         R – renal failure

K – ketones 

Post by Ailish Nimmo

Renal Grand Rounds - What Lurks in the Gap

I recently presented the case of a middle-aged man with a history of a remote Roux-en-Y gastric bypass, chronic diarrhea, and colon cancer on chemotherapy who initially presented with progressive fatigue and weakness in the setting of increased diarrhea. Shortly after admission he developed agitation that progressed to encephalopathy with dysarthria. His baseline labs from a month prior to presentation were notable for a chronically low serum bicarbonate of 15-17 with no anion gap. When he presented he was hypokalemic to 2.5 and his bicarbonate had dropped to 11 with a new elevated anion gap of 25 and normal L-lactate. Metabolic acidosis was confirmed on VBG. Interestingly, his urine electrolytes demonstrated a positive urine anion gap of 26.

He was ultimately diagnosed with D-lactic acidosis based on his clinical presentation which was confirmed with a serum D-lactate of 6.28. For the week prior to admission, he had been drinking 1.5 L of Gatorade (224 g of sugar!) daily to replace diarrhea losses.

This was a classic presentation of D-lactic acidosis in which overgrowth of gram positive anaerobes in the setting of short bowel syndrome is combined with a large carbohydrate load resulting in bacterial fermentation and D-lactate production.  He even had the classic neurologic findings!  His chronic non-gap acidosis likely represented chronic diarrhea and D-lactate production, and his rising anion gap when he presented was consistent with increased D-lactate production.

In D-lactic acidosis, the findings of hypokalemia and a positive urine anion gap can provide a helpful clue. With elevated serum D-lactate levels, the fractional excretion of D-lactate approaches 100%, i.e. everything that's filtered is excreted. This is because the stereospecificity of the sodium-L-lactate cotransporter in the proximal tubule results in poor reabsorption of D-lactate relative to L-lactate. The negatively charged D-lactate essentially drags positively charged sodium and potassium into the urine causing hypokalemia as well as a positive urine anion gap (Na + K - Cl) due to the increased urine sodium and potassium.


This patient did well after his Gatorade was cut off and he was treated with antibiotics to address gram positive anaerobic overgrowth.

Posted by Patrick Reeves

(Image taken from here - an educational blog for ED residents)

The Painless Guide to Mastering Clinical Acid Base

Apologies to Ben for the delay in posting about this.

Ben Abelow is an MD in New Haven who has long had an interest in teaching basic acid base physiology. In the late 1990s he published a primer for acid base that was very well received. Earlier this year, he published a new book, also on acid base physiology called "The Painless Guide to Mastering Clinical Acid Base". The purpose of this book is to help medical students and junior trainees grasp the basics of how to approach acid base problems while also give them the tools that they need to effectively teach acid-base in a simple and easy to understand way.

The first part of the book in particular very simply explains the basic chemistry behind acid base physiology and is very useful - I learned a few pearls that I will be using on rounds in the future. The rest of the book may be a little simple for renal fellows but it is short and very accessible so I think it is well worth reviewing at least once.

Ben's book is available on Amazon. He has also offered it for free to all first year renal fellows in the US. He is contacting program directors around the country to send them the book. If they are not responsive, he will be able to provide the books to individual fellows.

Thanks again Ben for this - students are always complaining that Renal Physiology is too complex but this really does make it simple

NephMadness 2014 Part 7 - Electrolyte Bracket

The electrolyte bracket contains a mixture of the old staples of nephrology mixed with some new kids on the block trying to muscle in on established territory, Vaptans vs hypertonic saline and ZS-9 vs Kayexalate. Hypertonic saline is well established and works when used correctly. In my experience inadequate monitoring and insufficient lab testing always complicates the correction of severe and acute hyponatremia. Severe hyponatremia has potentially devastating consequences and so should be managed in an ICU setting where frequent labs can be drawn and most importantly acted upon. The role of Vaptans is probably more in the chronic setting, in particular for longstanding hyponatremia in the setting of heart failure. In fact the SALT 1+2 trials excluded patients with acute symptomatic hyponatremia. Dr Berl wrote a nice review in KI.

Bicarbonate is center stage in the 2 and 7 seed match up. Bicarbonate for acute acidosis such as lactic acidosis, when extreme, is widely used I would imagine. This is despite lack of good evidence to suggest it improves outcomes. However, when faced with severe acidosis it makes physiological sense to give alkali. Another area were iv bicarbonate has fallen out of favor is in cardiopulmonary resuscitation. The 2010 ACLS guidelines recommended against the routine use of iv bicarbonate. This was due to fears of it causing intracellular acidosis, hypernatremia, respiratory depression and metabolic acidosis once perfusion is restored. One study from the 1990s looked at 273 successful out of hospital cardiac arrest outcomes. 58 patients got no HCO3 and had short CPR times (7.4 +/- 5.5 minutes). 215 patients did receive HCO3 and had significantly longer CPR times (23.3 +/- 13.5 minutes, (P =< 0.001). Initial emergency department blood gas results of both groups were not significantly different. No patients in the no HCO3 group had hypernatremia (sodium [Na]+ greater than 150), whereas four patients (2%) in the HCO3 group were hypernatremic. Eight patients (14%) in the no HCO3 group and 37 patients (17%) in theHCO3 group were alkalotic with pH values greater than 7.49 (P = NS). Six patients (10%) of the no HCO3 group and 24 patients (11%) of the HCO3 group had a metabolic component to the alkalosis as defined by a positive base excess value (P = NS). These are interesting findings given that these patients are the sickest and probably most acidemic you will encounter!

Despite this entire blurb I went for serum anion gap in this bracket!Very useful equation.

Spare the Chloride

Fluid therapy is essential in ICUs and not surprisingly there is still much controversy about which fluid to use, how much and when. Nephrologists often roll their eyes at other subspecialty's preferences, e.g. surgeon's preferences for Ringers, citing the risk of hyperkalemia in renal failure patients given Ringers. I learned that normal saline is the preferred agent unless there is a special consideration such as acidemia necessitating alternatives. Now chloride, the partner of sodium that gets considerably less attention most of the time, enters the stage.

Yunos et al in JAMA suggest that too much of chloride increases acute kidney injury (AKI) episodes in tertiary ICUs and increases the need for renal replacement therapy (RRT) but does not affect mortality.

The physiological rationale for the detrimental effect of chloride on the kidney is described as vasoconstriction mediated by chloride in dog experiments and a possible role of tubuloglomerular feedback mediated vasoconstriction as well as decrease in GFR caused by increased distal chloride delivery. Furthermore they cite thromboxane mediated vasoconstriction caused by chloride and enhanced responsiveness to vasoconstrictor agents as possible physiological sequelae of chloride administration.

The authors of the JAMA article conducted a prospective, open-label sequential pilot study of patients admitted consecutively to the ICU. Initially patients were treated with chloride-rich IV fluids (0.9% saline, 4% succinylated gelatin solution or 4% albumin solution) and after that initial control period a chloride-restricted strategy was implemented with lactate (Hartmann solution), a balanced solution (Plasma-lyte 148) or chloride-poor 20% albumin as preferred agents.

The results were a lower increase in serum creatinine levels and fewer episodes of RRT in the chloride-restricted group but no differences in mortality, hospital or ICU length of stay or need for RRT after discharge.

How does this study affect our choice of ICU fluids? Certainly, these results are hypothesis generating and important but need to be viewed as preliminary given the design of the study. An accompanying editorial by Waikar mentions the Hawthorne effect as potential major concern. Clearly these important preliminary data need follow up in a controlled prospective trial. 

Posted by Florian Toegel

From acid to nephrocalcinosis to stones

Can you have an acidosis with normal serum bicarbonate? Of course you can, it's just incomplete. Incomplete distal renal tubular acidosis (idRTA) that is.

RTA was first described in 1935, confirmed as a renal tubular disorder in 1946, and designated “renal tubular acidosis” in 1951 (see here for an excellent review). Now it gets complicated, not only with regard to nomenclature but also with mechanisms.

I was a little surprised to hear that you can have distal RTA with a normal bicarbonate. It is just disguised. Patients with incomplete distal RTA have persistently high urine pH but are still able to excrete acid under normal conditions (therefore the normal serum bicarbonate). However, in states of high acid loads (high protein diet, catabolic stress) they are unable to excrete that acid which then triggers alkali release from the bone and thus causes greater bone resorption, therefore these patients have frequently osteopenia and osteoporosis.

Distal RTA occurs with a number of conditions, amongst them classically Sjogrens syndrome but also other autoimmune conditions. Cisplatin has been mentioned as one of the causes of idRTA in this blog earlier. idRTA is a common cause of nephrocalcinosis - with or without stones - and it has a number of prominent victims as also mentioned in a previous post.

idRTA can be diagnosed by induction of a systemic metabolic acidosis by means of acid loading. This is  commonly done with ammonium chloride (NH4Cl) but there is also a furosemide and fludrocortisone test that apparently causes less abdominal discomfort. Failure to acidify urine to a pH of less than 5.3 is consistent with incomplete distal renal tubular acidosis. However, testing is a little bit tedious and therefore not commonly done. The urinary citrate is commonly low in dRTA which contributes to nephrocalcinosis and stone formation.

A recent study from Switzerland showed that 6.7% of 150 male recurrent calcium stone formers (RCSFs) had idRTA, i.e., 1 out of 15 male RCSFs can be expected to have idRTA. They therefore suggest that idRTA is overall underdiagnosed.

Posted by Florian Toegel

Hyperammonemia in Myeloma: Dialyze?

 A middle aged man with IgG kappa multiple myeloma previously treated with bortezomib and lenalidomide presented to the hospital with altered mental status. He had completed chemotherapy months prior to presentation. Shortly after being admitted, he progressed to obtundation associated with tachypnea and a profound respiratory alkalosis requiring intubation for airway protection. His initial arterial blood gas at the time of intubation revealed a pH of 7.35, an undetectably low pCO2, and a bicarbonate of 14 (on concurrent labs) with an anion gap of 14. Mechanical ventilation was initiated with a minimal amount of pressure support. All subsequent blood gases demonstrated a pH greater than 7.55 with ongoing respiratory alkalosis. The anion gap normalized. Intensive work-up of the altered mental status resulted in the sole finding of hyperammonemia with a serum ammonia level of 100 umol/L. There was no liver injury evident on labs. Lactulose was initiated to treat the elevation in ammonia with no improvement noted.

We were consulted regarding the possibility of dialysis to correct the hyperammonemia. 

Do we need to correct high ammonia levels?

Hyperammonemia carries a significant morbidity and mortality, and patients frequently require ICU-level care for encephalopathy. With acute presentations of hyperammonemia, levels of ammonia greater than 200 umol/L are associated with cerebral edema and herniation due to cerebral dysautoregulation. In the presence of chronic hyperammonemia, compensatory increases in ammonia metabolism by the muscles and hepatic and splanchnic vascular beds may blunt symptoms. Interestingly, arterial, venous, and brain levels of ammonia typically do not correlate in patients with chronic hyperammonemia but have a better correlation in acute hyperammonemia. In our patient, we did not check arterial ammonia levels to look for a correlation.

Why is our patient hyperammonemic?

Ammonia is produced primarily in the gut as a product of protein breakdown and bacterial metabolism, and it is broken down primarily in the liver. Increased production of ammonia can occur in the presence of protein breakdown from GI bleeding. In patients with liver failure who are already predisposed to having high ammonia levels, GI bleeding is a known risk factor for the precipitation of hepatic hyperammonemic encephalopathy.

Our patient had no laboratory evidence of liver dysfunction. He had recently suffered an episode of GI bleeding from a bleeding mechanical abnormality seen on EGD that was corrected. Perhaps this could have been the inciting factor for the elevated ammonia, but the patient's ammonia levels remained elevated throughout his hospital stay despite termination of the bleeding.

Inborn errors of metabolism can be considered, but most of these present in childhood. However, urea cycle disorders can be unmasked in adulthood by medications, protein intake, and infections. The drugs most likely to be involved include salicylates, valproate, carbamazepine, sulfadiazine, pyrimethamine, glycine, and TPN. None of these were implicated in our patient. Urea-splitting organisms and herpes infection can also raise ammonia levels. Neither were present.

Alas, multiple myeloma can be a cause of hyperammonemia. Rising beta-2 microglobulin levels in the absence of acute kidney injury in our patient suggested worsening myeloma off of chemotherapy.

Hyperammonemic encephalopathy in multiple myeloma

In vitro, myeloma cell lines secrete ammonia into culture medium in greater amounts than other hematological malignant cells. This may be due to excess protein synthesis in myeloma cells. In vivo, the exact mechanism for hyperammonemia in multiple myeloma patients is unknown.

It is important to rule out hypercalcemia and hyperviscosity as causes of altered mental status in patients with multiple myeloma before encephalopathy is attributed to elevated ammonia levels. In our patient, calcium and viscosity levels were checked and found to be normal.

In a published review of 27 cases of hyperammonemic encephalopathy in multiple myeloma patients, depressed levels of consciousness were noted to occur at ammonia levels ranging from 35 to 39,342 umol/L. The degree of ammonia elevation did not appear to correlate with death (if one ignores the outlier of 39,342) but in all cases where the patient's ammonia level did not improve, death was the unfortunate outcome. Presenting symptoms included respiratory alkalosis, asterixis, myoclonus, hallucinations, and hyperdynamic heart failure. Of the 27 reported cases, 4 patients received dialysis (3 HD, 1 PD) and 9 received ammonia-lowering medications such as antibiotics, lactulose, carnitine, and flumazenil. All patients received chemotherapy.

Should we dialyze our patient?

In drug intoxications associated with hyperammonemic encephalopathy, dialysis serves a definitive role in clearing the toxin and correcting the hyperammonemia. However, in cases resulting from malignancy, the answer is less clear.

Of the 4 patients who received dialysis in the study described above, 3 survived. Of the remaining 23 patients who were not dialyzed, 12 survived. Ammonia levels decreased in all 4 patients who received dialysis and in 19/23 patients who did not undergo dialysis. This suggests that dialysis plays perhaps only a minor role in lowering ammonia in this patient population. Given the potential for harm associated with dialysis catheter placement, we felt that the risks outweighed the unclear (if any) benefits of dialysis.

Our patient received steroids and further chemotherapy. Interestingly, administration of steroids can raise ammonia levels in the short term because of increased catabolism. Ammonia levels fluctuated wildly but improved slightly. The patient was extubated succesfully. His mental status improved but not to baseline. He continued to have a respiratory alkalosis at the time of discharge. 

Ammonia: Chicken, Egg, or Bystander? 

In hepatic encephalopathy, it is well known that ammonia levels do not correlate with the degree of encephalopathy. For this reason, following ammonia levels after initiating treatment is discouraged. The same may be true here. Perhaps ammonia is the cause of the encephalopathy; perhaps it is a biomarker of disease; perhaps it is an innocent bystander. Further study is needed to elucidate this as it may clarify the role of dialysis as a treatment for hyperammonemia in myeloma.

References

1. Clay AS, Hainline BE. Hyperammonemia in the ICU. Chest. 2007 Oct;132(4):1368-78.

2. Lora-Tamayo J, Palom X, Sarrá J, Gasch O, Isern V, Fernández de Sevilla A, Pujol R.‏ Multiple myeloma and hyperammonemic encephalopathy: review of 27 cases.‏ Clin Lymphoma Myeloma. 2008 Dec;8(6):363-9.‏

3. Furer V, Heyd J. Hyperammonemic Encephalopathy in Multiple Myeloma. Isr Med Assoc J. 2007 Jul;9(7):557-9.