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 editorialby 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.

Low Anion Gap

Classically, we are taught to look out for an elevated anion gap in patients with a metabolic acidosis. Although much less common, a low anion gap can also be a useful sign and there are a variety of causes.

The commonest cause is lab error, particularly in the measurement of the serum sodium. As previously discussed, high serum lipids or high serum proteins can lead to spuriously low serum sodium measurements thus altering the AG. Severe hypernatremia can also lead to errors in measuring the sodium concentration (usually underestimating the real result) and will lower the AG. Similarly, errors in measuring the chloride or the HCO3 will alter the perceived AG. The bicarbonate is usually measured indirectly and allowing the sample to sit without separating the cells can lead to increased production of CO2 and thus lower the AG.

Apart from lab errors, the commonest cause of a low AG is due to alterations in serum protein levels. Most of the AG is due to negative charges on circulating proteins, primarily albumin so that if the albumin concentration falls, the AG will fall also. It is generally accepted that the AG should be corrected upwards by 2.5 for every 1g/dl fall in the serum albumin. This applies also for patients with an elevated serum albumin; the AG should be corrected downwards in that scenario. Although they do not normally contribute significantly to the AG, immunoglobulins can be important in patients with paraproteinemias. IgG tends to be cationic while IgA is an anion. Thus, patients with an IgG paraproteinemia and a high tumor burden can have a low or even negative AG. In contrast, patients with IgA paraproteinemia will have an elevated AG.

Calcium and magnesium could theoretically decrease the AG if they are significantly increased. In practice, however, hypercalcemia does not usually cause a lowered AG unless it is due to hyperparathyroidism. Other causes of hypercalcemia are not associated with changes in the AG. It is uncertain why this is the case. Hypermagnesemia usually does not affect the AG because it is normally accompanied by sulphates and as these are unmeasured anions, they balance each other out.

Several drugs are associated with reductions in the AG. As mentioned by Nate before, bromide intoxication is a rare cause of a negative anion gap. At first, this does not appear to make sense; bromide is an anion, similar to chloride. As a result, elevated bromide levels should cause an increase in the AG. However, bromide interferes with the chloride analyzer – every 1 mEq increase in bromide leads to a reported 3 mEq increase in chloride. Thus, patients with bromide intoxication can have extremely negative AG. Iodide can also interfere with the chloride assay and lead to a negative AG.

Lithium is a cation, in the same family as sodium and thus lithium poisoning will lead to a reduction in the AG although usually only when the level is above 4. This can be a clue to a lithium overdose in a patient with suspected poisoning where there is no ready access to lithium levels.

I would recommend an excellent review of the uses of the anion gap published in CJASN in 2007 that addresses all of these in great detail.

There's no such thing as a contraction alkalosis

We recently discussed an excellent paper on the classification of metabolic alkalosis. The three suggested subtypes were primary and secondary stimulation of collecting duct ion transport and exogenous alkali administration. Another interesting editorial was just published in JASN that further expands on the idea that chloride deficiency is central to the maintenance of a metabolic alkalosis.

The traditional view of a contraction alkalosis was that in a volume depleted patient, there would be increased reabsorption of sodium in the proximal tubule. Because this sodium must be reabsorbed with an anion, bicarbonate was also reabsorbed in the proximal tubule along with this in preference to chloride, thus perpetuating the alkalosis. The first challenge to this viewpoint came in the 1960s when it was shown that a chloride deficient alkalosis generated by diuretics or gastric aspiration was corrected by treatment with NaCl or KCl but not with Na or K repletion without Cl. This did not however deal with the issue of volume depletion.

More recently, the authors of the editorial have shown that a chloride deficient alkalosis could be corrected in rats by infusion of a chloride containing solution despite ongoing volume depletion, while restoration of the ECF volume with albumin did not correct the acid-base abnormality. In fact, the urinary excretion of bicarbonate increased in the rats that received chloride while it fell further in those that received volume expansion with albumin alone.

Finally, they treated normal human subjects with a low chloride diet along with furosemide and Na and K supplementation. These subjects developed an alkalosis that was maintained for 5 days and corrected with oral KCl alone without any expansion of plasma volume. This elegantly demonstrated that volume is not the issue in these cases and that it truly is an effect of chloride depletion alone.

So what is the mechanism for the maintenance of the alkalosis? Previous posts have discussed the role of Pendrin, the HCO3-Cl exchanger in the collecting duct. The main stimuli for pendrin activation are decreased distal delivery of chloride and intracellular alkalosis. However, where there is little or no distal Cl delivery, it is not available to exchange with HCO3 and thus the alkalosis is maintained. This also helps explain the alkalosis induced by hypokalemia. Hypokalemia induces intracellular acidosis which inhibits HCO3 excretion by pendrin thus exacerbating the extracellular alkalosis.

Can we now finally get rid of the concept of a contraction alkalosis?